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.

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.

Essential variables for reporting research studies on fetal growth restriction: a Delphi consensus.

OBJECTIVE: To determine, by expert consensus using a Delphi procedure, a minimum reporting set of study variables for fetal growth restriction (FGR) research studies. METHODS: A panel of experts, identified based on their publication record as lead or senior author of studies on FGR, was asked to select a set of essential reporting study parameters from a literature-based list of variables, utilizing the Delphi consensus methodology. Responses were collected in four consecutive rounds by online questionnaires presented to the panelists through a unique token-secured link for each round. The experts were asked to rate the importance of each parameter on a five-point Likert scale. Variables were selected in the three first rounds based on a 70% threshold for agreement on the Likert-scale scoring. In the final round, retained parameters were categorized as essential (to be reported in all FGR studies) or recommended (important but not mandatory). RESULTS: Of the 100 invited experts, 87 agreed to participate and of these 62 (71%) completed all four rounds. Agreement was reached for 16 essential and 30 recommended parameters including maternal characteristics, prenatal investigations, prenatal management and pregnancy/neonatal outcomes. Essential parameters included hypertensive complication in the current pregnancy, smoking, parity, maternal age, fetal abdominal circumference, estimated fetal weight, umbilical artery Doppler (pulsatility index and end-diastolic flow), fetal middle cerebral artery Doppler, indications for intervention, pregnancy outcome (live birth, stillbirth or neonatal death), gestational age at delivery, birth weight, birth-weight centile, mode of delivery and 5-min Apgar score. CONCLUSIONS: We present a list of essential and recommended parameters that characterize FGR independent of study hypotheses. Uniform reporting of these variables in prospective clinical research is expected to improve data quality, study consistency and ultimately our understanding of FGR. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

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.

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.

Impact of aspirin on trophoblastic invasion in women with abnormal uterine artery Doppler at 11-14 weeks: a randomized controlled study.

OBJECTIVE: Defective trophoblastic invasion is a key feature in many cases of pre-eclampsia (PE). Uterine artery (UtA) Doppler is a validated non-invasive proxy for trophoblastic invasion. The aim of this study was to explore whether low-dose aspirin, administered from the first trimester, improves trophoblastic invasion, evaluated by UtA Doppler during the second and third trimesters in women defined as high risk by abnormal first-trimester UtA Doppler. METHODS: This randomized Phase-II study had a triple-blind, parallel-arm, controlled design. Singleton pregnancies with abnormal mean UtA Doppler at 11-14 weeks and absence of other major risk factors for PE received 150 mg extended-release aspirin or identical-appearing placebo tablets from study inclusion to 28 weeks. Main outcome measure was UtA pulsatility index (PI) at 28 weeks' gestation. Secondary outcomes included frequency of development of PE and growth restriction/small-for-gestational age (SGA). RESULTS: A total of 155 women completed the follow-up and were analyzed. No difference in mean UtA-PI was found between women in the aspirin and placebo groups at 28 weeks (mean UtA-PI Z-score (mean ± SD), 0.99 ± 1.48 vs 0.85 ± 1.25; P = 0.52). Seven women developed PE: four (5%) in the aspirin group and three (4%) in the placebo group. There was a trend toward lower incidence of SGA in the aspirin group (8.8% vs 17.3%; P = 0.11). CONCLUSION: In women with defective trophoblastic invasion, as reflected by abnormal UtA Doppler, low-dose aspirin started in the first trimester does not have a significant effect on UtA impedance as pregnancy progresses; however, the study was underpowered to detect potential small effects . Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Performance of third-trimester combined screening model for prediction of adverse perinatal outcome.

OBJECTIVE: To explore the potential value of third-trimester combined screening for the prediction of adverse perinatal outcome (APO) in the general population and among small-for-gestational-age (SGA) fetuses. METHODS: This was a nested case-control study within a prospective cohort of 1590 singleton gestations undergoing third-trimester evaluation (32 + 0 to 36 + 6 weeks' gestation). Maternal baseline characteristics, mean arterial blood pressure, fetoplacental ultrasound and circulating biochemical markers (placental growth factor (PlGF), lipocalin-2, unconjugated estriol and inhibin A) were assessed in all women who subsequently had an APO (n = 148) and in a control group without perinatal complications (n = 902). APO was defined as the occurrence of stillbirth, umbilical artery cord blood pH < 7.15, 5-min Apgar score < 7 or emergency operative delivery for fetal distress. Logistic regression models were developed for the prediction of APO in the general population and among SGA cases (defined as customized birth weight < 10th centile). RESULTS: The prevalence of APO was 9.3% in the general population and 27.4% among SGA cases. In the general population, a combined screening model including a-priori risk (maternal characteristics), estimated fetal weight (EFW) centile, umbilical artery pulsatility index (UA-PI), estriol and PlGF achieved a detection rate for APO of 26% (area under receiver-operating characteristics curve (AUC), 0.59 (95% CI, 0.54-0.65)), at a 10% false-positive rate (FPR). Among SGA cases, a model including a-priori risk, EFW centile, UA-PI, cerebroplacental ratio, estriol and PlGF predicted 62% of APO (AUC, 0.86 (95% CI, 0.80-0.92)) at a FPR of 10%. CONCLUSIONS: The use of fetal ultrasound and maternal biochemical markers at 32-36 weeks provides a poor prediction of APO in the general population. Although it remains limited, the performance of the screening model is improved when applied to fetuses with suboptimal fetal growth. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Changes in uterine artery Doppler velocimetry and circulating angiogenic factors in the first half of pregnancies delivering a small-for-gestational-age neonate.

OBJECTIVE: To assess the relationship between longitudinal changes in placental Doppler indices and maternal circulating angiogenic factors in the first half of pregnancy and delivery of a small-for-gestational-age (SGA) neonate, and ascertain whether longitudinal evaluation of these variables improves the prediction achieved by second-trimester cross-sectional evaluation. METHODS: From a prospective cohort of unselected singleton pregnancies undergoing first-trimester screening for aneuploidy, 138 were included in this study. Of these, 46 were complicated by SGA (delivering after 34 weeks' gestation with a birth weight < 10th centile) and 92 were appropriate-for-gestational-age (AGA) pregnancies, which were included as controls (ratio 1:2). First-to-second trimester longitudinal changes in uterine artery (UtA) Doppler indices and maternal circulating levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were analyzed. RESULTS: Compared with the AGA group, SGA pregnancies had significantly higher UtA impedance in the first (Z-score: 0.46 vs -0.57; P < 0.001) and second (Z-score: 1.71 vs -0.75; P < 0.001) trimesters. Likewise, the sFlt-1/PlGF ratio was significantly higher in SGA than in AGA pregnancies in the first (98.0 vs 67.9; P = 0.01) and early second (22.4 vs 8.8; P < 0.001) trimesters. The predictive performance of the longitudinal changes in UtA Doppler indices for SGA was significantly lower than that of second-trimester cross-sectional values (area under receiver-operating characteristics curve (AUC), 60.8% vs 84.3%; P = 0.0035). The detection rate of SGA, at a 10% false-positive rate (FPR), was 17.7% by longitudinal changes in UtA Doppler and 56.2% by second-trimester cross-sectional UtA Doppler values. Similarly, the predictive performance of the longitudinal changes in PlGF was significantly lower than that of early second-trimester cross-sectional values (AUC, 71.4% vs 76.5%; P = 0.008). The detection rate of SGA at a 10% FPR was 40.6% when screening by longitudinal changes in PlGF and 52.1% when screening by early second-trimester cross-sectional values. CONCLUSIONS: First- and second-trimester UtA Doppler velocimetry and maternal circulating angiogenic markers have clinical utility as a cross-sectional assessment for the identification of pregnancies at high risk of delivering a SGA neonate, however, they do not improve prediction when their longitudinal changes are used. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester screening with specific algorithms for early- and late-onset fetal growth restriction.

OBJECTIVE: To develop optimal first-trimester algorithms for the prediction of early and late fetal growth restriction (FGR). METHODS: This was a prospective cohort study of singleton pregnancies undergoing first-trimester screening. FGR was defined as an ultrasound estimated fetal weight < 10(th) percentile plus Doppler abnormalities or a birth weight < 3(rd) percentile. Logistic regression-based predictive models were developed for predicting early and late FGR (cut-off: delivery at 34 weeks). The model included the a-priori risk (maternal characteristics), mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). RESULTS: Of the 9150 pregnancies included, 462 (5%) fetuses were growth restricted: 59 (0.6%) early and 403 (4.4%) late. Significant contributions to the prediction of early FGR were provided by black ethnicity, chronic hypertension, previous FGR, MAP, UtA-PI, PlGF and sFlt-1. The model achieved an overall detection rate (DR) of 86.4% for a 10% false-positive rate (area under the receiver-operating characteristics curve (AUC): 0.93 (95% CI, 0.87-0.98)). The DR was 94.7% for FGR with pre-eclampsia (PE) (64% of cases) and 71.4% for FGR without PE (36% of cases). For late FGR, significant contributions were provided by chronic hypertension, autoimmune disease, previous FGR, smoking status, nulliparity, MAP, UtA-PI, PlGF and sFlt-1. The model achieved a DR of 65.8% for a 10% false-positive rate (AUC: 0.76 (95% CI, 0.73-0.80)). The DR was 70.2% for FGR with PE (12% of cases) and 63.5% for FGR without PE (88% of cases). CONCLUSIONS: The optimal screening algorithm was different for early vs late FGR, supporting the concept that screening for FGR is better performed separately for the two clinical forms. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Contingent versus routine third-trimester screening for late fetal growth restriction.

OBJECTIVE: To evaluate the use of third-trimester ultrasound screening for late fetal growth restriction (FGR) on a contingent basis, according to risk accrued in the second trimester, in an unselected population. METHODS: Maternal characteristics, fetal biometry and second-trimester uterine artery (UtA) Doppler were included in logistic regression analysis to estimate risk for late FGR (birth weight < 3(rd) percentile, or 3(rd) -10(th) percentile plus abnormal cerebroplacental ratio or UtA Doppler, with delivery ≥ 34 weeks). Based on the second-trimester risk, strategies for performing contingent third-trimester ultrasound examinations in 10%, 25% or 50% of the cohort were tested against a strategy of routine ultrasound scanning in the entire population at 32 + 0 to 33 + 6 weeks. RESULTS: Models were constructed based on 1393 patients and validated in 1303 patients, including 73 (5.2%) and 82 late FGR (6.3%) cases, respectively. At the second-trimester scan, the a-posteriori second-trimester risk (a-posteriori first-trimester risk (baseline a-priori risk and mean arterial blood pressure) combined with second-trimester abdominal circumference and UtA Doppler) yielded an area under the receiver-operating characteristics curve (AUC) of 0.81 (95% CI, 0.74-0.87) (detection rate (DR), 43.1% for a 10% false-positive rate (FPR)). The combination of a-posteriori second-trimester risk plus third-trimester estimated fetal weight (full model) yielded an AUC of 0.92 (95% CI, 0.88-0.96) (DR, 74% for a 10% FPR). Subjecting 10%, 25% or 50% of the study population to third-trimester ultrasound, based on a-posteriori second-trimester risk, gave AUCs of 0.81 (95% CI, 0.75-0.88), 0.84 (95% CI, 0.78-0.91) and 0.89 (95% CI, 0.84-0.94), respectively. Only the 50% contingent model proved statistically equivalent to performing routine third-trimester ultrasound scans (AUC, 0.92 (95% CI, 0.88-0.96), P = 0.11). CONCLUSION: A strategy of selecting 50% of the study population to undergo third-trimester ultrasound examination, based on accrued risk in the second trimester, proved equivalent to routine third-trimester ultrasound scanning in predicting late FGR.

An integrated model with classification criteria to predict small-for-gestational-age fetuses at risk of adverse perinatal outcome.

OBJECTIVE: To develop an integrated model with the best performing criteria for predicting adverse outcome in small-for-gestational-age (SGA) pregnancies. METHODS: A cohort of 509 pregnancies with a suspected SGA fetus, eligible for trial of labor, was recruited prospectively and data on perinatal outcome were recorded. A predictive model for emergency Cesarean delivery because of non-reassuring fetal status or neonatal acidosis was constructed using a decision tree analysis algorithm, with predictors: maternal age, body mass index, smoking, nulliparity, gestational age at delivery, onset of labor (induced vs spontaneous), estimated fetal weight (EFW), umbilical artery pulsatility index (PI), mean uterine artery (UtA) PI, fetal middle cerebral artery PI and cerebroplacental ratio (CPR). RESULTS: An adverse outcome occurred in 134 (26.3%) cases. The best performing predictors for defining a high risk for adverse outcome in SGA fetuses was the presence of a CPR < 10th centile, a mean UtA-PI > 95th centile or an EFW < 3rd centile. The algorithm showed a sensitivity, specificity and positive and negative predictive values for adverse outcome of 82.8% (95% CI, 75.1-88.6%), 47.7% (95% CI, 42.6-52.9%), 36.2% (95% CI, 30.8-41.8%) and 88.6% (95% CI, 83.2-92.5%), respectively. Positive and negative likelihood ratios were 1.58 and 0.36. CONCLUSIONS: Our model could be used as a diagnostic tool for discriminating SGA pregnancies at risk of adverse perinatal outcome.

Angiogenic factors at diagnosis of late-onset small-for-gestational age and histological placental underperfusion.

OBJECTIVE: This study was designed to explore the association between angiogenic factors levels at diagnosis of small-for-gestational age (SGA) and placental underperfusion (PUP). METHODS: In a cohort of SGA singleton pregnancies, each delivered at >34 weeks, uterine (UtA), umbilical (UA), and middle cerebral (MCA) arteries were evaluated by Doppler upon diagnosis of SGA status. In addition, maternal circulating concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were assayed by ELISA, and each placenta was evaluated for histologic signs of PUP using a hierarchical and standardized classification system. Logistic regression was applied to analyze independent relationships (at diagnosis) between angiogenic factors and Doppler parameters. RESULTS: A total of 122 suspected SGA pregnancies were studied, 70 (57.4%) of which ultimately met PUP criteria. In this group, 85 placental findings qualified as PUP. Both mean UtA pulsatility index z-values (1.26 vs. 0.84; p = 0.038) and PlGF multiples of normal median (0.21 vs. 0.55; p = 0.002) differed significantly in pregnancies with and without PUP, respectively. By logistic regression, PlGF alone was independently predictive of PUP (OR = 0.11 [95% CI 0.025-0.57]; p = 0.008). DISCUSSION: Histologic placental abnormalities in term SGA neonates reflect latent insufficiency in uteroplacental blood supply. The heightened risk of adverse perinatal outcomes in this context underscores a need for new Doppler or biochemical prenatal markers of placental disease. Angiogenic factors may be pivotal identifying SGA neonates. CONCLUSIONS: Diminished circulating levels of placental growth factor, determined upon discovery of SGA status, are associated with histologic evidence of PUP.

Angiogenic factors vs Doppler surveillance in the prediction of adverse outcome among late-pregnancy small-for- gestational-age fetuses.

OBJECTIVES: To compare the value of Doppler surveillance with maternal blood angiogenic factors at diagnosis for the prediction of adverse outcome in late-pregnancy small-for-gestational-age (SGA) fetuses. METHODS: In a cohort of 198 SGA fetuses we evaluated the association of Doppler indices (mean uterine artery pulsatility index (UtA-PI) and cerebroplacental ratio (CPR)) and angiogenic factors (maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)) with the development of pre-eclampsia and adverse perinatal outcome (operative delivery for non-reassuring fetal status or neonatal metabolic acidosis). RESULTS: In SGA fetuses subsequently developing pre-eclampsia, mean UtA-PI (P < 0.001), sFlt-1 MoM (P < 0.001) and sFlt-1/PlGF MoM ratio (P < 0.001) were higher, while PlGF MoM was lower (P = 0.004). In SGA fetuses with adverse perinatal outcome, CPR (P < 0.002) and PlGF MoM (P < 0.001) were lower, and sFlt-1/PlGF MoM ratio was higher (P = 0.001). For predicting pre-eclampsia, the areas under the receiver-operating characteristics (ROC) curves for mean UtA-PI, sFlt-1 MoM and the combination of both were 0.852, 0.839 and 0.860, respectively. For adverse perinatal outcome, the areas under the ROC curves for CPR, PlGF MoM and the combination of both were 0.652, 0.656 and 0.684, respectively. The combination of Doppler indices and angiogenic factors did not significantly improve prediction of either pre-eclampsia (P = 0.851) or adverse outcome (P = 0.579). CONCLUSIONS: In SGA fetuses, angiogenic factors at diagnosis and follow-up with Doppler ultrasound both predict adverse outcome with a similar performance.

Neurodevelopmental outcome of full-term small-for-gestational-age infants with normal placental function.

OBJECTIVE: To evaluate the 2-year neurodevelopmental outcome of full-term, small-for-gestational-age (SGA) newborns with normal placental function, according to current criteria based on umbilical artery Doppler findings. METHODS: A cohort of consecutive full-term, SGA newborns with normal prenatal umbilical artery Doppler was compared with a group of full-term, appropriate-for-gestational-age (AGA) infants sampled from our general neonatal population. Neurodevelopmental outcome was evaluated at 24 months' corrected age using the Bayley Scales of Infant and Toddler Development, 3(rd) Edition (Bayley-III), which evaluates cognitive, language, motor, social-emotional and adaptive competencies. The effect of the study group on each domain was adjusted with MANCOVA and logistic regression for gestational age at delivery, socioeconomic status, gender, tobacco smoking and breastfeeding. RESULTS: A total of 223 infants (112 SGA and 111 AGA) were included. The groups differed significantly with respect to socioeconomic status and gestational age at delivery. All studied neurodevelopmental domains were poorer in the SGA group, reaching significance for the cognitive (92.9 vs 100.2, adjusted P = 0.027), language (94.7 vs 101, adjusted P = 0.025), motor (94.2 vs 100, adjusted P = 0.027) and adaptive (89.2 vs 96.5, adjusted P = 0.012) scores. Likewise, the SGA group had a higher risk of low scores in language (odds ratio (OR) = 2.63; adjusted P = 0.045) and adaptive (OR = 2.72; adjusted P = 0.009) domains. CONCLUSIONS: Compared with normal-sized babies, full-term SGA infants, without placental insufficiency defined according to currently used criteria, have lower 2-year neurodevelopmental scores. These data challenge the concept that SGA fetuses with normal umbilical artery Doppler are 'constitutionally small' but otherwise completely normal.

Cisterna magna width at 11-13 weeks in the detection of posterior fossa anomalies.

OBJECTIVE: To construct reference ranges for cisterna magna (CM) width at 11-13 weeks' gestation in healthy fetuses and determine whether open spina bifida and posterior fossa anomalies could be diagnosed in the first trimester. METHODS: This was a retrospective study. CM width reference ranges were constructed based on the measurements obtained from 80 healthy fetuses with normal postnatal outcome undergoing routine first-trimester ultrasound at 11-13 weeks, using the Lambda-Mu-Sigma method. CM was measured in the fetal mid-sagittal view, as routinely used for nuchal translucency assessment. In addition, first-trimester ultrasound images in 11 fetuses with open spina bifida or posterior fossa anomalies, most of which were diagnosed later in pregnancy, were retrospectively reviewed, and CM measurements were compared against reference ranges. RESULTS: CM width was noted to increase with gestational age in normal fetuses. The anomalies in the 11 fetuses we reviewed were: open spina bifida (n = 5), megacisterna magna (n = 3), Blake's pouch cyst (n = 2) and posterior fossa arachnoid cyst (n = 1). All fetuses with open spina bifida had a CM width below the 5(th) percentile. In the two fetuses with Blake's pouch cyst and in two with megacisterna magna, CM width was above the 95(th) percentile. In one of the fetuses with a megacisterna magna and the one with an arachnoid cyst, CM width was within normal range. CONCLUSION: We have constructed reference ranges for CM width at 11-13 weeks using the mid-sagittal view. It appears that first-trimester CM width can be used as a marker for the early detection of open spina bifida. However, our findings need to be confirmed in prospective large series.

Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing.

OBJECTIVE: To evaluate the neurobehavioral outcomes of preterm infants with intrauterine growth restriction (IUGR), with and without prenatal advanced brain-sparing. METHODS: A cohort of IUGR infants (birth weight < 10(th) percentile with abnormal umbilical artery Doppler) born before 34 weeks of gestation was compared with a control group of appropriate-for-gestational age infants matched for gestational age at delivery. MCA pulsatility index was determined in all cases within 72 hours before delivery. Neonatal neurobehavior was evaluated at 40 weeks' ( ± 1) corrected age using the Neonatal Behavioral Assessment Scale. The effect of abnormal MCA pulsatility index (< 5(th) percentile) on each neurobehavioral area was adjusted for maternal smoking status and socioeconomic level, mode of delivery, gestational age at delivery, pre-eclampsia, newborn illness severity score and infant sex by multiple linear and logistic regression. RESULTS: A total of 126 preterm newborns (64 controls and 62 IUGR) were included. Among IUGR fetuses, the proportion of abnormal MCA Doppler parameters was 53%. Compared with appropriate-for-gestational age infants, newborns in the IUGR subgroup with abnormal MCA Doppler had significantly lower neurobehavioral scores in the areas of habituation, motor system, social-interactive and attention. Similarly, the proportion of infants with abnormal neurobehavioral scores was significantly higher in the IUGR subgroup with abnormal MCA Doppler parameters in the areas of habituation, social-interactive, motor system and attention. CONCLUSION: Abnormal MCA Doppler findings are predictive of neurobehavioral impairment among preterm newborns with IUGR, which suggests that this reflects an advanced stage of brain injury with a higher risk of abnormal neurological maturation.

Catalytic nanomedicine: a new field in antitumor treatment using supported platinum nanoparticles. In vitro DNA degradation and in vivo tests with C6 animal model on Wistar rats.

Novel nanostructured TiO2 and SiO2 based biocatalysts, with 3-4 wt. % of Pt have been developed. The obtained materials exhibit a high surface area together with a broad pore size distribution. The method of synthesis allowed obtaining high dispersed platinum metal nanoparticles. In vitro DNA reactivity test of the biocatalysts were carried out by electrophoresis and formation of DNA adducts was observed. The most active biocatalyst was H2PtCl6/SiO2. These biocatalysts were also tested in an experimental model of C6 brain tumours in Wistar rats. Administration of the material was made by stereotactic brain surgery to place it directly in the malignant tissue. A significant decrease in tumour size and weight as well as morphologic changes in cancer cells were observed.

Customized birthweight standards for a Spanish population.

OBJECTIVE: To analyse the biological factors affecting birthweight and to derive customized birthweight standards for a Spanish population. METHODS: A retrospective cohort was created with all the singleton pregnancies delivered at term and free of pathology in our Institution. Birthweight was modeled by multiple linear regression from maternal (ethnic origin, maternal height, booking weight, smoking, and parity), and fetal (gender, gestational age) characteristics. RESULTS: In addition to gestational age and sex, height, booking weight, ethnic origin, parity, and smoking all have significant and independent effects on birthweight. Women from East-Asia, Morocco and South-America had newborns on average 83 g, 74 g and 95 g heavier than White-European Spanish women. The effect of smoking was found to be dose-related. CONCLUSION: We found the relative effect of the maternal and fetal characteristics to be very similar to that reported in previous studies. We report coefficients for ethnic groups that account for a sizeable proportion of the population composition of several European countries.

Association of smoking during pregnancy and fetal growth restriction: subgroups of higher susceptibility.

OBJECTIVE: To analyze the association between maternal smoking and fetal growth restriction, defined as a failure to achieve the growth potential, and to define subgroups of higher susceptibility for this association. STUDY DESIGN: A definition of growth restriction by customized birthweight standards applied to 13,661 non-malformed singleton deliveries. Customization was performed by maternal ethnic origin, height, booking weight, parity, gestational age at delivery and fetal gender. The adjusted risk of smoking for customized smallness-for-gestational age and the identification of subgroups with higher susceptibility were assessed by logistic regression. RESULTS: Overall, the adjusted odds ratio of smoking (all levels of exposure grouped) for the occurrence of growth restriction was 1.9 (95% confidence interval: 1.69-2.13). Smoking was etiologically responsible for 13.9% (95% confidence interval: 11.2-16.5) of the cases of growth restriction occurring in the population. Smoking resulted in an increasingly greater risk of growth restriction with progressive levels of cigarette consumption. The risk of smoking for fetal growth restriction was significantly greater in older women and those with a previous history of spontaneous preterm delivery. CONCLUSIONS: Smoking is associated with a higher risk for growth restriction. In addition, older pregnant women and those with a previous history of preterm delivery have an increased susceptibility.

Doppler assessment of the aortic isthmus and perinatal outcome in preterm fetuses with severe intrauterine growth restriction.

OBJECTIVES: To evaluate the characteristics and association with perinatal outcome of the aortic isthmus (AoI) circulation as assessed by Doppler imaging in preterm growth-restricted fetuses with placental insufficiency. METHODS: This was a prospective cross-sectional study. Fifty-one fetuses with intrauterine growth restriction (IUGR) and either an umbilical artery (UA) pulsatility index (PI) > 95(th) centile or a cerebroplacental ratio < 5(th) centile were examined at 24-36 weeks' gestation. AoI impedance indices (PI and resistance index) and absolute velocities (peak systolic (PSV), end-diastolic and time-averaged maximum (TAMXV) velocities), were measured in all cases and compared with reference ranges by gestational age. Furthermore, fetuses were stratified into two groups according to the direction of the diastolic blood flow in the AoI: those with antegrade flow (n = 41) and those with retrograde flow (n = 10). Clinical surveillance was based on gestational age and Doppler assessment of the UA, middle cerebral artery and ductus venosus (DV). Adverse perinatal outcome was defined as stillbirth, neonatal death and severe morbidity (respiratory distress syndrome, bronchopulmonary dysplasia, Grade III/IV intraventricular hemorrhage, necrotizing enterocolitis and a neonatal intensive care unit stay > 14 days). RESULTS: Adverse perinatal outcome was significantly associated with an increased AoI-PI (area under the curve 0.77; 95% CI, 0.63-0.92; P < 0.005). A significant correlation (P < 0.001) was found between retrograde blood flow in the AoI and adverse perinatal outcome, the overall perinatal mortality being higher in the retrograde group (70% vs. 4.8%, P < 0.001). In 4/5 (80%) fetuses the reversal of flow in the AoI preceded that in the DV by 24-48 h. AoI-PSV and AoI-TAMXV were < 5(th) centile in 40/51 (78%) and 48/51 (94%) cases, respectively, whereas AoI-PI was > 95(th) centile in 21/51 (41%) cases. CONCLUSIONS: Retrograde flow in the AoI in growth-restricted fetuses correlates strongly with adverse perinatal outcome. Absolute velocities in the AoI are decreased in growth-restricted fetuses. The data suggest a potential role for Doppler imaging of the AoI in the clinical surveillance of fetuses with severe IUGR, which should be confirmed in larger prospective studies.