Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Human phenotype ontology; Prenatal diagnosis; Prenatal phenotypingOntología del fenotipo humano; Diagnóstico prenatal; Fenotipado prenatalOntologia del fenotip humà; Diagnòstic prenatal; Fenotipat prenatalTechnological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.European Commission; National Human Genome Research Institute; NIH Office of the Director; The European Union's EIT-Health Innovation Program bp2020-2022, Grant/Award Numbers: #211015, #20062; NIH Office of the Director (OD), the European Union's Horizon 2020 research and innovation program, Grant/Award Number: 779257; NHGRI, Grant/Award Numbers: 2R24OD011883-05A1, 1U24HG011449-01A

Transplantation of Human-Fetal-Spinal-Cord-Derived NPCs Primed with a Polyglutamate-Conjugated Rho/Rock Inhibitor in Acute Spinal Cord Injury

NPC transplantation; Cell priming; Human fetal neural precursorTrasplante de NPC; Cebado celular; Precursor neuronal fetal humanoTrasplantament de NPC; Cebament cel·lular; Precursor neuronal fetal humàNeural precursor cell (NPC) transplantation represents a promising therapy for treating spinal cord injuries (SCIs); however, despite successful results obtained in preclinical models, the clinical translation of this approach remains challenging due, in part, to the lack of consensus on an optimal cell source for human neuronal cells. Depending on the cell source, additional limitations to NPC-based therapies include high tumorigenic potential, alongside poor graft survival and engraftment into host spinal tissue. We previously demonstrated that NPCs derived from rat fetal spinal cords primed with a polyglutamate (PGA)-conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS) displayed enhanced neuronal differentiation and graft survival when compared to non-primed NPCs. We now conducted a similar study of human-fetal-spinal-cord-derived NPCs (hfNPCs) from legal gestational interruptions at the late gestational stage, at 19–21.6 weeks. In vitro, expanded hfNPCs retained neural features, multipotency, and self-renewal, which supported the development of a cell banking strategy. Before transplantation, we established a simple procedure to prime hfNPCs by overnight incubation with PGA-SS-FAS (at 50 μM FAS equiv.), which improved neuronal differentiation and overcame neurite-like retraction after lysophosphatidic-acid-induced Rho/Rock activation. The transplantation of primed hfNPCs into immune-deficient mice (NU(NCr)-Foxn1nu) immediately after the eighth thoracic segment compression prompted enhanced migration of grafted cells from the dorsal to the ventral spinal cord, increased preservation of GABAergic inhibitory Lbx1-expressing and glutamatergic excitatory Tlx3-expressing somatosensory interneurons, and elevated the numbers of preserved, c-Fos-expressing, activated neurons surrounding the injury epicenter, all in a low percentage. Overall, the priming procedure using PGA-SS-FAS could represent an alternative methodology to improve the capabilities of the hfNPC lines for a translational approach for acute SCI treatment.This research was funded by Fundació Marató TV3 2017/refs.20172230, 20172231, Agencia Valenciana de Innovación (AVI) (INNVAL10/19/047 and Grants RTI2018-095872-B-C21 and PDI2021-1243590B-I00/ERDF funded by MCIN/AEI//10.13039/501100011033 and by ERDF A way of making Europe). This project was also funded by Project 964562 (RISEUP), H2020 FetOpen program

Gestational age-based reference ranges for cervical length and preterm birth prediction in triplet pregnancies: an observational retrospective study

Cervical length; Preterm delivery; Triplet pregnancyLongitud cervical; Parto prematuro; Embarazo de trillizosLongitud cervical; Part prematur; Embaràs de trillissosObjectives To develop gestational age-based reference ranges for cervical length in triplet pregnancies. The secondary objective was to assess the performance of cervical length measured between 18 and 20 + 6 days for the prediction of preterm delivery before 28 and 32 weeks, respectively. Methods Observational retrospective study of triplet pregnancies in three Spanish tertiary-care hospitals between 2001 and 2019. Cervical length measurements were consecutively obtained between 15 and 34 weeks of gestation. Pregnancies undergoing multifetal reduction or fetal surgery were excluded. Results Two hundred and six triplet pregnancies were included in the final analysis. There was a quadratic decrease in cervical length with gestational age. The median and fifth centiles for cervical length at 20 weeks were 35 and 13 mm. In the prediction of preterm birth < 28 weeks, for a false positive rate of 5%, and 10%, the detection rates were 40.9%, and 40.9%, respectively, and the prediction of preterm birth < 32 weeks, 22.0% and 26.0%, respectively. Conclusions In triplet pregnancies, cervical length decreases with gestational age. The performance of cervical length at 18–20 + 6 in screening for preterm birth before 28 and 32 weeks is poor

First-trimester screening for pre-eclampsia and small for gestational age: A comparison of the gaussian and Fetal Medicine Foundation algorithms

Preeclampsia d'inici precoç; Primer trimestreEarly-onset pre-eclampsia; First trimesterPreeclampsia de inicio precoz; Primer trimestreObjective Pre-eclampsia (PE) and small for gestational age (SGA) can be predicted from the first trimester. The most widely used algorithm worldwide is the Fetal Medicine Foundation (FMF) algorithm. The recently described Gaussian algorithm has reported excellent results although it is unlikely to be externally validated. Therefore, as an alternative approach, we compared the predictive accuracy for PE and SGA of the Gaussian and FMF algorithms. Methods Secondary analysis of a prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) with 2641 singleton pregnancies. The areas under the curve for the predictive performance for early-onset and preterm PE and early-onset and preterm SGA were calculated with the Gaussian and FMF algorithms and subsequently compared. Results The FMF and Gaussian algorithms showed a similar predictive performance for most outcomes and marker combinations. Nevertheless, significant differences for early-onset PE prediction favored the Gaussian algorithm in the following combinations: mean arterial blood pressure (MAP) with pregnancy-associated plasma protein A, MAP with placental growth factor, and MAP alone. Conclusions The first-trimester Gaussian and FMF algorithms have similar performances for PE and SGA prediction when applied with all markers within a routine care setting in a Spanish population, adding evidence to the external validity of the FMF algorithm

The challenge of the laboratory diagnosis in a confirmed congenital Zika virus syndrome in utero: A case report

Zika virus; Diagnosis; Infection in uteroVirus Zika; Diagnòstic; Infecció uterinaVirus Zika; Diagnóstico; Infección uterinaINTRODUCTION: Zika virus (ZIKV) has caused one of the most challenging global infectious epidemics in recent years because of its causal association with severe microcephaly and other congenital malformations. The diagnosis of viral infections usually relies on the detection of virus proteins or genetic material in clinical samples as well as on the infected host immune responses. Serial serologic testing is required for the diagnosis of congenital infection when diagnostic molecular biology is not possible. PATIENT CONCERNS: A 2-year-old girl, born to a mother with confirmed ZIKV infection during pregnancy, with a confirmed ZIKV infection in utero, showed at birth a severe microcephaly and clinical characteristics of fetal brain disruption sequence compatible with a congenital ZIKV syndrome (CZS). DIAGNOSIS: ZIKV-RNA and ZIKV-IgM serological response performed at birth and during the follow-up time tested always negative. Serial serologic ZIKV-IgG tests were performed to assess the laboratory ZIKV diagnosis, ZIKV-IgG seroreversion was observed at 21 months of age. ZIKV diagnosis of this baby had to be relied on her clinical and radiological characteristics that were compatible with a CZS. INTERVENTIONS: The patient was followed-up as per protocol at approximately 1, 4, 9, 12, 18-21, and 24 months of age. Neurological, radiological, audiological, and ophthalmological assessment were performed during this period of time. Prompt rehabilitation was initiated to prevent potential adverse long-term neurological outcomes. OUTCOMES: The growth of this girl showed a great restriction at 24 months of age with a weight of 8.5 kg (-2.5 z-score) and a head circumference of 40.5 cm (-4.8 z-score). She also had a great neurodevelopmental delay at the time of this report. CONCLUSION: We presume that as a consequence of prenatal ZIKV infection, the fetal brain and other organs are damaged before birth through direct injury. Following this, active infection ends during intrauterine life, and as a consequence the immune system of the infant is unable to build up a consistent immune response thereafter. Further understanding of the mechanisms taking part in the pathogenesis of ZIKV congenital infection is needed. This finding might change our paradigm regarding serological response in the ZIKV congenital infection

Reference values for interleukin-6 in the amniotic fluid of asymptomatic pregnant women

Amniocentesis; Interleukin-6; Intra-amniotic inflammationAmniocentesi; Interleucina-6; Inflamació intraamniòticaAmniocentesis; Interleucina-6; Inflamación intraamnióticaIntroduction Nowadays, proinflammatory factors are considered to play an important role in the pathophysiology of threatened preterm labor or chorioamnionitis. The aim of this study was to establish the normal reference range for interleukin-6 (IL-6) levels in the amniotic fluid and to identify factors which may alter this value. Material and methods Prospective study in a tertiary-level center including asymptomatic pregnant women undergoing amniocentesis for genetic studies from October 2016 to September 2019. IL-6 measurements in amniotic fluid were performed using a fluorescence immunoassay with microfluidic technology (ELLA Proteinsimple, Bio Techne). Maternal history and pregnancy data were also recorded. Results This study included 140 pregnant women. Of those, women who underwent termination of pregnancy were excluded. Therefore, a total of 98 pregnancies were included in the final statistical analysis. The mean gestational age was 21.86 weeks (range: 15–38.7) at the time of amniocentesis, and 38.6 weeks (range: 30.9–41.4) at delivery. No cases of chorioamnionitis were reported. The log10 IL-6 values follow a normal distribution (W = 0.990, p = 0.692). The median, and the 5th, 10th, 90th, and 95th percentiles for IL-6 levels were 573, 105, 130, 1645, and 2260 pg/mL, respectively. The log10 IL-6 values were not affected by gestational age (p = 0.395), maternal age (p = 0.376), body mass index (p = 0.551), ethnicity (p = 0.467), smoking status (p = 0.933), parity (p = 0.557), method of conception (p = 0.322), or diabetes mellitus (p = 0.381). Conclusions The log10 IL-6 values follow a normal distribution. IL-6 values are independent of gestational age, maternal age, body mass index, ethnicity, smoking status, parity and method of conception. Our study provides a normal reference range for IL-6 levels in the amniotic fluid that can be used in future studies. We also observed that normal IL-6 values were higher in the amniotic fluid than in serum.Some of the authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516)

Protocol d'actuació davant de casos de febre vírica de Zika en l'àmbit obstètric i pediàtric de Catalunya

Virus del Zika; Obstetrícia; PediatriaZika virus; Obstetrics; PediatricsObstetricia; PediatríaAquest document dóna recomanacions d'actuació per a la prevenció, detecció i tractament del virus del Zika a Catalunya

Impacte de la infecció per virus del zika durant la gestació

Antecedents El virus Zika és un agent teratogènic amb tropisme predominant per al cervell fetal. S’ha demostrat que pot causar lesions neurològiques severes en fetus però es desconeix la incidència real de la infecció i la afectació fetal. Material i mètode Des del brot del virus del Zika a Brasil el novembre de 2015 es van estudiar de forma prospectiva totes les dones embarassades amb vincle epidemiològic a zona endèmica de virus Zika. Seguint el protocol de l’Agència Catalana de Salut Pública, es van utilitzar proves biològiques i serològiques per tal d’identificar les dones infectades. Es va fer un seguiment ecogràfic mensual amb ecografia i neurosonografia; i se'ls va oferir ressonància magnètica i amniocentesi. També es van obtenir mostres de placenta i teixits fetals i neonatals. Resultats Setanta-dues dones embarassades van ser positives per a la infecció per virus del Zika; deu van ser casos confirmats i 62 van ser casos probables. La taxa global de mal resultat perinatals en dones amb infecció confirmada i seguiment complet va ser del 33% (95% IC: 12,1 a 64,6%). Va haver-hi dos casos de síndrome congènita per virus del Zika i un cas d’avortament espontani, tots ells en dones amb infecció confirmada durant el primer trimestre. El 25% de les dones van referir símptomes durant l'embaràs, en general erupció cutània i febre. Totes les dones amb infecció confirmada tenien virèmies persistents de més de 14 dies (mitjana de 61.50 dies (IQR 35.50 - 80.75 dies)). Conclusió La taxa global de mal resultat perinatal en dones amb infecció pel virus Zika confirmada és del 33%. Les infeccions durant el primer trimestre s'associen a pitjor resultat en un país no endèmic.Background Zika virus is a teratogenic agent with predominant tropism for the fetal brain. The real incidence of fetal infection and affection is unknown, and severe disease has been demonstrated throughout pregnancy. Methods Since the Zika virus outbreak in Brazil in November 2015 all pregnant women with epidemiological link to an endemic area were prospectively screened for Zika virus in Catalonia, Spain. According to the Spanish protocol, serological and biological tests were used to identify infected pregnant women. They were followed-up in a monthly basis with ultrasound scans and neurosonograms; magnetic resonance and amniotic fluid testing were performed after signed informed consent. Samples of placenta and fetal and neonatal tissues were also obtained. Results Seventy-two pregnant women tested positive for Zika virus infection; ten were confirmed cases and 62 were probable cases. The overall rate of adverse perinatal outcome in women with confirmed Zika virus infection and complete follow-up was 33% (95%CI, 12.1-64.6%). Two cases of Zika virus congenital syndrome and one miscarriage, all of them born to women with confirmed infection in the first trimester. 25% of women reported symptoms during pregnancy, mostly rash and fever. All women with confirmed infection had persistent viremias beyond the expected time (median 61.50 days (IQR 35.50-80.75)). Conclusion The overall adverse outcome rate in women with confirmed Zika virus infection is 33%. First trimester infections of Zika virus are associated with worse outcomes in a non-endemic country

Impacte de la infecció per virus del zika durant la gestació

Antecedents El virus Zika és un agent teratogènic amb tropisme predominant per al cervell fetal. S’ha demostrat que pot causar lesions neurològiques severes en fetus però es desconeix la incidència real de la infecció i la afectació fetal. Material i mètode Des del brot del virus del Zika a Brasil el novembre de 2015 es van estudiar de forma prospectiva totes les dones embarassades amb vincle epidemiològic a zona endèmica de virus Zika. Seguint el protocol de l’Agència Catalana de Salut Pública, es van utilitzar proves biològiques i serològiques per tal d’identificar les dones infectades. Es va fer un seguiment ecogràfic mensual amb ecografia i neurosonografia; i se'ls va oferir ressonància magnètica i amniocentesi. També es van obtenir mostres de placenta i teixits fetals i neonatals. Resultats Setanta-dues dones embarassades van ser positives per a la infecció per virus del Zika; deu van ser casos confirmats i 62 van ser casos probables. La taxa global de mal resultat perinatals en dones amb infecció confirmada i seguiment complet va ser del 33% (95% IC: 12,1 a 64,6%). Va haver-hi dos casos de síndrome congènita per virus del Zika i un cas d’avortament espontani, tots ells en dones amb infecció confirmada durant el primer trimestre. El 25% de les dones van referir símptomes durant l'embaràs, en general erupció cutània i febre. Totes les dones amb infecció confirmada tenien virèmies persistents de més de 14 dies (mitjana de 61.50 dies (IQR 35.50 - 80.75 dies)). Conclusió La taxa global de mal resultat perinatal en dones amb infecció pel virus Zika confirmada és del 33%. Les infeccions durant el primer trimestre s'associen a pitjor resultat en un país no endèmic.Background Zika virus is a teratogenic agent with predominant tropism for the fetal brain. The real incidence of fetal infection and affection is unknown, and severe disease has been demonstrated throughout pregnancy. Methods Since the Zika virus outbreak in Brazil in November 2015 all pregnant women with epidemiological link to an endemic area were prospectively screened for Zika virus in Catalonia, Spain. According to the Spanish protocol, serological and biological tests were used to identify infected pregnant women. They were followed-up in a monthly basis with ultrasound scans and neurosonograms; magnetic resonance and amniotic fluid testing were performed after signed informed consent. Samples of placenta and fetal and neonatal tissues were also obtained. Results Seventy-two pregnant women tested positive for Zika virus infection; ten were confirmed cases and 62 were probable cases. The overall rate of adverse perinatal outcome in women with confirmed Zika virus infection and complete follow-up was 33% (95%CI, 12.1-64.6%). Two cases of Zika virus congenital syndrome and one miscarriage, all of them born to women with confirmed infection in the first trimester. 25% of women reported symptoms during pregnancy, mostly rash and fever. All women with confirmed infection had persistent viremias beyond the expected time (median 61.50 days (IQR 35.50-80.75)). Conclusion The overall adverse outcome rate in women with confirmed Zika virus infection is 33%. First trimester infections of Zika virus are associated with worse outcomes in a non-endemic country

Maternal Infection and Adverse Pregnancy Outcomes among Pregnant Travellers: Results of the International Zika Virus in Pregnancy Registry

Síndrome congènit del Zika; Embaràs; ViatgersSíndrome congénito del Zika; Embarazo; ViajerosCongenital Zika syndrome; Pregnancy, TravelersIn this multicentre cohort study, we evaluated the risks of maternal ZIKV infections and adverse pregnancy outcomes among exposed travellers compared to women living in areas with ZIKV circulation (residents). The risk of maternal infection was lower among travellers compared to residents: 25.0% (n = 36/144) versus 42.9% (n = 309/721); aRR 0.6; 95% CI 0.5–0.8. Risk factors associated with maternal infection among travellers were travelling during the epidemic period (i.e., June 2015 to December 2016) (aOR 29.4; 95% CI 3.7–228.1), travelling to the Caribbean Islands (aOR 3.2; 95% CI 1.2–8.7) and stay duration >2 weeks (aOR 8.7; 95% CI 1.1–71.5). Adverse pregnancy outcomes were observed in 8.3% (n = 3/36) of infected travellers and 12.7% (n = 39/309) of infected residents. Overall, the risk of maternal infections is lower among travellers compared to residents and related to the presence of ongoing outbreaks and stay duration, with stays <2 weeks associated with minimal risk in the absence of ongoing outbreaks