Clinical outcomes and antibody transfer in a cohort of infants with in utero or perinatal exposure to SARS-CoV-2 (Coronascope Study).

We aimed to describe the outcomes, focusing on the hearing and neurological development, of infants born to mothers with COVID-19 during pregnancy and to evaluate the persistence of maternal antibodies in the first months of life. An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers with COVID-19 during pregnancy between March and September 2020 was conducted. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on nasopharyngeal swab, and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age. Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected, and neurodevelopment was normal in 96% of the infants (median Z score: 0). CONCLUSION: In this cohort, the majority of infants born to mothers with COVID-19 during pregnancy were healthy infants with a normal cUS, no hearing loss, and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up. WHAT IS KNOWN: • Hearing loss and neurodevelopmental delay in infants born to mothers with COVID-19 during pregnancy has been suggested, although data is inconsistent. Maternal antibody transfer seems to be high, with a rapid decrease during the first weeks of life. WHAT IS NEW: • Most infants born to mothers with COVID-19 during pregnancy had normal hearing screening, cranial ultrasound, and neurodevelopmental status at 12 months of life. Antibodies against SARS-CoV-2 were only detected in 50% of the infants at two months of life.

Natural history and mid-term neurodevelopmental outcome of fetuses with isolated mild ventriculomegaly diagnosed in the second half of pregnancy.

INTRODUCTION: Prenatal diagnosis and counseling of isolated ventriculomegaly (VM) represent a considerable challenge. We aimed to analyze the intrauterine evolution, associated anomalies, and neurodevelopmental outcome using the Battelle Development Inventory (BDI) of fetuses with an initial diagnosis of isolated mild VM. MATERIAL AND METHODS: Retrospective cohort study of fetuses diagnosed with mild isolated VM (10 -12 mm) between 2012 and 2016 in a tertiary hospital. In 2018, parents were invited to complete the structured BDI test for the neurodevelopmental evaluation of their children in five domains (personal-social skills, adaptive behavior, psychomotor ability, communication, and cognition). Results exceeding two standard deviations were considered abnormal and referred to an expert neuropediatrician. RESULTS: We identified 43 cases of mild isolated VM. In 5 (11%), structural abnormalities were detected during prenatal follow-up, being related to non-regressive forms (p = .01) and bilateral VM (p = .04). The BDI test was completed by 19/43 (44%). The global score was abnormal in 10/19 (53%). Of them, the neuropediatrician confirmed a neurodevelopmental delay solely in 3 cases that had already been diagnosed with neurological disorders. The most affected domains were gross motor skills (63%), personal-social (63%), and adaptive domains (47%). Communicative and cognitive areas were abnormal in 26% of cases. CONCLUSION: In fetuses with isolated mild VM detected in the second half of pregnancy, 53% had an abnormal BDI test at 2-6 years, but a neurological disorder was only confirmed in the 30% of them.

Common Arterial Trunk in Fetal Life: Accuracy of Diagnosis and Prediction of Outcome.

INTRODUCTION: Common arterial trunk (CAT) is a congenital heart disease with significant perinatal mortality in which diagnostic agreement remains low. METHODS: We conducted a retrospective cohort study on fetuses with suspected CAT. Diagnostic accuracy was tested considering gold-standard postnatal ultrasound or necropsy. Prenatal sonographic markers were evaluated by logistic regression for perinatal survival. RESULTS: There were 79 fetuses with suspected CAT, and 55 cases had available necropsy/postnatal ultrasound confirming the study population. The diagnostic accuracy was 90.9% for CAT and 83.6% at a subtype level. In those with a confirmed diagnosis and intention-to-treat (n = 28) composite early mortality (intrauterine, presurgical, and early surgery) was of 25%, 10.5% in isolated cases. The OR for early-mortality of isolated cases was 0.13 (95% confidence interval [CI]: 0.03-0.75). After adjusting for isolated cases, the only prognostic prenatal markers of perinatal mortality were a dysplastic truncal valve OR 7.78 (95% CI: 1.23-49.13) and a stenotic flow OR 8.48 (95% CI: 1.40-51.10). CONCLUSION: CAT is a condition that if evaluated by experts, can be diagnosed with a high degree of accuracy. It remains an entity with high perinatal mortality. Its most important prognostic factor is its association with other anomalies. In isolated cases, the presence of a dysplastic truncal valve and a stenotic flow increase the chances of perinatal death.

Prediction of Delivery Within 7 Days After Diagnosis of Early Onset Preeclampsia Using Machine-Learning Models.

Background: Early onset preeclampsia (eoPE) is a hypertensive disorder of pregnancy with endothelial dysfunction manifested before 34 weeks where expectant management is usually attempted. However, the timing of hospitalization, corticosteroids, and delivery remain a challenge. We aim to develop a prediction model using machine-learning tools for the need for delivery within 7 days of diagnosis (model D) and the risk of developing hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome or abruptio placentae (model HA). Materials and Methods: A retrospective cohort of singleton pregnancies with eoPE and attempted expectant management between 2014 and 2020. A Mono-objective Genetic Algorithm based on supervised classification models was implemented to develop D and HA models. Maternal basal characteristics and data gathered during eoPE diagnosis: gestational age, blood pressure, platelets, creatinine, transaminases, angiogenesis biomarkers (soluble fms-like tyrosine kinase-1, placental growth factor), and ultrasound data were pooled for analysis. The most relevant variables were selected by bio-inspired algorithms. We developed basal models that solely included demographic characteristics of the patient (D1, HA1), and advanced models adding information available at diagnosis of eoPE (D2, HA2). Results: We evaluated 215 eoPE cases and 47.9% required delivery within 7 days. The median time-to-delivery was 8 days. Basal models were better predicted by K-nearest-neighbor in D1, which had a diagnostic precision of 0.68 ± 0.09, with 63.6% sensitivity (Sn), 71.4% specificity (Sp), 70% positive predictive value (PPV), and 65.2% negative predictive value (NPV) using 13 variables and HA1 of 0.77 ± 0.09, 60.4% Sn, 80% Sp, 50% PPV, and 87.9% NPV. Models at diagnosis were better developed by support vector machine (SVM) using 18 variables, where D2's precision improved to 0.79 ± 0.05 with 77.3% Sn, 80.1% Sp, 81.5% PPV, and 76.2% NPV, and HA2 had a precision of 0.79 ± 0.08 with 66.7% Sn, 82.8% Sp, 51.6% PPV, and 90.3% NPV. Conclusion: At the time of diagnosis of eoPE, SVM with evolutionary feature selection process provides good predictive information of the need for delivery within 7 days and development of HELLP/abruptio placentae, using maternal characteristics and markers that can be obtained routinely. This information could be of value when assessing hospitalization and timing of antenatal corticosteroid administration.

Retos en el diagnóstico prenatal de coartación de aorta: actualización y perspectiva actual / Challenges associated with the prenatal diagnosis of aortic coarctation: update and current perspectives

Resumen La coartación de aorta es una cardiopatía congénita frecuente y potencialmente mortal. Su diagnóstico prenatal es un reto, ya que está dificultado por características inherentes a la circulación fetal, siendo relativamente bajas sus tasas de detección (30-50%). A diferencia de lo que sucede con otras cardiopatías congénitas, el diagnóstico prenatal de la coartación de aorta es en la mayoría de los casos solo de sospecha y únicamente podrá confirmarse de forma posnatal. Su identificación es de gran importancia, ya que mejora el pronóstico neonatal, y se basa sobre todo en la visualización de signos indirectos, como asimetría de cavidades o grandes vasos, con dominancia derecha. La principal limitación de estos es su bajo valor predictivo positivo, en especial en edades gestacionales tardías. Existen otros signos directos con mayor especificidad, como la hipoplasia de arco, el cociente istmo/ductus o el shelf contraductal, que en ocasiones solo son evidentes en el tercer trimestre dado el carácter evolutivo de la enfermedad. No obstante, ningún parámetro aislado presenta un rendimiento diagnóstico adecuado, siendo la combinación de algunos en distintos modelos multiparamétricos la que ha presentado mejores valores predictivos. Estos permiten al clínico un mejor asesoramiento a los padres, así como una planificación de la asistencia perinatal.

Abstract Coarctation of the aorta is a relatively common and potentially fatal congenital cardiac defect. Prenatal diagnosis remains a challenge, as it is limited by the inherent characteristics of the fetal circulation, with overall low detection rates (30-50%). Opposite to other congenital cardiac defects, prenatal diagnosis of coarctation of the aorta will be a suspicion one and can only be confirmed postnatally. Its identification is of paramount importance as it improves neonatal prognosis and is mainly based on the identification of indirect signs such as cardiac or great vessels asymmetry with right dominance. The main limitation of these signs is their low positive predictive value, especially in later gestational ages. There are direct signs with higher specificity such as arch hypoplasia, the isthmus/ductus ratio or the contraductal shelf, which may only be apparent in the third trimester given the progressive nature of the disease. However, no isolated parameter has an adequate diagnostic performance and it is their combination in multiparametric models that has shown the best predictive values. These models allow clinicians to give parents better counselling as well as tailor perinatal management.

Longitudinal changes in angiogenesis biomarkers within 72 h of diagnosis and time-to-delivery in early-onset preeclampsia.

OBJECTIVES: To evaluate the association between the increment of the sFlt-1/PlGF ratio within the first 72 h after the diagnosis of early-onset preeclampsia (PE) and the time-to-delivery. Secondarily we aimed to test its predictive value for maternal adverse outcomes. STUDY DESIGN: Retrospective cohort study of 155 women with early-onset PE and measurement of sFlt-1/PlGF at diagnosis and delivery from which the expected distributions of the daily increment (Δ) of sFlt-1/PlGF ratio, sFlt-1 and PlGF were obtained. Of them, in 110 a short-term evaluation at 72 +/- 24 h was available and Δ72h were calculated and compared to the expected distributions. The high-risk groups were those with Δ72h sFlt-1/PlGF and Δ72h sFlt-1 > 3rd expected quartile or Δ72h PlGF < 1st expected quartile. The low-risk groups were those with Δ72h ≤ 0 for sFlt-1/PlGF and sFlt-1 or Δ72h PlGF ≥ 0. The rest were considered intermediate risk. MAIN OUTCOME MEASURES: Time-to-delivery and maternal adverse outcomes were compared between the three groups. RESULTS: Δ72h sFlt-1/PlGF and sFlt-1 > 3rd quartile had a significant reduction of time-to-delivery when compared to increments < 3rd quartile or ≤ 0 (5 vs 11 vs 14 days, p < 0.01) and (6 vs 8 vs 15 days, p < 0.01), respectively. Both were limited for the prediction of maternal adverse outcomes. Δ72h PlGF showed no significant relation with time-to-deliver but all abruptio placentae had PlGF < 70 pg/mL at diagnosis. CONCLUSION: High Δ72h sFlt-1/PlGF and sFlt-1 are associated to a shorter time-to-delivery while low PlGF at diagnosis is associated to abruptio placentae.

Quantitative proteomic analysis of serum-purified exosomes identifies putative pre-eclampsia-associated biomarkers.

BACKGROUND: The high incidence of pre-eclampsia, which affects 2-7% of all pregnancies, remains a major health concern. Detection of pre-eclampsia before the appearance of clinical symptoms is essential to allow early intervention, and would benefit from identification of plasma/serum biomarkers to help guide diagnosis and treatment. Liquid biopsy has emerged as a promising source of protein biomarkers that circumvents some of the inherent challenges of proteome-wide analysis of plasma/serum. In this respect, purified exosomes have the added benefit of being carriers of intercellular communication both in physiological and pathological conditions. METHODS: We compared the protein complement of purified exosomes from three different collections of control and pre-eclamptic serum samples, obtained at the end of the second trimester of pregnancy and at delivery. We employed shotgun label-free proteomics to investigate differential protein expression, which was then validated by targeted proteomics. RESULTS: We developed a purification method that yielded highly enriched exosome preparations. The presence of specific pregnancy protein markers suggested that a significant proportion of purified exosomes derived from tissues related to pregnancy. Quantitative proteomic analyses allowed us to identify 10, 114 and 98 differentially-regulated proteins in the three sample collections, with a high degree of concordance. Functional analysis suggested that these proteins participate in biological processes related to pre-eclampsia, including angiogenesis, inflammation and cell migration. The differential abundance of 66 proteins was validated by targeted proteomics. Finally, we studied the impact of the pre-eclampsia-associated exosomes in the proteome using an in vitro cellular model. CONCLUSIONS: We have identified and validated differential exosomal proteins in liquid biopsy of pregnant women that open new possibilities for early detection of pre-eclampsia. Additionally, the functional impact of the proteome composition of purified pre-eclamptic exosomes in target cells provides new information to better understand changes in embryo-maternal interactions and, consequently, the pathogenesis of this disease.

Predictors of adverse perinatal outcome up to 34 weeks, a multivariable analysis study.

The objective was to evaluate the best predictors of adverse perinatal outcome (APO) in foetuses examined up to 34 weeks and delivered by spontaneous or induced labour. This was a retrospective study of 129 pregnancies that underwent an ultrasound Doppler examination at 23-34 weeks and entered into labour within 30 days. Cerebroplacental ratio (CPR) and mean uterine artery pulsatility index (mUtA PI) were converted into multiples of the median (MoM) and estimated foetal weight (EFW) into centiles to adjust for gestational age (GA). Sonographic and clinical parameters were evaluated using logistic regression analysis.The multivariable model for the prediction of APO presented a notable accuracy: Detection rate (DR) was 39.5% for a false positive rate (FPR) of 5% and 56.8% for a FPR of 10%, AUC 0.82, p < .0001. Significant predictors were GA, EFW centile, and CPR MoM, but not mUtA PI MoM. Moreover, the type of labour onset did not exert any influence on APO. In conclusion, up to 34 weeks, prediction of APO after spontaneous or induced labour may be done measuring CPR and EFW.IMPACT STATEMENTWhat is already known on this subject? Earlier in pregnancy, foetal growth restriction is caused by placental disease causing progressive hemodynamic changes. These changes have been exhaustively described. Conversely, information about the best predictors of adverse outcome is scarce.What do the results of this study add? The findings of this study show that prior to 34 weeks and up to 1 month before labour, labour outcome might be predicted by gestational age, foetal cerebroplacental ratio (CPR) and estimated foetal weight (EFW).What are the implications of these findings for clinical practice and/or further research? If CPR behaves as a good marker of outcome not only at the end of pregnancy but also earlier in gestation, it might be interrogated along with EFW in foetuses attempting vaginal delivery to determine the risk of adverse outcome.

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

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%, p = .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.

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

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.

Smoking influence on early and late fetal growth.

OBJECTIVES: Smoking during pregnancy is a leading and modifiable risk factor for fetal growth restriction (FGR) and low birthweight (<10th centile). We studied the effects of smoking in the development of early and late FGR or low birthweight, as well as in uteroplacental and fetoplacental hemodynamics of growth-restricted fetuses. METHODS: Retrospective cohort study of 5,537 consecutive singleton pregnancies delivered at ≤34 + 0 ("early delivery" group, n=95) and >34 + 0 ("late delivery" group, n=5,442) weeks of gestation. Each group was divided into smokers and non-smokers. Prenatal diagnosis of FGR was based on customized fetal growth standards and fetal Doppler, and postnatal birthweight was assessed using the Olsen newborn chart. RESULTS: There were 15/95 (15.8%) and 602/5,442 (11.1%) smokers in the early and late delivery groups, respectively. In early deliveries, FGR was diagnosed in 3/15 (20%) of smokers and in 20/80 (25%) of non-smokers (p=0.68). We also found no differences in birthweights and hemodynamics. In late deliveres, FGR was detected in 30/602 (5%) smokers and 64/4,840 (1.3%) non-smokers (p<0.001). Birthweights <3rd centile and <10th centile were more common in smokers vs. non-smokers: 38/602 (6.3%) vs. 87/4,840 (1.8%) and 89/602 (14.8%) vs. 288/4,840 (6%), respectively (all p<0.01). Fetal Doppler of late FGR showed slightly higher umbilical artery resistances in smokers. CONCLUSIONS: Smoking in pregnancy is associated with FGR, low birthweight and higher umbilical artery Doppler resistances after 34 weeks of gestation, but we could not confirm this association in earlier deliveries.

Role of prenatal magnetic resonance imaging in fetuses with isolated severe ventriculomegaly at neurosonography: A multicenter study.

OBJECTIVE: The aim of this study was to report the rate of additional anomalies detected exclusively at prenatal magnetic resonance imaging (MRI) in fetuses with isolated severe ventriculomegaly undergoing neurosonography. METHOD: Multicenter, retrospective, cohort study involving 20 referral fetal medicine centers in Italy, United Kingdom, Spain and Denmark. Inclusion criteria were fetuses affected by isolated severe ventriculomegaly (≥15 mm), defined as ventriculomegaly with normal karyotype and no other additional central nervous system (CNS) and extra-CNS anomalies on ultrasound. In all cases, a multiplanar assessment of fetal brain as suggested by ISUOG guidelines on fetal neurosonography had been performed. The primary outcome was the rate of additional CNS anomalies detected exclusively at fetal MRI within two weeks from neurosonography. Subgroup analyses according to gestational age at MRI (

Assessment of an intervention to optimise antenatal management of women admitted with preterm labour and intact membranes using amniocentesis-based predictive risk models: study protocol for a randomised controlled trial (OPTIM-PTL Study).

INTRODUCTION: The majority of women admitted with threatened preterm labour (PTL) do not delivery prematurely. While those with microbial invasion of the amniotic cavity (MIAC) represent the highest risk group, this is a condition that is not routinely ruled out since it requires amniocentesis. Identification of low-risk or high-risk cases might allow individualisation of care, that is, reducing overtreatment with corticosteroids and shorten hospital stay in low-risk women, while allowing early antibiotic therapy in those with MIAC. Benefits versus risks of amniocentesis-based predictor models of spontaneous delivery within 7 days and/or MIAC have not been evaluated. METHODS AND ANALYSIS: This will be a Spanish randomised, multicentre clinical trial in singleton pregnancies (23.0-34.6 weeks) with PTL, conducted in 13 tertiary centres. The intervention arm will consist in the use of amniocentesis-based predictor models: if low risk, hospital discharge within 24 hours of results with no further medication will be recommended. If high risk, antibiotics will be added to standard management. The control group will be managed according to standard institutional protocols, without performing amniocentesis for this indication. The primary outcome will be total antenatal doses of corticosteroids, and secondary outcomes will be days of maternal stay and the occurrence of clinical chorioamnionitis. A cost analysis will be undertaken. To observe a reduction from 90% to 70% in corticosteroid doses, a reduction in 1 day of hospital stay (SD of 2) and a reduction from 24% to 12% of clinical chorioamnionitis, a total of 340 eligible patients randomised 1 to 1 to each study arm is required (power of 80%, with type I error α=0.05 and two-sided test, considering a dropout rate of 20%). Randomisation will be stratified by gestational age and centre. ETHICS AND DISSEMINATION: Prior to receiving approval from the Ethics Committee (HCB/2020/1356) and the Spanish Agency of Medicines and Medical Devices (AEMPS) (identification number: 2020-005-202-26), the trial was registered in the European Union Drug Regulating Authorities Clinical Trials database (2020-005202-26). AEMPS approved the trial as a low-intervention trial. All participants will be required to provide written informed consent. Findings will be disseminated through workshops, peer-reviewed publications and national/international conferences. PROTOCOL VERSION: V.4 10 May 2021. TRIAL REGISTRATION NUMBERS: NCT04831086 and Eudract number 2020-005202-26.

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

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.

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

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.

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

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

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.

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.

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

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.

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

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.