Comparison of different methods of first-trimester screening for preterm pre-eclampsia: cohort study.

OBJECTIVE: To compare the predictive performance of three different mathematical models for first-trimester screening of pre-eclampsia (PE), which combine maternal risk factors with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF), and two risk-scoring systems. METHODS: This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with singleton pregnancy and a non-malformed live fetus attending their routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate in the study. Maternal characteristics and medical history were recorded and measurements of MAP, UtA-PI, serum PlGF and pregnancy-associated plasma protein-A (PAPP-A) were converted into multiples of the median (MoM). Risks for term PE, preterm PE (< 37 weeks' gestation) and early PE (< 34 weeks' gestation) were calculated according to the FMF competing-risks model, the Crovetto et al. logistic regression model and the Serra et al. Gaussian model. PE classification was also performed based on the recommendations of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG). We estimated detection rates (DR) with their 95% CIs at a fixed 10% screen-positive rate (SPR), as well as the area under the receiver-operating-characteristics curve (AUC) for preterm PE, early PE and all PE for the three mathematical models. For the scoring systems, we calculated DR and SPR. Risk calibration was also assessed. RESULTS: The study population comprised 10 110 singleton pregnancies, including 32 (0.3%) that developed early PE, 72 (0.7%) that developed preterm PE and 230 (2.3%) with any PE. At a fixed 10% SPR, the FMF, Crovetto et al. and Serra et al. models detected 82.7% (95% CI, 69.6-95.8%), 73.8% (95% CI, 58.7-88.9%) and 79.8% (95% CI, 66.1-93.5%) of early PE; 72.7% (95% CI, 62.9-82.6%), 69.2% (95% CI, 58.8-79.6%) and 74.1% (95% CI, 64.2-83.9%) of preterm PE; and 55.1% (95% CI, 48.8-61.4%), 47.1% (95% CI, 40.6-53.5%) and 53.9% (95% CI, 47.4-60.4%) of all PE, respectively. The best correlation between predicted and observed cases was achieved by the FMF model, with an AUC of 0.911 (95% CI, 0.879-0.943), a slope of 0.983 (95% CI, 0.846-1.120) and an intercept of 0.154 (95% CI, -0.091 to 0.397). The NICE criteria identified 46.7% (95% CI, 35.3-58.0%) of preterm PE at 11% SPR and ACOG criteria identified 65.9% (95% CI, 55.4-76.4%) of preterm PE at 33.8% SPR. CONCLUSIONS: The best performance of screening for preterm PE is achieved by mathematical models that combine maternal factors with MAP, UtA-PI and PlGF, as compared to risk-scoring systems such as those of NICE and ACOG. While all three algorithms show similar results in terms of overall prediction, the FMF model showed the best performance at an individual level. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

A dynamically young and perturbed Milky Way disk.

The evolution of the Milky Way disk, which contains most of the stars in the Galaxy, is affected by several phenomena. For example, the bar and the spiral arms of the Milky Way induce radial migration of stars1 and can trap or scatter stars close to orbital resonances2. External perturbations from satellite galaxies can also have a role, causing dynamical heating of the Galaxy3, ring-like structures in the disk4 and correlations between different components of the stellar velocity5. These perturbations can also cause 'phase wrapping' signatures in the disk6-9, such as arched velocity structures in the motions of stars in the Galactic plane. Some manifestations of these dynamical processes have already been detected, including kinematic substructure in samples of nearby stars10-12, density asymmetries and velocities across the Galactic disk that differ from the axisymmetric and equilibrium expectations13, especially in the vertical direction11,14-16, and signatures of incomplete phase mixing in the disk7,12,17,18. Here we report an analysis of the motions of six million stars in the Milky Way disk. We show that the phase-space distribution contains different substructures with various morphologies, such as snail shells and ridges, when spatial and velocity coordinates are combined. We infer that the disk must have been perturbed between 300 million and 900 million years ago, consistent with estimates of the previous pericentric passage of the Sagittarius dwarf galaxy. Our findings show that the Galactic disk is dynamically young and that modelling it as time-independent and axisymmetric is incorrect.

Uterine artery Doppler in early labor and perinatal outcome in low-risk term pregnancy: prospective multicenter study.

OBJECTIVE: The prediction of adverse perinatal outcomes in low-risk pregnancies is poor, mainly owing to the lack of reliable biomarkers. Uterine artery (UtA) Doppler is closely associated with placental function and may facilitate the peripartum detection of subclinical placental insufficiency. The objective of this study was to evaluate the association of mean UtA pulsatility index (PI) measured in early labor with obstetric intervention for suspected intrapartum fetal compromise and adverse perinatal outcome in uncomplicated singleton term pregnancies. METHODS: This was a prospective multicenter observational study conducted across four tertiary maternity units. Low-risk term pregnancies with spontaneous onset of labor were included. The mean UtA-PI was recorded between uterine contractions in women admitted for early labor and converted into multiples of the median (MoM). The primary outcome of the study was the occurrence of obstetric intervention, i.e. Cesarean section or instrumental delivery, for suspected intrapartum fetal compromise. Secondary outcomes were the occurrence of adverse perinatal outcomes, including 5-min Apgar score < 7, low cord arterial pH, raised cord arterial base excess, admission to the neonatal intensive care unit (NICU) and postnatal diagnosis of small-for-gestational-age fetus. Composite adverse perinatal outcome was defined as the occurrence of at least one of the following: acidemia in the umbilical artery, defined as pH < 7.10 and/or base excess > 12 mmol/L, 5-min Apgar score < 7 or admission to the NICU. RESULTS: Overall, 804 women were included, of whom 40 (5.0%) had abnormal mean UtA-PI MoM. Women who had an obstetric intervention for suspected intrapartum fetal compromise were more frequently nulliparous (72.2% vs 53.6%; P = 0.008), had a higher frequency of increased mean UtA-PI MoM (13.0% vs 4.4%; P = 0.005) and had a longer duration of labor (456 ± 221 vs 371 ± 192 min; P = 0.01). On logistic regression analysis, only increased mean UtA-PI MoM (adjusted odds ratio (aOR), 3.48 (95% CI, 1.43-8.47); P = 0.006) and parity (aOR, 0.45 (95% CI, 0.24-0.86); P = 0.015) were independently associated with obstetric intervention for suspected intrapartum fetal compromise. Increased mean UtA-PI MoM was associated with a sensitivity of 0.13 (95% CI, 0.05-0.25), specificity of 0.96 (95% CI, 0.94-0.97), positive predictive value of 0.18 (95% CI, 0.07-0.33), negative predictive value of 0.94 (95% CI, 0.92-0.95), positive likelihood ratio of 2.95 (95% CI, 1.37-6.35) and negative likelihood ratio of 0.91 (95% CI, 0.82-1.01) for obstetric intervention for suspected intrapartum fetal compromise. Pregnancies with increased mean UtA-PI MoM also showed a higher incidence of birth weight < 10th percentile (20.0% vs 6.7%; P = 0.002), NICU admission (7.5% vs 1.2%; P = 0.001) and composite adverse perinatal outcome (15.0% vs 5.1%; P = 0.008). CONCLUSION: Our study, conducted in a cohort of low-risk term pregnancies enrolled in early spontaneous labor, showed an independent association between increased mean UtA-PI and obstetric intervention for suspected intrapartum fetal compromise, albeit with moderate capacity to rule in, and poor capacity to rule out, this condition. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Postnatal genetic and neurodevelopmental assessment in infants born at term with severely low birth weight of non-placental origin.

OBJECTIVE: To determine the frequency of genetic syndromes and childhood neurodevelopmental impairment in non-malformed infants born at term with severely low birth weight and no evidence of placental insufficiency. METHODS: This case series was constructed from the data of infants delivered at term between 2013 and 2018 with severely low birth weight, defined as birth weight more than 2.5 SD below the mean, with normal maternal and fetal Doppler (umbilical artery, fetal middle cerebral artery, cerebroplacental ratio and uterine artery) and no maternal hypertensive disorder during pregnancy or fetal structural anomaly on prenatal ultrasound examination. Clinical exome sequencing and copy number variation (CNV) analysis were performed using DNA extracted from the children's saliva. Cognitive and psychomotor development was evaluated using the Bayley Scales of Infant and Toddler Development, 3rd edition or the Wechsler Intelligence Scale for Children, 5th edition tests, according to the child's age at testing. RESULTS: Among the 36 405 infants born within the study period, 274 (0.75%) had a birth weight below -2.5 SD, of whom 98 met the inclusion criteria. Among the 63 families contacted, seven (11%) reported a postnatal diagnosis of a genetic syndrome and a further 18 consented to participate in the study. Median gestational age at delivery was 38.0 (interquartile range (IQR), 37.3-38.5) weeks and median birth weight was 2020 (IQR, 1908-2248) g. All 18 children showed a normal result on clinical exome sequencing and CNV analysis, but six (33%) obtained a low score on neurodevelopmental testing. CONCLUSION: Non-malformed severely small term infants with no clinical or Doppler signs of placental insufficiency present a high rate of genetic syndromes and neurodevelopmental impairment during childhood. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Halo sign in fetal cytomegalovirus infection: cerebral imaging abnormalities and postmortem histopathology in 35 infected fetuses.

OBJECTIVE: To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection. METHODS: This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions. RESULTS: Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06). CONCLUSIONS: In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Mortality and severe neurological morbidity in extremely preterm growth-restricted fetuses.

OBJECTIVE: To develop a model for the prediction of adverse perinatal outcome in growth-restricted fetuses requiring delivery before 28 weeks in order to provide individualized patient counseling. METHODS: This was a retrospective multicenter cohort study of singleton pregnancies with antenatal suspicion of fetal growth restriction requiring delivery before 28 weeks' gestation between January 2010 and January 2020 in six tertiary public hospitals in the Barcelona area, Spain. Separate predictive models for mortality only and mortality or severe neurological morbidity were created using logistic regression from variables available antenatally. For each model, predictive performance was evaluated using receiver-operating-characteristics (ROC)-curve analysis. Predictive models were validated externally in an additional cohort of growth-restricted fetuses from another public tertiary hospital with the same inclusion and exclusion criteria. RESULTS: A total of 110 cases were included. The neonatal mortality rate was 37.3% and, among the survivors, the rate of severe neurological morbidity was 21.7%. The following factors were retained in the multivariate analysis as significant predictors of mortality: magnesium sulfate neuroprotection, gestational age at birth, estimated fetal weight, male sex and Doppler stage. This model had a significantly higher area under the ROC curve (AUC) compared with a model including only gestational age at birth (0.810 (95% CI, 0.730-0.889) vs 0.695 (95% CI, 0.594-0.795); P = 0.016). At a 20% false-positive rate, the model showed a sensitivity, negative predictive value and positive predictive value of 66%, 80% and 66%, respectively. For the prediction of the composite adverse outcome (mortality or severe neurological morbidity), the model included: gestational age at birth, male sex and Doppler stage. This model had a significantly higher AUC compared with a model including only gestational age at birth (0.810 (95% CI, 0.731-0.892) vs 0.689 (95% CI, 0.588-0.799); P = 0.017). At a 20% false-positive rate, the model showed a sensitivity, negative predictive value and positive predictive value of 55%, 63% and 74%, respectively. External validation of both models yielded similar AUCs that did not differ significantly from those obtained in the original sample. CONCLUSIONS: Estimated fetal weight, fetal sex and Doppler stage can be combined with gestational age to improve the prediction of death or severe neurological sequelae in growth-restricted fetuses requiring delivery before 28 weeks. This approach may be useful for parental counseling and decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Severe smallness as predictor of adverse perinatal outcome in suspected late small-for-gestational-age fetuses: systematic review and meta-analysis.

OBJECTIVE: To investigate the performance of severe smallness in the prediction of adverse perinatal outcome among fetuses with suspected late-onset small-for-gestational age (SGA). METHODS: A systematic search was performed to identify relevant studies in PubMed, Web of Science and Scopus. Late-onset SGA was defined as estimated fetal weight (EFW) or abdominal circumference (AC) < 10th percentile diagnosed at or after 32 weeks' gestation, while severe SGA was defined as EFW or AC < 3rd percentile or < 2 SD. Random-effects modeling was used to generate hierarchical summary receiver-operating-characteristics (HSROC) curves. The performance of severe SGA (as a presumptive diagnosis) in predicting adverse perinatal outcome among singleton pregnancies with suspected late-onset SGA was expressed as area under the HSROC curve (AUC), sensitivity, specificity and positive/negative likelihood ratios. The association between suspected severe SGA and adverse perinatal outcome was also assessed by random-effects modeling using the Mantel-Haenszel method and presented as odds ratio (OR). The non-exposed group was defined as non-severe SGA (EFW ≥ 3rd centile). RESULTS: Twelve cohort studies were included in this systematic review and meta-analysis. The studies included a total of 3639 fetuses with suspected late-onset SGA, of which 1246 had suspected severe SGA. Significant associations were found between suspected severe SGA and composite adverse perinatal outcome (OR, 1.97 (95% CI, 1.33-2.92)), neonatal intensive care unit admission (OR, 2.87 (95% CI, 1.84-4.47)) and perinatal death (OR, 4.26 (95% CI, 1.07-16.93)). However, summary ROC curves showed limited performance of suspected severe SGA in predicting perinatal outcomes, with AUCs of 60.9%, 66.9%, 53.6%, 57.2%, 54.6% and 64.9% for composite adverse perinatal outcome, neonatal intensive care unit admission, neonatal acidosis, Cesarean section for intrapartum fetal compromise, low Apgar score and perinatal death, respectively. CONCLUSION: Although suspected severe SGA was associated with a higher risk of perinatal complications, it performed poorly as a standalone parameter in predicting adverse perinatal outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Added prognostic value of longitudinal changes of angiogenic factors in early-onset severe pre-eclampsia: a prospective cohort study.

OBJECTIVE: To assess in women with early-onset severe pre-eclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. DESIGN: Prospective cohort study. SETTING: Maternity units in two Spanish hospitals. POPULATION: Women with diagnosis of early-onset severe pre-eclampsia. METHODS: Levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-) and sFlt-1/PlGF ratio were measured at admission and before delivery, and average daily change calculated. The association of longitudinal changes of angiogenic factors with the time interval to delivery and with complications was evaluated by logistic and Cox regression. MAIN OUTCOME MEASURES: Interval to delivery and composite of adverse outcomes. RESULTS: We included 63 women, of which 26 (41.3%) had a complication. Longitudinal changes of sFlt-1 were more pronounced in complicated pregnancies (median: 1047 versus 342 pg/ml/day; P = 0.04). On the multivariate analysis, the clinical risk score and sFlt-1 at admission explained 6.2% of the uncertainty for complication; the addition of sFlt-1 longitudinal changes improved this to 25.3% (P = 0.002). The median time from admission to delivery was 4 days (95% CI 1.6-6.04) in those in the highest quartile of sFlt-1 longitudinal changes versus 16 days (95% CI 12.4-19.6) in the remaining women (Log-rank test P < 0.001). CONCLUSIONS: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe pre-eclampsia add to baseline characteristics in the prediction of adverse outcome and interval to delivery. TWEETABLE ABSTRACT: In early-onset severe pre-eclampsia, longitudinal changes in sFlt-1 levels improve the prediction of complications and interval to delivery.

Routine third-trimester ultrasound for the detection of small-for-gestational age in low-risk pregnancies (ROTTUS study): randomized controlled trial.

OBJECTIVE: To compare the proportion of small-for-gestational-age (SGA) infants detected by routine third-trimester ultrasound vs those detected by selective ultrasound based on serial symphysis-fundus height (SFH) measurements (standard care) in low-risk pregnancy. METHODS: This was an open-label randomized controlled trial conducted at a hospital in Kenya between May 2018 and February 2020. Low-risk pregnant women were randomly allocated (ratio of 1:1) to routine ultrasound for fetal growth assessment between 36 + 0 and 37 + 6 weeks' gestation (intervention group) or to standard care, which involved a selective growth scan on clinical suspicion of fetal growth abnormality based on serial SFH measurements (control group). During ultrasound examination, fetal growth was assessed by measurement of the abdominal circumference (AC), and AC < 10th centile was used to diagnose a SGA fetus. The main prespecified outcomes were the detection of neonatal SGA, defined as birth weight < 10th centile, and of severe neonatal SGA, defined as birth weight < 3rd centile. The predictive performance of routine third-trimester ultrasound and selective ultrasound based on serial SFH measurements was determined using receiver-operating-characteristics (ROC)-curve analysis. RESULTS: Of 566 women assessed for eligibility, 508 (89.8%) were randomized, of whom 253 were allocated to the intervention group and 255 to the control group. Thirty-six babies in the intervention group and 26 in the control group had a birth weight < 10th centile. The detection rate of SGA infants by routine third-trimester ultrasound vs that by standard care was 52.8% (19/36) vs 7.7% (2/26) (P < 0.001) and the specificity was 95.5% (191/200) and 97.9% (191/195), respectively (P = 0.08). The detection rate of severe SGA was 66.7% (12/18) by routine ultrasound vs 8.3% (1/12) by selective ultrasound based on SFH measurements (P < 0.001), with specificities of 91.7% (200/218) and 98.1% (205/209), respectively (P = 0.006). The area under the ROC curve of routine third-trimester ultrasound in prediction of SGA was significantly greater than that of selective ultrasound based on SFH measurements (0.92 (95% CI, 0.87-0.96) vs 0.68 (95% CI, 0.58-0.77); P < 0.001). CONCLUSIONS: In low-risk pregnancy, routine ultrasound performed between 36 + 0 and 37 + 6 weeks is superior to selective ultrasound based on serial SFH measurements for the detection of true SGA, with high specificity. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Incidence of pre-eclampsia and other perinatal complications among pregnant women with congenital heart disease: systematic review and meta-analysis.

OBJECTIVE: It has been proposed recently that pre-eclampsia (PE) may originate from maternal cardiac maladaptation rather than primary placental insult. As congenital heart disease (CHD) is associated with reduced adaptation to the hemodynamic needs of pregnancy, it is hypothesized that women with CHD have an increased risk of PE. The aim of this systematic review was to investigate the risk of PE in pregnant women with CHD. METHODS: A systematic search was performed to identify relevant studies published in English, Spanish, French, Italian, Chinese or German, with no time restrictions, using databases such as PubMed, Web of Science and SCOPUS. Randomized controlled trials and observational studies (prospective or retrospective cohorts) of pregnant women with a history of CHD were sought. The main outcome was the incidence of PE (including eclampsia and HELLP syndrome). For quality assessment of the included studies, two reviewers assessed independently the risk of bias. For the meta-analysis, the incidence of PE in pregnancies (those beyond 20 weeks' gestation) was calculated using single-proportion analysis by random-effects modeling (weighted by inverse variance). Heterogeneity between studies was assessed using the χ2 (Cochran's Q), tau2 and I2 statistics. Subgroup analysis was performed, and meta-regression was used to assess the influence of several covariates on the pooled results. RESULTS: A total of 33 studies were included in the meta-analysis, including 40 449 women with CHD and a total of 40 701 pregnancies. The weighted incidence of PE was 3.1% (95% CI, 2.2-4.0%), with true-effect heterogeneity of 93% according to I2 , and no publication bias found. No difference was found in the weighted incidence of PE between studies including cyanotic CHD vs those excluding (or not reporting) cyanotic CHD (2.5% (95% CI, 1.6-3.4%) vs 4.1% (95% CI, 2.4-5.7%); P = 0.0923). Meta-regression analysis showed that the only cofactor that significantly influenced the incidence of PE in each study was the reported incidence of aortic stenosis; studies with a higher incidence of aortic stenosis had a higher incidence of PE (estimate: 0.0005; P = 0.038). CONCLUSIONS: We failed to demonstrate an incidence of PE above the expected baseline risk in women with CHD. This observation contradicts the theory of the cardiac origin of PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ten-year experience of protocol-based management of small-for-gestational-age fetuses: perinatal outcome in late-pregnancy cases diagnosed after 32 weeks.

OBJECTIVE: To report our 10-year experience of protocol-based management of small-for-gestational-age (SGA) fetuses, based on standardized clinical and Doppler criteria, in late-pregnancy cases. METHODS: A retrospective cohort was constructed of consecutive singleton pregnancies referred for late-onset (> 32 weeks) SGA (defined as estimated fetal weight (EFW) < 10th centile) that were classified as fetal growth restriction (FGR) or low-risk SGA, based on the severity of smallness (EFW < 3rd centile) and the presence of Doppler abnormalities (uterine artery pulsatility index (UtA-PI) ≥ 95th centile or cerebroplacental ratio (CPR) < 5th centile). Low-risk SGA pregnancies were followed at 2-week intervals and delivered electively at 40 weeks. FGR pregnancies were followed at 1-week intervals, or more frequently if there were signs of fetal deterioration, and were delivered electively after 37 + 0 weeks' gestation. The occurrence of stillbirth and composite adverse outcome (CAO; defined as neonatal death, metabolic acidosis, need for endotracheal intubation or need for admission to the neonatal intensive care unit) was analyzed in low-risk SGA and FGR pregnancies. RESULTS: A total of 1197 pregnancies with EFW < 10th centile were identified and classified at diagnosis as low-risk SGA (n = 619; 51.7%) or FGR (n = 578; 48.3%). Of these, 160 were delivered before 37 weeks' gestation; for obstetric reasons in 93 (58.1%) cases, severe pre-eclampsia in 33 (20.6%), FGR with severe hypoxia in 47 (29.4%) and stillbirth in four (2.5%) (indications are non-exclusive). During follow-up, 52/574 (9.1%) low-risk SGA pregnancies were reclassified as FGR, whereas 22/463 (4.8%) FGR pregnancies were reclassified as low-risk SGA. Overall, there were no stillbirths in the low-risk SGA group and four in the FGR group, all of which occurred before 37 weeks. There were no instances of neonatal death in pregnancies delivered ≥ 37 weeks. The risk of CAO was higher in those meeting antenatal criteria for FGR at 37 weeks than in those classified as low-risk SGA (32/493 (6.5%) vs 15/544 (2.8%); odds ratio, 2.5 (95% CI, 1.3-4.6)). In FGR pregnancies, the adjusted odds ratio (95% CI) for CAO was 6.3 (1.8-21.1) in those with EFW < 3rd centile, while it was 3.2 (1.5-6.8) and 4.2 (1.9-8.9) in those with UtA-PI ≥ 95th centile and CPR < 5th centile, respectively, as compared to FGR pregnancies without each of these criteria. CONCLUSION: Protocol-based risk stratification with different management and monitoring schemes for late pregnancy with a suspected SGA baby, based on clinical and Doppler criteria, enables identification and tailored assessment of high-risk FGR, while allowing expectant management with safe perinatal outcome for low-risk SGA fetuses. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Pregnant women with SARS-CoV-2 infection are at higher risk of death and pneumonia: propensity score matched analysis of a nationwide prospective cohort (COV19Mx).

OBJECTIVE: There are limited, unmatched data reporting low complication rates in pregnant women with coronavirus disease 2019 (COVID-19). The aim of this study was to compare COVID-19-related outcomes between pregnant and non-pregnant women after adjusting for potential risk factors for severe outcomes. METHODS: Data were obtained from the COVID-19 National Data Registry of Mexico, which is an ongoing prospective cohort of people of any age with clinically suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and admitted to 475 monitoring hospitals. This study included pregnant and non-pregnant women of reproductive age (15-45 years) with COVID-19 confirmed by reverse transcription polymerase chain reaction. To adjust for underlying risk factors, propensity score matching was conducted for chronic obstructive pulmonary disease, asthma, smoking, hypertension, cardiovascular disease, obesity, diabetes, chronic renal disease, immunosuppression, age, language, nationality and level of health insurance. The primary outcome was death. Secondary outcomes were pneumonia, intubation and intensive care unit (ICU) admission. RESULTS: The cohort comprised 5183 pregnant and 175 905 non-pregnant women with COVID-19. The crude (unmatched) rates of death, pneumonia, intubation and ICU admission in pregnant compared with non-pregnant women were 1.5% vs 1.5%, 9.9% vs 6.5%, 8.1% vs 9.9% and 13.0% vs 6.9%, respectively. After propensity score matching (5183 pregnant and 5183 non-pregnant matched women), pregnant women had a higher odds of death (odds ratio (OR), 1.84; 95% CI, 1.26-2.69), pneumonia (OR, 1.86; 95% CI, 1.60-2.16) and ICU admission (OR, 1.86; 95% CI, 1.41-2.45) than non-pregnant women, but similar odds of intubation (OR, 0.93; 95% CI, 0.70-1.25). CONCLUSION: After adjusting for background demographic and medical factors, pregnancy is a risk factor for death, pneumonia and ICU admission in SARS-CoV-2-infected women of reproductive age. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester prediction of small-for-gestational age in pregnancies at false-positive high or intermediate risk for fetal aneuploidy.

OBJECTIVES: To explore the risk of small-for-gestational age (SGA) and fetal growth restriction (FGR) and to test the performance of first-trimester screening for SGA and FGR in women with a false-positive high or intermediate risk for aneuploidy. METHODS: This was a prospective cohort study of women with a singleton pregnancy attending for a routine first-trimester scan. The risks of aneuploidy and preterm SGA (defined as birth weight < 10th percentile with delivery before 37 weeks) were determined according to Fetal Medicine Foundation algorithms. In non-malformed euploid pregnancies, the predictive performance of both the aneuploidy and preterm SGA risks was evaluated for SGA, FGR (defined as birth weight < 3rd centile), preterm SGA and early SGA (delivery before 34 weeks), using receiver-operating-characteristics (ROC) curve analysis, in those with a high or intermediate risk of aneuploidy and in the overall population. RESULTS: A total of 2053 pregnancies were included in the analysis, of which 191 (9.3%) were at high or intermediate risk for aneuploidy (≥ 1/1000) and 304 (14.8%) were at high risk for preterm SGA (≥ 1/100). In total, there were 140 (6.8%) cases of SGA, 61 (3.0%) of FGR, 44 (2.1%) of preterm SGA and 33 (1.6%) of early SGA. Among women with a false-positive high or intermediate risk for aneuploidy, the rates of SGA, FGR, preterm SGA and early SGA were 13.6% (26/191), 7.9 % (15/191), 6.8% (13/191) and 5.8% (11/191), respectively. Compared with women with a first-trimester low risk for preterm SGA, regardless of aneuploidy risk, those with a high risk for preterm SGA and a high or intermediate risk for aneuploidy had relative risks for SGA, FGR, preterm SGA and early SGA of 6 (95% CI, 3.9-9), 9.2 (95% CI, 5.1-16.5), 13.4 (95% CI, 6.9-26.1) and 17.6 (95% CI, 8.1-38.2), respectively. The predictive performance for SGA of the preterm SGA algorithm was higher in women at high or intermediate risk for aneuploidy than in the overall population (area under the ROC curve (AUC), 0.8 vs 0.7; P < 0.001). Among women at high or intermediate risk for aneuploidy, the predictive performance of the preterm SGA algorithm was better than that of the aneuploidy algorithm for SGA (AUC, 0.80 vs 0.58; P = 0.003), preterm SGA (AUC, 0.85 vs 0.65; P = 0.013) and early SGA (AUC, 0.86 vs 0.60; P = 0.002). CONCLUSION: In women with a first-trimester false-positive high or intermediate risk of aneuploidy, further screening for SGA allows stratification of the risk for fetal growth disorders. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Third-trimester uterine artery Doppler for prediction of adverse outcome in late small-for-gestational-age fetuses: systematic review and meta-analysis.

OBJECTIVE: To investigate the predictive ability for adverse perinatal outcome of abnormal third-trimester uterine artery Doppler in late small-for-gestational-age (SGA) fetuses. METHODS: A systematic search was performed to identify relevant observational studies and randomized controlled trials evaluating the performance of abnormal third-trimester uterine artery Doppler for the prediction of adverse perinatal outcome in suspected SGA fetuses and SGA neonates. Abnormal uterine artery Doppler was defined as uterine artery pulsatility index > 95th percentile or ≥ 2 SD above the mean, or bilateral uterine artery notching. Hierarchical summary receiver-operating-characteristics (ROC) curves were constructed using random-effects modeling. Bayesian analysis was used to calculate the posterior probability of adverse perinatal outcome following an abnormal or normal uterine artery Doppler assessment. RESULTS: Seventeen observational studies (including 7552 fetuses either diagnosed with suspected SGA (n = 3461) or later diagnosed as a SGA neonate (n = 4091)) met the inclusion criteria; no randomized-controlled trials met the inclusion criteria. Summary ROC curves showed that, among suspected SGA fetuses, the best predictive accuracy of abnormal third-trimester uterine artery Doppler was for perinatal mortality and the worst was for composite adverse perinatal outcome, with areas under the summary ROC curves of 0.90 and 0.66, respectively. The corresponding positive and negative likelihood ratios were 16.5 and 0.6 for perinatal mortality and 2.82 and 0.65 for composite adverse perinatal outcome, respectively. Following an abnormal vs normal uterine artery Doppler assessment, the posterior risks for composite adverse perinatal outcome, admission to the neonatal intensive care unit, Cesarean section for intrapartum fetal compromise, 5-min Apgar score < 7, neonatal acidosis and perinatal death were: 52.3% vs 20.2%, 48.6% vs 18.7%, 23.1% vs 15.2%, 3.59% vs 1.32%, 9.15% vs 5.12% and 31.4% vs 1.64%, respectively. CONCLUSION: Abnormal uterine artery Doppler in the third trimester appears to be moderately useful in predicting perinatal death in pregnancies with suspected SGA. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Doppler uterino en el tercer trimestre para la predicción de resultados adversos en fetos pequeños para la edad gestacional: revisión sistemática y metaanálisis OBJETIVO: Investigar la capacidad de predicción de resultados perinatales adversos del Doppler uterino anómalo en el tercer trimestre en fetos pequeños para la edad gestacional (PEG). MÉTODOS: Se realizó una búsqueda sistemática para identificar estudios observacionales pertinentes y ensayos controlados aleatorizados que hubieran evaluado el comportamiento del Doppler uterino anómalo en el tercer trimestre para la predicción de resultados perinatales adversos en fetos con sospecha de ser PEG y en neonatos PEG. El Doppler uterino anómalo se definió como el índice de pulsatilidad de la arteria uterina >95 percentil o DE ≥2 por encima de la media, o escotadura bilateral de la arteria uterina. Se elaboraron modelos de efectos aleatorizados para la elaboración de una curva jerárquica resumen de las características operativas del receptor (ROC, por sus siglas en inglés). Se utilizó el análisis bayesiano para calcular la probabilidad a posteriori de un resultado perinatal adverso después de una evaluación de Doppler uterino anómalo o normal. RESULTADOS: Diecisiete estudios observacionales (incluidos 7552 fetos diagnosticados como sospechosos de ser PEG (n=3461) o diagnosticados posteriormente como neonatos PEG (n=4091)) cumplieron los criterios de inclusión; ningún ensayo controlado aleatorizado cumplió los criterios de inclusión. Las curvas resumen ROC mostraron que, entre los fetos sospechosos de ser PEG, la mayor precisión predictiva del Doppler uterino anómalo en el tercer trimestre fue para la muerte perinatal y la peor fue para el resultado perinatal adverso compuesto, con áreas por debajo de las curvas resumen ROC de 0,90 y 0,66, respectivamente. Los cocientes de verosimilitud correspondientes, positivo y negativo, fueron de 16,5 y 0,6 para la mortalidad perinatal y de 2,82 y 0,65 para el resultado perinatal adverso compuesto, respectivamente. Los riesgos posteriores a una evaluación de Doppler uterino anómalo vs normal, para el resultado perinatal adverso compuesto, la admisión en la unidad de cuidados intensivos para neonatos, la cesárea por deterioro fetal durante el parto, el test de Apgar a los 5 minutos <7, la acidosis neonatal y la muerte perinatal, fueron: 52,3% vs 20,2%, 48,6% vs 18,7%, 23,1% vs 15,2%, 3,59% vs 1,32%, 9,15% vs 5,12% y 31,4% vs 1,64%, respectivamente. CONCLUSIÓN: El Doppler uterino anómalo en el tercer trimestre parece ser moderadamente útil para predecir la muerte perinatal en embarazos con sospecha de ser PEG.

Quality assessment of fetal middle cerebral and umbilical artery Doppler images using an objective scale within an international randomized controlled trial.

OBJECTIVES: To determine the quality of Doppler images of the fetal middle cerebral artery (MCA) and umbilical artery (UA) using an objective scale, and to determine the reliability of this scale, within a multicenter randomized controlled trial (Revealed versus concealed criteria for placental insufficiency in unselected obstetric population in late pregnancy (Ratio37)). METHODS: The Ratio37 trial is an ongoing randomized, open-label, multicenter controlled study of women with a low-risk pregnancy recruited at 20 weeks. Doppler measurements of the fetal MCA and UA were performed at 37 weeks. Twenty patients from each of the six participating centers were selected randomly, with two images evaluated per patient (one each for the MCA and UA). The quality of a total of 240 images was evaluated by six experts, scored on an objective scale of six items. Inter- and intrarater reliability was assessed using the Fleiss-modified kappa statistic for ordinal scales. RESULTS: On average, 89.2% of MCA images and 85.0% of UA images were rated as being of perfect (score of 6) or almost perfect (score of 5) quality. Kappa values for intrarater reliability of quality assessment were 0.90 (95% CI, 0.88-0.92) and 0.90 (95% CI, 0.88-0.93) for the MCA and UA, respectively. The corresponding inter-rater reliability values were 0.85 (95% CI, 0.81-0.89) and 0.84 (95% CI, 0.80-0.89), respectively. CONCLUSION: The quality of MCA and UA Doppler ultrasound images can be evaluated reliably using an objective scale. Over 85% of images, which were obtained by operators from a broad range of clinical practices within a multicenter study, were rated as being of perfect or almost perfect quality. Intra- and inter-rater reliability of quality assessment was very good. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

[A clinical management protocol for COVID-19 infection in pregnant women]. / Guía de actuación para el manejo de la infección por COVID-19 durante en el embarazo.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has caused a large global outbreak and has had a major impact on health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. Very few studies have reported on the effects of the infection on maternal health, since its onset. The mother and foetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-foetal medicine practice have made profound changes in order to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists. In this review an evidenced-based protocol is presented for the management of COVID-19 in pregnancy.

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

First-trimester and combined first- and second-trimester prediction of small-for-gestational age and late fetal growth restriction.

OBJECTIVE: To develop a first-trimester or combined first- and second-trimester screening algorithm for the prediction of small-for-gestational age (SGA) and late fetal growth restriction (FGR). METHODS: This was a retrospective study of women with singleton pregnancy, who underwent routine first-, second- and third-trimester ultrasound assessment. Late FGR was defined, at ≥ 32 weeks' gestation in the absence of congenital anomalies, as either (i) estimated fetal weight (EFW) or birth weight (BW) < 3rd centile, or (ii) EFW < 10th centile and either uterine artery mean pulsatility index (UtA-PI) > 95th centile or cerebroplacental ratio (CPR) < 5th centile. Neonates with BW < 10th centile, regardless of prenatal parameters, were defined as SGA. The predictive effectiveness of maternal and first- and second-trimester factors was tested using logistic regression and receiver-operating characteristics curve analyses. RESULTS: A total of 3520 fetuses were included (late FGR, n = 109 (3.1%); SGA, n = 292 (8.3%)). Of the late FGR cases, 56 (1.6%) fulfilled the antenatal criteria (EFW < 3rd centile or EFW < 10th centile plus abnormal UtA-PI or CPR) and were defined as prenatally detected late FGR. A first-trimester screening model (comprising conception method, smoking status, maternal height, pregnancy-associated plasma protein-A (PAPP-A) and UtA-PI) could predict 50.0% of the prenatally diagnosed and 36.7% of the overall late FGR fetuses for a 10% false-positive rate (FPR). A model combining first- and second-trimester screening parameters (conception method, smoking status, PAPP-A, second- trimester EFW, head circumference/abdominal circumference ratio and UtA-PI) could predict 78.6% of the prenatally detected, and 59.6% of the overall late FGR fetuses, for a 10% FPR (area under the curve 0.901 (95% CI, 0.856-0.947) and 0.855 (95% CI, 0.818-0.891), respectively). The prediction of SGA was suboptimal for both first-trimester and combined screening. CONCLUSIONS: A simple model combining maternal and first- and second-trimester predictors can detect 60% of fetuses that will develop late FGR, and 79% of those fetuses that will be classified prenatally as late FGR, for a 10% FPR. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Cerebroplacental ratio assessment in early labor in uncomplicated term pregnancy and prediction of adverse perinatal outcome: prospective multicenter study.

OBJECTIVE: It has been suggested that the use of Doppler ultrasound in term pregnancies with normal-sized fetuses is able to identify those at high risk of subclinical placental function impairment. The objective of this study was to evaluate the relationship between cerebroplacental ratio (CPR) measured in early labor and perinatal and delivery outcomes in a cohort of uncomplicated singleton term pregnancies. METHODS: This was a prospective multicenter observational study conducted at three tertiary centers between January 2016 and July 2017. Low-risk term pregnancies, defined by the absence of maternal morbidity or pregnancy complication, accompanied by normal ultrasound and clinical screening of fetal growth in the third trimester, with spontaneous onset of labor were included. Umbilical artery (UA) and fetal middle cerebral artery (MCA) Doppler was assessed on admission for early labor. All measurements were performed in between uterine contractions and according to international standards. CPR was computed by dividing MCA pulsatility index by UA pulsatility index and converted into multiples of the median (MoM) in order to adjust for gestational age. Doctors and midwives involved in the clinical management of the women were blinded to the results of the Doppler evaluation. Mode of delivery and perinatal outcome were compared between pregnancies with reduced CPR MoM, defined as CPR MoM within the lowest decile of the study population, and those with normal CPR MoM. Receiver-operating characteristics curve analysis was used to assess the predictive performance of CPR for obstetric intervention due to fetal distress and composite adverse perinatal outcome. RESULTS: Overall, 562 women were included. The rate of obstetric intervention for suspected fetal distress in labor was more than three times higher among cases with reduced CPR MoM compared to those with normal CPR MoM (9/54 (16.7%) vs 28/508 (5.5%); P = 0.004). Furthermore, a significantly higher rate of composite adverse perinatal outcome was found in fetuses with CPR MoM < 10th percentile compared to those with CPR MoM ≥ 10th percentile (6/54 (11.1%) vs 19/508 (3.7%); P = 0.012). CPR had low sensitivity and low positive predictive value for prediction of obstetric intervention due to fetal distress (24.3% and 18.0%, respectively) and composite adverse perinatal outcome (24.0% and 11.1%, respectively). CONCLUSIONS: Data on a wide cohort of low-risk term pregnancies in early labor showed that, while reduced CPR is associated with a higher risk of obstetric intervention due to fetal distress and composite adverse perinatal outcome, it is a poor predictor of adverse perinatal outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Maternal and perinatal outcomes after elective induction of labor at 39 weeks in uncomplicated singleton pregnancy: a meta-analysis.

OBJECTIVE: The rate of maternal and perinatal complications increases after 39 weeks' gestation in both unselected and complicated pregnancies. The aim of this study was to synthesize quantitatively the available evidence on the effect of elective induction of labor at 39 weeks on the risk of Cesarean section, and on maternal and perinatal outcomes. METHODS: PubMed, US Registry of Clinical Trials, SCOPUS and CENTRAL databases were searched from inception to August 2018. Additionally, the references of retrieved articles were searched. Eligible studies were randomized controlled trials of singleton uncomplicated pregnancies in which participants were randomized between 39 + 0 and 39 + 6 gestational weeks to either induction of labor or expectant management. The risk of bias of individual studies was assessed using the Cochrane Risk of Bias Tool. The overall quality of evidence was assessed according to the GRADE guideline. Primary outcomes included Cesarean section, maternal death and admission to the neonatal intensive care unit (NICU). Secondary outcomes included operative delivery, Grade-3/4 perineal laceration, postpartum hemorrhage, maternal infection, hypertensive disease of pregnancy, maternal thrombotic events, length of maternal hospital stay, neonatal death, need for neonatal respiratory support, cerebral palsy, length of stay in NICU and length of neonatal hospital stay. Pooled risk ratios (RRs) were calculated using random-effects models. RESULTS: The meta-analysis included five studies (7261 cases). Induction of labor was associated with a decreased risk for Cesarean section (moderate quality of evidence; RR 0.86 (95% CI, 0.78-0.94); I2  = 0.1%), maternal hypertension (moderate quality of evidence; RR 0.65 (95% CI, 0.57-0.75); I2  = 0%) and neonatal respiratory support (moderate quality of evidence; RR 0.73 (95% CI, 0.58-0.95); I2  = 0%). Neonates born after induction weighed, on average, 81 g (95% CI, 63-100 g) less than those born after expectant management. No significant effects were found for the other outcomes with the available data. The main limitation of our analysis was that the majority of data were derived from a single large study. A second limitation arose from the open-label design of the studies, which may theoretically have affected the readiness of the attending clinician to resort to Cesarean section. CONCLUSIONS: Elective induction of labor in uncomplicated singleton pregnancy at 39 weeks' gestation is not associated with maternal or perinatal complications and may reduce the need for Cesarean section, risk of hypertensive disease of pregnancy and need for neonatal respiratory support. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.