Publications by authors named "Ignacio Herraiz"

48 Publications

Comparison between Cerebroplacental Ratio and Umbilicocerebral Ratio in Predicting Adverse Perinatal Outcome in Pregnancies Complicated by Late Fetal Growth Restriction: A Multicenter, Retrospective Study.

Fetal Diagn Ther 2021 15;48(6):448-456. Epub 2021 Jun 15.

Center for High Risk Pregnancy and Fetal Care, Department of Obstetrics and Gynecology, University of Chieti, Chieti, Italy.

Introduction: The role of cerebroplacental ratio (CPR) or umbilicocerebral ratio (UCR) to predict adverse intrapartum and perinatal outcomes in pregnancies complicated by late fetal growth restriction (FGR) remains controversial.

Methods: This was a multicenter, retrospective cohort study involving 5 referral centers in Italy and Spain, including singleton pregnancies complicated by late FGR, as defined by Delphi consensus criteria, with a scan 1 week prior to delivery. The primary objective was to compare the diagnostic accuracy of the CPR and UCR for the prediction of a composite adverse outcome, defined as the presence of either an adverse intrapartum outcome (need for operative delivery/cesarean section for suspected fetal distress) or an adverse perinatal outcome (intrauterine death, Apgar score <7 at 5 min, arterial pH <7.1, base excess of >-11 mEq/mL, or neonatal intensive care unit admission).

Results: Median CPR absolute values (1.11 vs. 1.22, p = 0.018) and centiles (3 vs. 4, p = 0.028) were lower in pregnancies with a composite adverse outcome than in those without it. Median UCR absolute values (0.89 vs. 0.82, p = 0.018) and centiles (97 vs. 96, p = 0.028) were higher. However, the area under the curve, 95% confidence interval for predicting the composite adverse outcome showed a poor predictive value: 0.580 (0.512-0.646) for the raw absolute values of CPR and UCR, and 0.575 (0.507-0.642) for CPR and UCR centiles adjusted for gestational age. The use of dichotomized values (CPR <1, UCR >1 or CPR <5th centile, UCR >95th centile) did not improve the diagnostic accuracy.

Conclusion: The CPR and UCR measured in the week prior delivery are of low predictive value to assess adverse intrapartum and perinatal outcomes in pregnancies with late FGR.
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http://dx.doi.org/10.1159/000516443DOI Listing
June 2021

Diagnostic performance of cerebroplacental and umbilicocerebral ratio in appropriate for gestational age and late growth restricted fetuses attempting vaginal delivery: a multicenter, retrospective study.

J Matern Fetal Neonatal Med 2021 Jun 8:1-7. Epub 2021 Jun 8.

Fetal Medicine Unit, Maternal and Child Health and Development Network, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain.

Background: Cerebroplacental Doppler studies have been advocated to predict the risk of adverse perinatal outcome (APO) irrespective of fetal weight.

Objective: To report the diagnostic performance of cerebroplacental (CPR) and umbilicocerebral (UCR) ratios in predicting APO in appropriate for gestational age (AGA) fetuses and in those affected by late fetal growth restriction (FGR) attempting vaginal delivery.

Study Design: Multicenter, retrospective, nested case-control study between 1 January 2017 and January 2020 involving five referral centers in Italy and Spain. Singleton gestations with a scan between 36 and 40 weeks and within two weeks of attempting vaginal delivery were included. Fetal arterial Doppler and biometry were collected. The AGA group was defined as fetuses with an estimated fetal weight and abdominal circumference >10th and <90th percentile, while the late FGR group was defined by Delphi consensus criteria. The primary outcome was the prediction of a composite of perinatal adverse outcomes including either intrauterine death, Apgar score at 5 min <7, abnormal acid-base status (umbilical artery pH < 7.1 or base excess of more than -11) and neonatal intensive care unit (NICU) admission. Area under the curve (AUC) analysis was performed.

Results: 646 pregnancies (317 in the AGA group and 329 in the late FGR group) were included. APO were present in 12.6% AGA and 24.3% late FGR pregnancies, with an odds ratio of 2.22 (95% CI 1.46-3.37). The performance of CPR and UCR for predicting APO was poor in both AGA [AUC: 0.44 (0.39-0.51)] and late FGR fetuses [AUC: 0.56 (0.49-0.61)].

Conclusions: CPR and UCR on their own are poor prognostic predictors of APO irrespective of fetal weight.
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http://dx.doi.org/10.1080/14767058.2021.1926977DOI Listing
June 2021

Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial.

Am J Obstet Gynecol 2021 09 3;225(3):308.e1-308.e14. Epub 2021 Apr 3.

BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia, Obstetrícia i Neonatologia Fetal i+D Fetal Medicine Research Center, Barcelona, Spain. Electronic address:

Background: In women with late preterm preeclampsia, the optimal time for delivery remains a controversial topic, because of the fine balance between the maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at highest risk for complications, in which case a selective, planned delivery may reduce the adverse maternal and perinatal outcomes.

Objective: This trial aimed to determine whether using an algorithm based on the maternal levels of placental growth factor in women with late preterm preeclampsia to evaluate the best time for delivery reduced the progression to preeclampsia with severe features without increasing the adverse perinatal outcomes.

Study Design: This parallel-group, open-label, multicenter, randomized controlled trial was conducted at 7 maternity units across Spain. We compared selective planned deliveries based on maternal levels of placental growth factor at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm preeclampsia from 34 to 36+6 weeks' gestation. The coprimary maternal outcome was the progression to preeclampsia with severe features. The coprimary neonatal outcome was morbidity at infant hospital discharge with a noninferiority hypothesis (noninferiority margin of 10% difference in incidence). Analyses were conducted according to intention-to-treat.

Results: Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to preeclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk, 0.5; 95% confidence interval, 0.33-0.76; P=.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted relative risk, 0.77; 95% confidence interval, 0.39-1.53; P=.45).

Conclusion: There is evidence to suggest that the use of an algorithm based on placental growth factor levels in women with late preterm preeclampsia leads to a lower rate of progression to preeclampsia with severe features and reduces maternal complications without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm preeclampsia to allow shared decision making about the timing of delivery.
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http://dx.doi.org/10.1016/j.ajog.2021.03.044DOI Listing
September 2021

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

Fetal Diagn Ther 2021 30;48(4):288-296. Epub 2021 Mar 30.

Department of Obstetrics and Gynecology, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Objective: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies.

Methods: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies.

Results: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation.

Conclusions: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.
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http://dx.doi.org/10.1159/000514378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117392PMC
March 2021

Maternal and perinatal outcomes in high compared to low risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection (phase 2): the World Association of Perinatal Medicine working group on coronavirus disease 2019.

Am J Obstet Gynecol MFM 2021 07 20;3(4):100329. Epub 2021 Feb 20.

Department of Obstetrics and Gynecology, Centre for High-Risk Pregnancy and Fetal Care, University of Chieti, Chieti, Italy (Dr Liberati, Dr Sebastiano, Dr Oronzi, Dr Cerra, and Dr Buca).

Background: It has still to be ascertained whether severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with worse maternal and fetal outcomes compared to low risk gestations.

Objective: This study aimed to evaluate maternal and perinatal outcomes in high- and low-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection.

Study Design: This was a multinational retrospective cohort study involving women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection from 76 centers from 25 countries in Europe, the United States, South America, Asia, and Australia from April 4, 2020, to October 28, 2020. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit, use of mechanical ventilation, or death. The secondary outcome was a composite measure of adverse perinatal outcome, including miscarriage, fetal loss, neonatal and perinatal death, and admission to the neonatal intensive care unit. All outcomes were assessed in high- and low-risk pregnancies. Pregnancies were considered high risk in case of either preexisting chronic medical conditions in pregnancy or obstetrical disorders occurring in pregnancy. The Fisher exact test and logistic regression analysis were used to analyze the data.

Results: A total of 887 singleton pregnancies who tested positive for severe acute respiratory syndrome coronavirus 2 infection using reverse transcription-polymerase chain reaction of nasal and pharyngeal swab specimens were included in the study. The risk of composite adverse maternal outcomes was higher in high-risk pregnancies than in low-risk pregnancies (odds ratio, 1.52; 95% confidence interval, 1.03-2.24; P=.035). In addition, women carrying high-risk pregnancies were at higher risk of hospital admission (odds ratio, 1.48; 95% confidence interval, 1.07-2.04; P=.002), presence of severe respiratory symptoms (odds ratio, 2.13; 95% confidence interval, 0.41-3.21; P=.001), admission to the intensive care unit (odds ratio, 2.63; 95% confidence interval, 1.42-4.88), and invasive mechanical ventilation (odds ratio, 2.65; 95% confidence interval, 1.19-5.94; P=.002). When exploring perinatal outcomes, high-risk pregnancies were at high risk of adverse perinatal outcomes (odds ratio, 1.78; 95% confidence interval, 0.15-2.72; P=.009). However, such association was mainly because of the higher incidence of miscarriage in high-risk pregnancies compared with that in low-risk pregnancies (5.3% vs 1.6%, P=.008); furthermore, there was no difference in other explored outcomes between the 2 study groups. At logistic regression analysis, maternal age (odds ratio, 1.12; 95% confidence interval, 1.02-1.22; P=.023) and high-risk pregnancy (odds ratio, 4.21; 95% confidence interval, 3.90-5.11; P<.001) were independently associated with adverse maternal outcomes.

Conclusion: High-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection were at higher risk of adverse maternal outcomes than low-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896113PMC
July 2021

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

Health Technol Assess 2020 12;24(72):1-252

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management.

Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers.

Design: This was an individual participant data meta-analysis of cohort studies.

Setting: Source data from secondary and tertiary care.

Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey.

Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia.

Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using and τ. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals.

Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia.

Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data.

Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings.

Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

Study Registration: This study is registered as PROSPERO CRD42015029349.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780127PMC
December 2020

Eculizumab in Early-Stage Pregnancy.

Kidney Int Rep 2020 Dec 10;5(12):2383-2387. Epub 2020 Oct 10.

Fetal Medicine Unit-Maternal and Child Health and Development Network, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute, Complutense University of Madrid, Madrid, Spain.

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http://dx.doi.org/10.1016/j.ekir.2020.09.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710878PMC
December 2020

Seroprevalence analysis of SARS-CoV-2 in pregnant women along the first pandemic outbreak and perinatal outcome.

PLoS One 2020 30;15(11):e0243029. Epub 2020 Nov 30.

Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.

Objectives: To evaluate the progression of the seroprevalence of SARS-CoV-2 in the pregnant population of the south of Madrid during the first wave of the COVID-19 pandemic. Secondarily we aimed to evaluate maternal and perinatal outcomes.

Study Design: Retrospective cohort study conducted at Hospital Universitario 12 de Octubre during weeks 10 to 19 of 2020, coinciding with the Spanish lockdown. We tested 769 serum samples obtained from routine serological testing during the first and third trimesters of pregnancy for specific IgG anti SARS-CoV-2 RBD and S proteins. RT-PCR tests were performed in suspected cases according to clinical practice. We compared maternal and perinatal outcomes in those with delivered pregnancies (n = 578) according to the presence or absence of specific IgG antibodies. Those with positive IgG were subdivided by the presence or absence of Covid-19 related symptoms at any time and the results of RT-PCR testing if performed. Therefore, we had 4 study groups: G1 (IgG negative), G2 (IgG positive, asymptomatic, RT-PCR testing negative or not done), G3 (IgG positive, symptomatic, RT-PCR testing negative or not done), and G4 (IgG positive, symptomatic, RT-PCR positive).

Results: Seropositivity increased from 0% to 21.4% (95% CI 11.8-31.0) during the study period, of which 27.9% had an asymptomatic course. Overall outcomes were favorable with a significant increased rate of preterm birth in G4 vs G1 (21.4% vs 6.7%) and cesarean/operative delivery (50% vs 26.9%). Asymptomatic and mild cases did not have differences regarding pregnancy course when compared to seronegative women. There were no documented cases of vertical or horizontal transmission.

Conclusion: Seroprevalence in pregnant women in southern Madrid went up to 21.4% of which 27.9% had an asymptomatic course. Overall perinatal results were favorable, especially in those asymptomatic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243029PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703887PMC
December 2020

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BMC Med 2020 11 2;18(1):302. Epub 2020 Nov 2.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting.

Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis.

Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%.

Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice.

Trial Registration: PROSPERO ID: CRD42015029349 .
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http://dx.doi.org/10.1186/s12916-020-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604970PMC
November 2020

Obstetric and pediatric growth charts for the detection of late-onset fetal growth restriction and neonatal adverse outcomes.

J Perinat Med 2021 Feb 7;49(2):216-224. Epub 2020 Oct 7.

Department of Obstetrics and Gynaecology, Fetal Medicine Unit-SAMID, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Objectives: Late-onset fetal growth restriction (FGR) has heterogeneous prenatal and postnatal diagnostic criteria. We compared the prenatal and postnatal diagnosis of late-onset FGR and their ability to predict adverse perinatal outcomes.

Methods: Retrospective cohort study of 5442 consecutive singleton pregnancies that delivered beyond 34 + 0 weeks. Prenatal diagnosis of FGR was based on customized fetal growth standards and fetal Doppler while postnatal diagnosis was based on a birthweight <3rd percentile according to newborn charts (Olsen's charts and Intergrowth 21st century programme). Perinatal outcomes were analyzed depending on whether the diagnosis was prenatal, postnatal or both.

Results: A total of 94 out of 5442 (1.7%) were diagnosed as late-onset FGR prenatally. Olsen's chart and Intergrowth 21st chart detected that 125/5442 (2.3%) and 106/5442 (2.0%) of infants had a birthweight <3rd percentile, respectively. These charts identified 35/94 (37.2%) and 40/94 (42.6%) of the newborns with a prenatal diagnosis of late-onset FGR. Prenatally diagnosed late-onset FGR infants were at a higher risk for hypoglycemia, jaundice and polycythemia. Both prenatally and postnatally diagnosed as late-onset FGR had a higher risk for respiratory distress syndrome when compared to non-FGR. The higher risks for intensive care admission and composite adverse outcomes were observed in those with a prenatal diagnosis of late-onset FGR that was confirmed after birth.

Conclusions: Current definitions of pre- and postnatal late-onset FGR do not match in more than half of cases. Infants with a prenatal or postnatal diagnosis of this condition have an increased risk of neonatal morbidity even if these diagnoses are not coincident.
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http://dx.doi.org/10.1515/jpm-2020-0210DOI Listing
February 2021

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

J Perinat Med 2020 11;48(9):950-958

Department of Obstetrics and Gynaecology, Ospedale di San Leonardo, Castellammare di Stabia, Italy.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.
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http://dx.doi.org/10.1515/jpm-2020-0355DOI Listing
November 2020

sFlt-1/PlGF ratio for the prediction of delivery within 48 hours and adverse outcomes in expectantly managed early-onset preeclampsia.

Pregnancy Hypertens 2020 Oct 15;22:17-23. Epub 2020 Jul 15.

Fetal Medicine Unit, Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016), Department of Obstetrics and Gynaecology, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital, 12 de Octubre (imas12). Av. de Córdoba, s/n, 28041 Madrid, Spain; Universidad Complutense de Madrid, Av. Séneca, 2, 28040 Madrid, Spain. Electronic address:

Objective: To analyze if sFlt-1/PlGF ratio is more useful than other parameters at diagnosis of early-onset (<34 weeks) preeclampsia (PE) in the prediction of delivery within 48 h and adverse maternal and perinatal outcomes.

Method: Observational retrospective study of a cohort of 76 singleton pregnancies with early-onset PE and expectant management. The predictive value of sFlt-1/PlGF ratio, blood pressure, proteinuria, creatinine, liver enzymes and platelets at diagnosis for delivery < 48 h and adverse outcomes was determined.

Results: Maternal and perinatal adverse outcomes occurred in 25/76 (32.9%) cases and 13/69 (18.8%) livebirths, respectively. Areas under the curve (AUC) for sFlt-1/PlGF ratio were 0.59 (95%CI 0.42-0.75) and 0.75 (95%CI 0.62-0.88) for maternal and perinatal complications, respectively. Mean (standard deviation) time to delivery for a sFlt-1/PlGF ratio > 655 vs. ≤ 655 was of 4.4 (7.5) vs. 12.1 (9.3) days, p < 0.01. Relative risk for delivery within 48 h for a sFlt-1/PlGF ratio > 655 was 5.3 (95% confidence interval 2.7-10.6), p < 0.01.

Conclusions: sFlt-1/PlGF ratio > 655 at diagnosis was associated with a 5-fold increased risk of delivery in ≤ 48 h. None of the parameters were good predictors of adverse maternal or perinatal outcomes.
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http://dx.doi.org/10.1016/j.preghy.2020.07.007DOI Listing
October 2020

SARS-CoV-2 in pregnancy: characteristics and outcomes of hospitalized and non-hospitalized women due to COVID-19.

J Matern Fetal Neonatal Med 2020 Jul 20:1-7. Epub 2020 Jul 20.

Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre. Instituto de Investigación Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain.

Background: There is little evidence about how novel coronavirus (SARS-CoV-2) affects pregnant women and their newborns. Comparisons with other members of the coronavirus family responsible for severe acute respiratory syndrome (SARS) have been done to predict maternal and neonatal outcomes; however, more information is required to establish clinical patterns, disease evolution and pregnancy prognosis in this group of patients.

Methods: This paper is reporting a series of 91 women diagnosed with SARS-CoV-2 infection during pregnancy and puerperium. The analysis showed that 40 patients developed pneumonia, bilateral in most cases, with a 46.2% rate of hospitalization and 4 patients requiring intensive care unit (ICU) admission. In confront with previous publications, we have found a higher rate of coronavirus disease (COVID-19) severe forms, even when compared to non-pregnant women with the same baseline characteristics. We have analyzed the demographic characteristics, pregnancy-related conditions and presenting symptoms to identify features that could determine which patients will need hospitalization because of COVID-19 (Group 1-G1) and those who not (Group 2-G2). We have found that obesity and Latin-American origin behave as risk factors: OR: 4.3; 95% CI: 1.4-13.2, and OR: 2.6; 95% CI: 1.1 - 6.2, respectively. Among the 23 patients that delivered with active SARS-CoV-2, the overall rate of cesarean section (CS) and preterm birth were 52.2% and 34.8%, respectively, but we observed that the rate of CS was even higher in G1 compared to G2: 81.8% versus 25%,  = .012. However, prematurity was equally distributed in both groups and only one preterm delivery was determined by poor maternal condition. There were no deaths among the patients neither their newborns.

Conclusion: In conclusion, the results of our cohort reveal that SARSC-CoV-2 infection may not behave as mild as suggested during pregnancy, especially when factors as obesity or Latin-American origin are present. No evidence of late vertical transmission was noticed but prematurity and high CS rate were common findings, although it is difficult to establish any causality between these conditions and COVID-19. Further evidence is required to establish if pregnancy itself can lead to severe forms of COVID-19 disease and whether risk factors for the general population are applicable to obstetric patients. Until larger studies are available, pregnant women should be monitored carefully to anticipate severe complications.
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http://dx.doi.org/10.1080/14767058.2020.1793320DOI Listing
July 2020

Universal screening for SARS-CoV-2 before labor admission during Covid-19 pandemic in Madrid.

J Perinat Med 2020 Nov;48(9):981-984

Fetal Medicine Unit - Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016), Department of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain.

Objectives Asymptomatic women admitted to labor may act as silent spreaders of COVID-19. Therefore, universal screening at admission has been proposed. The objective of the study was to evaluate the performance of universal screening for SARS-CoV-2 using quantitative reverse transcription polymerase-chain-reaction (qRT-PCR) tests in women admitted to labor. Methods Observational retrospective study of a cohort of pregnant women admitted to labor and delivery between April 8 and May 2, 2020 in a large maternity in Madrid. SARS-CoV-2 screening with qRT-PCR from combined nasopharyngeal and oropharyngeal swabs was carried out systematically. Screening performance was described. Results We attended 212 deliveries. Nine cases with COVID-19 diagnosis before admission were excluded. In the remaining 203 women, seven referred COVID-19-related symptoms but only one had a positive qRT-PCR. Among the 194 asymptomatic women, only one case (0.5%) was positive. Conclusions The percentage of positive tests in asymptomatic women admitted to delivery was only 0.5% during the post-peak period.
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http://dx.doi.org/10.1515/jpm-2020-0236DOI Listing
November 2020

Maternal and Perinatal Outcomes Associated With Extremely High Values for the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio.

J Am Heart Assoc 2020 04 4;9(7):e015548. Epub 2020 Apr 4.

Fetal Medicine Unit-SAMID Department of Obstetrics and Gynaecology Hospital Universitario 12 de Octubre Instituto de Investigación Hospital 12 de Octubre (imas12) Universidad Complutense de Madrid Madrid Spain.

Background There is little knowledge about the significance of extremely high values (>655) for the ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor). We aim to describe the time-to-delivery interval and maternal and perinatal outcomes when such values are demonstrated while assessing suspected or confirmed placental dysfunction based on clinical or sonographic criteria. Methods and Results A multicenter retrospective cohort study was performed on 237 singleton gestations between 20+0 and 37+0 weeks included at the time of first demonstrating a sFlt-1/PlGF ratio >655. Clinicians were aware of this result, but standard protocols were followed for delivery indication. Main outcomes were compared for women with and without preeclampsia at inclusion. In those with preeclampsia (n=185, of whom 77.3% had fetal growth restriction), severe preeclampsia features and fetal growth restriction in stages III or IV were present in 49.2% and 13.5% cases, respectively, at inclusion and in 77.3% and 28.6% cases, respectively, at delivery. In the group without preeclampsia (n=52, 82.7% had fetal growth restriction), these figures were 0% and 30.8%, respectively, at inclusion and 21.2% and 50%, respectively, at delivery. Interestingly, 28% of women without initial preeclampsia developed it later. The median time to delivery was 4 days (interquartile range: 1-6 days) and 7 days (interquartile range: 3-12 days), respectively (<0.01). Overall, perinatal mortality was 62.1% before 24 weeks; severe morbidity surpassed 50% before 29 weeks but became absent from 34 weeks. Maternal serious morbidity was high at any gestational age. Conclusions An sFlt-1/PlGF ratio >655 is almost invariably associated with preeclampsia or fetal growth restriction that progresses rapidly. In our tertiary care settings, we observed that maternal adverse outcomes were high throughout gestation, whereas perinatal adverse outcomes diminished as pregnancy advanced.
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http://dx.doi.org/10.1161/JAHA.119.015548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428600PMC
April 2020

Correlation of Kryptor and Elecsys® immunoassay sFlt-1/PlGF ratio on early diagnosis of preeclampsia and fetal growth restriction: A case-control study.

Pregnancy Hypertens 2020 Apr 3;20:44-49. Epub 2020 Mar 3.

Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain.

Objectives: The measurement of the soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio on automated platforms has improved the detection of preeclampsia and fetal growth restriction (PE/FGR). The cut-off points of >38 and ≥85 has been defined for "rule in" and "aid in diagnosis", respectively, using the Elecsys® platform. We aimed to compare the performance of these cut-offs between the Elecsys® and Kryptor platforms at 24-28 weeks.

Study Design: Observational case-control study of singleton pregnancies at high risk for PE/FGR and sFlt-1/PlGF measurement at 24-28 weeks' gestation: 21 cases (9 early PE/FGR with delivery <32 weeks) were 1:1 matched for body mass index and parity with 21 controls. Correlations of the sFlt-1, PlGF and sFlt-1/PlGF values and diagnostic accuracy of the >38 and ≥85 cutoffs for early and late PE/FGR using Elecsys® and Kryptor assays were evaluated.

Main Outcome Measures: PE/FGR cases showed significantly higher median (IQR) sFlt-1/PlGF values at 24-28 weeks vs. controls, using both Elecsys® and Kryptor platforms: 55 (13-254) and 97 (13-530) vs. 4.1 (2.0-6.5) and 3.9 (1.8-7.7), respectively. The sFlt-1/PlGF correlation between both methods was excellent (r = 0.95) although lower PlGF and higher sFlt-1/PlGF values were observed with Kryptor. The higher diagnostic accuracy was obtained for early PE/FGR with the ≥85 cutoff (95.2%; 95%CI: 83.8-99.4%) in both platforms.

Conclusion: sFlt-1/PlGF measurements correlates well between Elecsys® and Kryptor platforms, and the cutoffs of >38 and ≥85 exhibit high diagnostic accuracy for assessing early PE/FGR at 24-28 weeks with both methods.
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http://dx.doi.org/10.1016/j.preghy.2020.03.002DOI Listing
April 2020

Prediction of Perinatal Mortality in Ebstein's Anomaly Diagnosed in the Second Trimester of Pregnancy.

Fetal Diagn Ther 2020 4;47(8):604-614. Epub 2020 Feb 4.

Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Objectives: Firstly, to describe the outcome of a series of fetuses with Ebstein's anomaly (EA) and, secondly, to study the utility of different second-trimester echocardiographic parameters to predict fetal and neonatal mortality.

Methods: 39 fetuses with EA diagnosed between 18 and 28 weeks of gestation were included. Fetal echocardiography included the cardiothoracic ratio (CTR); right atrial (RA) area index; displacement of the tricuspid valve (TV); tricuspid regurgitation; pulmonary artery; and ductus arteriosus flow characteristics. Additionally, 2 novel parameters were obtained: the relative RA area ratio (RA area/cardiac area) and the TV displacement index (TVDI, TV displacement distance/longi-tudinal diameter of the left ventricle). Correlation between the echocardiographic variables and the primary outcome of perinatal mortality or survival at 1 year of life was evaluated.

Results: From the initial cohort, 8 cases were excluded due to complex congenital heart defects. Termination of pregnancy (TOP) was performed in 15 cases, and fetal death was diagnosed in 3 cases. In the live-born cohort of 13 patients, 4 died in the neonatal period, yielding a perinatal survival rate of 29 and 56%, respectively, after excluding TOP cases. Compared with survivors, nonsurvivors showed a significantly higher CTR (56.7 ± 16.2 vs. 42.6 ± 8.6; p = 0.04), relative RA area ratio (0.39 ± 0.13 vs. 0.25 ± 0.05; p = 0.01), and TVDI (0.62 ± 0.17 vs. 0.44 ± 0.12; p = 0.03) at diagnosis. The best model to predict perinatal mortality was obtained by using a scoring system which included the relative RA area ratio and TVDI (AUC 0.905 [95% CI 0.732-1.000]).

Conclusions: Fetuses with a relative RA area ratio ≥0.29 and TVDI ≥0.65 at the second trimester have the highest risk of dying in the perinatal stage.
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http://dx.doi.org/10.1159/000504979DOI Listing
June 2021

New Insights into the Anterior Complex.

Fetal Diagn Ther 2020 13;47(6):514-518. Epub 2020 Jan 13.

Fetal Medicine Unit - Maternal and Child Health and Development Network, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Objective: To introduce visualization of the germinal matrix (GM), external angle of the frontal horn, and periventricular white matter while evaluating the anterior complex (AC) during basic ultrasound assessment of the fetal brain.

Case Presentations: This is a retrospective observational study of healthy women with singleton pregnancies, with no increased risk of fetal central nervous system anomalies, attending routine ultrasound screening at 20-32 weeks' gestation. Seventeen cases are presented in which an abnormal aspect of the GM or external angle of the frontal horn or periventricular white matter on AC evaluation has allowed a prenatal diagnosis of peri-intraventricular hemorrhage, subependymal cysts, connatal cysts, periventricular venous hemorrhagic infarction, and white matter injury.

Conclusion: An extended AC evaluation could significantly improve the -diagnosis of hemorrhagic/cystic/hypoxic-ischemic lesions during the performance of a basic ultrasound study of the fetal brain.
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http://dx.doi.org/10.1159/000504980DOI Listing
April 2021

Angiogenesis biomarkers for the prediction of severe adverse outcomes in late-preterm preeclampsia.

Pregnancy Hypertens 2020 Jan 9;19:74-80. Epub 2020 Jan 9.

Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain.

Objectives: The optimal timing for delivery in non-severe late-preterm (34 + 0-36 + 6 weeks) preeclampsia (PE) is uncertain. It is attempted to reach term pregnancy safely but current clinical and analytical parameters fail to determine which cases will develop severe features that require preterm delivery. We aim to establish if angiogenic biomarkers may identify cases that would benefit from earlier delivery.

Study Design: Prospective case-control study of 96 women (n = 48 controls and n = 48 cases with PE) with maternal determinations of the sFlt-1/PlGF ratio between 34 + 0 and 36 + 6 weeks. The PE group was classified in two groups based on the need (n = 26) or not (n = 22) for preterm delivery due to criteria of severity. Diagnostic accuracy of these biomarkers for predicting preterm delivery for severe PE was evaluated.

Main Outcome Measures: Women with PE showed higher median sFlt-1/PlGF ratio than controls (122 vs 5, p < 0.01) and lower PlGF MoM (0.7 vs 1.0, p < 0.01). However, these differences did not remain when both PE subgroups were compared. Diagnostic performance of the sFlt-1/PlGF ratio and PlGF at different cut-offs was poor for detecting PE requiring delivery before term.

Conclusions: Angiogenic biomarkers are not useful to predict which late-preterm PE cases will develop severe features that require preterm delivery.
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http://dx.doi.org/10.1016/j.preghy.2019.12.004DOI Listing
January 2020

Prognostic Factors of Successful Cervical Ripening and Labor Induction in Late-Onset Fetal Growth Restriction.

Fetal Diagn Ther 2020 13;47(7):536-544. Epub 2019 Dec 13.

Fetal Medicine Unit, Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016), Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain,

Objective: The aim of this work was to identify independent risk factors influencing the achievement of vaginal delivery among women undergoing labor induction for late-onset fetal growth restriction (FGR).

Methods: This was a retrospective cohort study of 201 singleton pregnancies with late-onset FGR (diagnosed >32 + 0 weeks) that required labor induction with cervical ripening from 37 + 0 weeks, either with dinoprostone (from 2014 to 2015) or Foley balloon (from 2016 to 2018). Independent factors for successful vaginal delivery were identified. A prediction model of vaginal delivery with the identified factors was made using logistic regression and bootstrapping with 1,000 re-samples performed for bias correction.

Results: Perinatal results were more favorable in the vaginal delivery group, with significantly lower neonatal admission rates (4.0 vs. 13.7%) and lower composite neonatal morbidity (4.0 vs. 15.7%). The labor induction method (Foley balloon), higher cerebro-placental ratio, lower pre-gestational BMI, and absence of pre-eclampsia were identified as independent factors associated to vaginal delivery. The area under the curve of the model was of 0.75 (95% CI 0.70-0.79).

Conclusions: The use of a Foley balloon is the only modifiable risk factor to improve the chances of vaginal delivery when attempting induction of labor in singleton pregnancies with late-onset FGR.
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http://dx.doi.org/10.1159/000503390DOI Listing
May 2021

A more accurate prediction to rule in and rule out pre-eclampsia using the sFlt-1/PlGF ratio and NT-proBNP as biomarkers.

Clin Chem Lab Med 2020 02;58(3):399-407

Clinical Biochemistry, Laboratory Medicine, Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011 Oviedo, Spain.

Background The management of potential pre-eclamptic patients using the soluble FMS-like tyrosine kinase 1 (sFlt-1)/ placental growth factor (PlGF) ratio is characterised by frequent false-positive results. Methods A retrospective cohort study was conducted to identify and validate cut-off values, obtained using a machine learning model, for the sFlt-1/PlGF ratio and NT-proBNP that would be predictive of the absence or presence of early-onset pre-eclampsia (PE) in singleton pregnancies presenting at 24 to 33 + 6 weeks of gestation. Results For the development cohort, we defined two sFlt-1/PlGF ratio cut-off values of 23 and 45 to rule out and rule in early-onset PE at any time between 24 and 33 + 6 weeks of gestation. Using an sFlt-1/PlGF ratio cut-off value of 23, the negative predictive value (NPV) for the development of early-onset PE was 100% (95% confidence interval [CI]: 99.5-100). The positive predictive value (PPV) of an sFlt-1/PlGF ratio >45 for a diagnosis of early-onset PE was 49.5% (95% CI: 45.8-55.6). When an NT-proBNP value >174 was combined with an sFlt-1/PlGF ratio >45, the PPV was 86% (95% CI: 79.2-92.6). In the validation cohort, the negative and positive values were very similar to those found for the development cohort. Conclusions An sFlt-1/PlGF ratio <23 rules out early-onset PE between 24 and 33 + 6 weeks of gestation at any time, with an NPV of 100%. An sFlt-1/PlGF ratio >45 with an NT-proBNP value >174 significantly enhances the probability of developing early-onset PE.
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http://dx.doi.org/10.1515/cclm-2019-0939DOI Listing
February 2020

Obstetric and pediatric growth charts for the detection of fetal growth restriction and neonatal adverse outcomes in preterm newborns before 34 weeks of gestation.

J Matern Fetal Neonatal Med 2021 Apr 9;34(7):1112-1119. Epub 2019 Jul 9.

Department of Obstetrics and Gynaecology, Fetal Medicine Unit, SAMID, University Hospital, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Introduction: Identification of fetal growth-restricted (FGR) infants depends on the fetal or newborn charts used to identify them. We aimed to compare the prenatal and postnatal diagnosis of FGR and their ability to predict adverse perinatal outcomes.

Methods: Observational retrospective cohort study of 95 consecutive mother-infant pairs with preterm birth between 24 and 34 weeks (study period: January 2014 to December 2015). Prenatal sonographic diagnosis of FGR, based on customized fetal growth standards and fetal Doppler, was compared with the postnatal diagnosis of FGR based on a birthweight < 3rd percentile according to newborn charts (International Newborn size references for the Intergrowth twenty-first century program, and Olsen's charts). Neonatal mortality and adverse neonatal outcomes were compared among groups.

Results: In 23/95 (24%) cases a prenatal diagnosis of early FGR was made. Postnatal FGR was confirmed in 11/23 (48%) cases using Olsen's charts and 8/23 (35%) using Intergrowth 21st charts. One postnatal FGR case was missed by prenatal ultrasound. Bronchopulmonary dysplasia, sepsis and hypoglycemia were more frequent in pre- and postnatal FGR versus non-FGR. After adjusting for gestational age and sex, only an increased relative risk of hypoglycemia (2.0, 95%CI 1.0-2.8) was observed in infants with pre- and postnatal FGR diagnosis. Nonsignificant differences on neonatal outcomes were identified between prenatal FGR cases with normal birthweight and the non-FGR group.

Conclusion: Only prenatal FGR cases in which a birthweight below the third percentile is confirmed by means of postnatal charts (Olsen or Intergrowth standard) are at higher risk of adverse postnatal outcome.
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http://dx.doi.org/10.1080/14767058.2019.1626368DOI Listing
April 2021

Impact of cell-free fetal DNA on invasive prenatal diagnostic tests in a real-world public setting.

J Perinat Med 2019 Jul;47(5):547-552

Fetal Medicine Unit, Maternal and Child Health and Development Network (SAMID), Department of Obstetrics and Gynaecology, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (Imas12), Universidad Complutense de Madrid, Madrid, Spain.

Objective To evaluate the impact of cell-free fetal DNA (cfDNA) test on the number of invasive tests carried out in a public hospital that does not include this test in its services. Methods This was a retrospective cohort study in singleton pregnancies with a high risk (>1:270) on the first-trimester screening for aneuploidies. The options of performing an invasive test or a cfDNA test were explained to all women, the latter being especially recommended to those with a 1:50-1:270 risk (Group 1). If the risk was >1:50 (Group 2), or nuchal translucency (NT) was >99th percentile or there were major malformations (Group 3), invasive test was recommended. Results A total of 755 of 14,398 (5.2%) cases had a high-risk first-trimester screening, of whom 46 cases were excluded due to incomplete follow-up. In the remaining 709 cases, the percentage of aneuploidies was 9.9% (70 cases) and 110 opted for a cfDNA test (15.5%). There were two true-positive results of cfDNA (one in Group 2 and another in Group 3). In Group 1, 67.4% [95% confidence interval (CI) 60.0%-72.1%, P < 0.01] fewer invasive procedures were performed in those who opted for a cfDNA test, without having false negatives. Conclusion Pregnant women with a 1:50-1:270 risk who opt for cfDNA save two out of three invasive tests, without affecting the aneuploidy detection rate.
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http://dx.doi.org/10.1515/jpm-2018-0410DOI Listing
July 2019

Is it possible to predict late antepartum stillbirth by means of cerebroplacental ratio and maternal characteristics?

J Matern Fetal Neonatal Med 2020 Sep 23;33(17):2996-3002. Epub 2019 Jan 23.

Servicio de Obstetricia y Ginecología, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

To examine the potential value of fetal ultrasound and maternal characteristics in the prediction of antepartum stillbirth after 32 weeks' gestation. This was a retrospective multicenter study in Spain. In 29 pregnancies, umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), estimated fetal weight (EFW), and maternal characteristics were recorded within 15 days prior to a stillbirth. The values of UA PI, MCA PI, and CPR were converted into multiples of the normal median (MoM) for gestational age and the EFW was expressed as percentile according to a Spanish reference range for gestational age. Data from the 29 pregnancies with stillbirths and 2298 control pregnancies resulting in livebirths were compared and multivariate logistic regression analysis was used to determine significant predictors of stillbirth. The only significant predictor of stillbirth was CPR (OR = 0.161, 95% confidence interval [CI] 0.035, 0.654;  = .014); the area under the receiver operating characteristics curve was 0.663 (95% CI 0.545, 0.782) and the detection rate (DR) was 32.14% at a 10% false-positive rate (FPR). In addition, when we included MCA and UA PI MoM instead of CPR, only MCA PI MoM was significant (OR = 0.104, 95% confidence interval [CI] 0.013, 0.735;  = .029), with similar prediction abilities (area under the curve (AUC) 0.645, DR 28.6%, FPR 10%). The CPR and MCA PI are predictors of late stillbirth but the performance of prediction is poor.
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http://dx.doi.org/10.1080/14767058.2019.1566900DOI Listing
September 2020

Labor Induction in Late-Onset Fetal Growth Restriction: Foley Balloon versus Vaginal Dinoprostone.

Fetal Diagn Ther 2019 24;46(1):67-74. Epub 2018 Sep 24.

Fetal Medicine Unit - Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016), Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Objective: To compare vaginal delivery rate and perinatal outcomes of fetuses with late-onset fetal growth restriction (FGR) undergoing labor induction, depending on the method for cervical ripening (dinoprostone vs. Foley balloon).

Material And Methods: We conducted a retrospective cohort study of 148 consecutive singleton gestations diagnosed with stage I late-onset FGR and Bishop score < 7, in which labor induction was indicated at ≥37 + 0 weeks. Before January 2016, cervical ripening was achieved with 10 mg of vaginal dinoprostone (n = 77) and afterwards with Fo-ley balloon (n = 71). Logistic regression analysis was used to estimate the association between mode of delivery and induction method.

Results: Foley balloon had lower percentages of uterine tachysystole with fetal repercussion (4.2 vs. 16.9%, p = 0.01) and cesarean sections for suspected fetal distress (7.0 vs. 26.0%, p < 0.01) when compared to dino-prostone. Lower percentages of cesarean sections were found in the Foley balloon group (15.5 vs. 37.7%, p < 0.01). The odds ratio and adjusted odds ratio of cesarean section with dinoprostone were of 3.3 and 4.4, respectively. Perinatal mortality and severe morbidity were null in both groups.

Conclusion: The use of Foley balloon resulted in a higher percentage of vaginal delivery compared to dinoprostone, with a favorable safety profile in both groups.
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http://dx.doi.org/10.1159/000491784DOI Listing
January 2020

Prognostic value of the aortic isthmus Doppler assessment on late onset fetal growth restriction.

J Perinat Med 2019 Feb;47(2):212-217

Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Background As conflicting results have been reported about the association of reversed flow on the aortic isthmus (AoI) and adverse perinatal results in fetal growth restriction (FGR), we aim to compare perinatal outcomes (including tolerance to labor induction) of late-onset FGR between those with anterograde and reversed AoI flow. Methods This was an observational retrospective cohort study on 148 singleton gestations diagnosed with late-onset FGR (diagnosis ≥32+0 weeks), with an estimated fetal weight (EFW) <10th centile and mild fetal Doppler alteration: umbilical artery (UA) pulsatility index (PI) >95th centile, middle cerebral artery (MCA)-PI <5th centile or cerebral-placental ratio <5th centile. Anterograde AoI flow was present in n=79 and reversed AoI flow in n=69. Delivery was recommended from 37 weeks in both groups. Perinatal results were compared between the groups. Results The global percentage of vaginal delivery of fetuses with anterograde and reversed blood flow was 55.7% vs. 66.7% (P=0.18) and the percentage of cesarean section (C-section) for non-reassuring fetal status was 12.7% vs. 15.9% (P=0.29), respectively. When evaluating those that underwent labor induction, the vaginal delivery rate was 67.9% vs. 77.2% (P=0.17), respectively. There were no significant differences regarding any other perinatal variables and there were no cases of severe morbidity or mortality. Conclusion We observed that the presence of reversed AoI flow does not worsen perinatal outcomes on fetuses with late-onset growth restriction with mild Doppler alterations. Attempt of labor induction is feasible in these fetuses regardless of the direction of AoI flow.
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http://dx.doi.org/10.1515/jpm-2018-0185DOI Listing
February 2019

Fetal Biometry and Doppler Study for the Assessment of Perinatal Outcome in Stage I Late-Onset Fetal Growth Restriction.

Fetal Diagn Ther 2018 4;44(4):264-270. Epub 2018 May 4.

Objective: To compare perinatal outcomes on fetuses classified as stage I late-onset fetal growth restriction (FGR) depending on the estimated fetal weight (EFW) centile category and the fetal and maternal Doppler study.

Material And Methods: Retrospective cohort study on 131 cases of stage I late-onset FGR (diagnosis ≥32+0 weeks), defined as: EFW < 3rd centile and normal Doppler (G1) or EFW < 10th centile and mean uterine artery pulsatility index (PI) > 95th centile (G2) or EFW < 10th centile and mild fetal Doppler alteration: umbilical artery PI > 95th centile, middle cerebral artery PI < 5th centile, or cerebroplacental ratio < 5th centile (G3). All groups were compared to their perinatal results.

Results: There were 37, 30, and 64 cases in G1, G2, and G3, respectively. G1 and G2 showed lower percentages of cesarean section when compared with G3 (18.4, 22.5, and 45.3% (p < 0.01), respectively), being attributable to an excess of cesarean sections for non-reassuring fetal status. These differences remained when definitive birth weight centile was above that considered to define FGR, being 5.9, 12.5, and 41.8% (p < 0.01), respectively.

Discussion: In stage I late-onset FGR fetuses, abnormal fetal Doppler is associated with a poorer tolerance to vaginal delivery, even when the birth weight is > 10th centile.
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http://dx.doi.org/10.1159/000485124DOI Listing
March 2019

Aortopulmonary Window, Absent Ductus, and Left Subclavian Artery Isolation.

Rev Esp Cardiol (Engl Ed) 2018 Aug 31;71(8):669. Epub 2017 Oct 31.

Unidad de Medicina Fetal-SAMID, Departamento de Obstetricia y Ginecología, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre (imas12), Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.

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http://dx.doi.org/10.1016/j.rec.2017.10.007DOI Listing
August 2018

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

Fetal Diagn Ther 2018 19;43(2):81-89. Epub 2017 Jul 19.

Fetal Medicine Unit, Maternal and Child Health and Development Network (SAMID-RD12/0026/0016), Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Department of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain.

Preeclampsia (PE) is involved in a group of obstetrical conditions closely related by the presence of placental dysfunction (PD), which also includes intrauterine growth restriction and placental abruption. The timely and accurate recognition and management of PE are often challenging because diagnostic criteria are still based on nonspecific signs and symptoms and because common severity criteria correlate poorly with adverse maternal and fetal outcomes. The discovery of the role of angiogenesis-related factors - soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) - in the underlying pathophysiology of PD has marked an important step for improving its early diagnosis and prognosis assessment before gestational week 34. Nowadays, an sFlt-1/PlGF ratio cutoff level of ≤38 is widely accepted for ruling out PE in patients with suspicion of the disease, and its use is cost-effective. However, the evidence is more limited regarding the management and prognosis of women with an abnormally high sFlt-1/PlGF ratio. This review summarizes the current evidence of the clinical application of the sFlt-1/PlGF ratio for the diagnosis and prognosis assessment of PE and points out the next challenges for these biomarkers, including their role as target for the development and monitoring of new therapies.
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http://dx.doi.org/10.1159/000477903DOI Listing
August 2018

Chemical Pathways of Corticosteroids, Industrial Synthesis from Sapogenins.

Authors:
Ignacio Herráiz

Methods Mol Biol 2017 ;1645:15-27

Research and Development Department, Gadea Pharmaceutical Group, A Division of Albany Molecular Research Inc. (AMRI), Parque Tecnológico de Boecillo, Parcela 105, Boecillo, 47151, Valladolid, Spain.

Corticosteroids are products of high industrial and commercial importance. There are dozens of different synthesis published for all of them. Some are coming from academia and some from industry. Here, industrial processes for the synthesis of prednisone, prednisolone, hydrocortisone, dexamethasone, betamethasone, and methylprednisolone are described. The starting material is diosgenin and the desired molecules are reached due to a good combination of chemistry and biotechnology that was developed along the second part of the twentieth century.
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http://dx.doi.org/10.1007/978-1-4939-7183-1_2DOI Listing
April 2018
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