Sickle cell disease and increased adverse maternal and perinatal outcomes in different genotypes.

BACKGROUND: Sickle cell disease (SCD) comprises a heterogeneous group of inherited hemolytic disorders that increases the risk of maternal and perinatal complications due to chronic systemic inflammatory response, endothelial damage and vaso-occlusion. The contribution of genotypes to the severity of outcomes during pregnancy is not completely established. METHODS: A retrospective study of medical charts was performed to compare maternal and perinatal outcomes in Hb SS, Hb SC disease and sickle-beta thalassemia (Hb Sß) pregnancies followed at a high-risk antenatal care unit over a 6-year period. A descriptive analysis of morphological findings was performed of the placenta when pathology reports were available. RESULTS: Sixty-two SCD pregnant women [25 Hb SS (40 %), 29 Hb SC (47 %) and 8 Hb Sß (13 %)] were included. Overall, SCD was associated with maternal complications (77 %), preterm birth (30 %), cesarean section (80 %) and a need of blood transfusion. In general there were no statistically significant differences between genotypes. The only significant difference was the hemoglobin level at first antenatal care visit which was lower for the homozygous genotype (7.7 g/dL) compared to Hb SC and Hb Sß (9.7 g/dL and 8.4 g/dL, respectively; p-value = 0.01). Ten of 15 evaluated placentas showed abnormal morphological findings CONCLUSION: SCD, regardless of the underlying genotype, is associated with increased adverse maternal and perinatal outcomes and placental abnormalities associated with maternal vascular malperfusion.

CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence.

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

Morphological placental findings in women infected with SARS-CoV-2 according to trimester of pregnancy and severity of disease.

INTRODUCTION: Placental morphology findings in SARS-CoV-2 infection are considered nonspecific, although the role of trimester and severity of infection are underreported. Therefore, we aimed to investigate abnormal placental morphology, according to these two criteria. METHODS: This is an ancillary analysis of a prospective cohort study of pregnant women with suspected SARS-CoV-2 infection, managed in one maternity, from March 2020 to October 2021. Charting of clinical/obstetric history, trimester and severity of COVID-19 infection, and maternal/perinatal outcomes were done. Placental morphological findings were classified into maternal and fetal circulatory injury and acute/chronic inflammation. We further compared findings with women with suspected disease which tested negative for COVID-19. Diseases' trimester of infection and clinical severity guided the analysis of confirmed COVID-19 cases. RESULTS: Ninety-one placental discs from 85 women were eligible as a COVID-19 group, and 42 discs from 41 women in negative COVID-19 group. SARS-CoV-2 infection occurred in 68.2% during third trimester, and 6.6% during first; 16.5% were asymptomatic, 61.5% non-severe and 22.0% severe symptomatic (two maternal deaths). Preterm birth occurred in 33.0% (one fetal death). Global maternal vascular malperfusion (MVM) were significant in COVID-19 group whether compared with negative COVID-19 tests group; however, fetal vascular malperfusion lesions and low-grade chronic villitis were not. Three placentas had COVID-19 placentitis. Decidual arteriopathy was associated with infection in first/mid trimester, and chorangiosis in asymptomatic infections. DISCUSSION: Placental abnormalities after an infection by COVID-19 were more frequent after first/mid-trimester infections. Extensive placental lesions are rare, although they may be more common upon underlying medical conditions.

Placental Findings in Preterm and Term Preeclampsia: An Integrative Review of the Literature.

INTRODUCTION: Preeclampsia (PE) is a pregnancy complication associated with increased maternal and perinatal morbidity and mortality. The disease presents with recent onset hypertension (after 20 weeks of gestation) and proteinuria, and can progress to multiple organ dysfunction, with worse outcomes among early onset preeclampsia (EOP) cases (< 34 weeks). The placenta is considered the root cause of PE; it represents the interface between the mother and the fetus, and acts as a macromembrane between the two circulations, due to its villous and vascular structures. Therefore, in pathological conditions, macroscopic and microscopic evaluation can provide clinically useful information that can confirm diagnosis and enlighten about outcomes and future therapeutic benefit. OBJECTIVE: To perform an integrative review of the literature on pathological placental findings associated to preeclampsia (comparing EOP and late onset preeclampsia [LOP]) and its impacts on clinical manifestations. RESULTS: Cases of EOP presented worse maternal and perinatal outcomes, and pathophysiological and anatomopathological findings were different between EOP and LOP placentas, with less placental perfusion, greater placental pathological changes with less villous volume (villous hypoplasia), greater amount of trophoblastic debris, syncytial nodules, microcalcification, villous infarcts, decidual arteriolopathy in EOP placentas when compared with LOP placentas. Clinically, the use of low doses of aspirin has been shown to be effective in preventing PE, as well as magnesium sulfate in preventing seizures in cases of severe features. CONCLUSION: The anatomopathological characteristics between EOP and LOP are significantly different, with large morphological changes in cases of EOP, such as hypoxia, villous infarctions, and hypoplasia, among others, most likely as an attempt to ascertain adequate blood flow to the fetus. Therefore, a better understanding of the basic macroscopic examination and histological patterns of the injury is important to help justify outcomes and to determine cases more prone to recurrence and long-term consequences.

INTRODUçãO: A pré-eclâmpsia (PE) é uma complicação da gravidez associada ao aumento da morbidade e mortalidade materna e perinatal. A doença se apresenta com hipertensão de início recente (após 20 semanas de gestação) e proteinúria, que pode progredir para disfunção de múltiplos órgãos, com resultados piores entre os casos de início precoce (<34 semanas). A placenta é considerada a principal causa da PE, representando a interface entre a mãe e o feto, e atuando como uma macromembrana entre as duas circulações, devido às suas estruturas vilosas e vasculares, de modo que, em condições patológicas, avaliações macroscópicas e microscópicas podem fornecer informações clinicamente úteis, que podem fornecer diagnóstico, prognóstico e benefício terapêutico. OBJETIVO: Realizar uma revisão integrativa da literatura para compreender e descrever os achados placentários patológicos associados à pré-eclâmpsia e seus impactos nas manifestações clínicas. RESULTADOS: Os casos de início precoce apresentaram piores desfechos maternos e perinatais, e os achados fisiopatológicos e anatomopatológicos foram diferentes entre as placentas de início precoce e início tardio, com menor perfusão placentária, maiores alterações patológicas placentárias com menor volume viloso (hipoplasia vilosa), maior quantidade de debris trofoblásticos, nódulos sinciciais, microcalcificação, infartos vilosos, arteriolopatia decidual em placentas de início precoce quando comparadas com placentas de início tardio. Clinicamente, o uso de baixas doses de aspirina tem se mostrado significativo na prevenção da PE, assim como o sulfato de magnésio na prevenção de convulsões na doença com manifestações de gravidade. CONCLUSãO: As características anatomopatológicas entre a pré-eclâmpsia precoce e tardia são significativamente diferentes, com grandes alterações morfológicas nos casos de início precoce, como hipóxia, infartos vilosos e hipoplasia, entre outros, na tentativa de estabilizar o fluxo sanguíneo para o feto. Portanto, um entendimento comum do exame macroscópico básico e dos padrões histológicos da lesão é importante para maximizar o benefício diagnóstico, prognóstico e terapêutico do exame da placenta e, consequentemente, reduzir os riscos para a mãe e o feto.

Placental Findings in Preterm and Term Preeclampsia: An Integrative Review of the Literature / Achados placentários na pré-eclâmpsia pré-termo e a termo: Uma revisão integrativa da literatura

Abstract Introduction Preeclampsia (PE) is a pregnancy complication associated with increased maternal and perinatal morbidity and mortality. The disease presents with recent onset hypertension (after 20 weeks of gestation) and proteinuria, and can progress to multiple organ dysfunction, with worse outcomes among early onset preeclampsia (EOP) cases (<34 weeks). The placenta is considered the root cause of PE; it represents the interface between the mother and the fetus, and acts as a macromembrane between the two circulations, due to its villous and vascular structures. Therefore, in pathological conditions, macroscopic and microscopic evaluation can provide clinically useful information that can confirm diagnosis and enlighten about outcomes and future therapeutic benefit. Objective To perform an integrative review of the literature on pathological placental findings associated to preeclampsia (comparing EOP and late onset preeclampsia [LOP]) and its impacts on clinical manifestations. Results: Cases of EOP presented worse maternal and perinatal outcomes, and pathophysiological and anatomopathological findings were different between EOP and LOP placentas, with less placental perfusion, greater placental pathological changes with less villous volume (villous hypoplasia), greater amount of trophoblastic debris, syncytial nodules, microcalcification, villous infarcts, decidual arteriolopathy in EOP placentas when compared with LOP placentas. Clinically, the use of low doses of aspirin has been shown to be effective in preventing PE, as well asmagnesium sulfate in preventing seizures in cases of severe features. Conclusion The anatomopathological characteristics between EOP and LOP are significantly different, with large morphological changes in cases of EOP, such as

Resumo Introdução A pré-eclâmpsia (PE) é uma complicação da gravidez associada ao aumento da morbidade e mortalidade materna e perinatal. A doença se apresenta com hipertensão de início recente (após 20 semanas de gestação) e proteinúria, que pode progredir para disfunção de múltiplos órgãos, com resultados piores entre os casos de início precoce (<34 semanas). A placenta é considerada a principal causa da PE, representando a interface entre a mãe e o feto, e atuando como uma macromembrana entre as duas circulações, devido às suas estruturas vilosas e vasculares, demodo que, em condições patológicas, avaliações macroscópicas e microscópicas podem fornecer informações clinicamente úteis, que podem fornecer diagnóstico, prognóstico e benefício terapêutico. Objetivo Realizar uma revisão integrativa da literatura para compreender e descrever os achados placentários patológicos associados à pré-eclâmpsia e seus impactos nas manifestações clínicas. Resultados Os casos de início precoce apresentaram piores desfechos maternos e perinatais, e os achados fisiopatológicos e anatomopatológicos foram diferentes entre as placentas de início precoce e início tardio, commenor perfusão placentária, maiores alterações patológicas placentárias commenor volume viloso (hipoplasia vilosa), maior quantidade de debris trofoblásticos, nódulos sinciciais, microcalcificação, infartos vilosos, arteriolopatia decidual em placentas de início precoce quando comparadas com placentas de início tardio. Clinicamente, o uso de baixas doses de aspirina tem se mostrado significativo na prevenção da PE, assim como o sulfato de magnésio na prevenção de convulsões na doença com manifestações de gravidade. Conclusão As características anatomopatológicas entre a pré-eclâmpsia precoce e tardia são significativamente diferentes, com grandes alterações morfológicas nos casos de início precoce, como hipóxia, infartos vilosos e hipoplasia, entre outros, na tentativa de estabilizar o fluxo sanguíneo para o feto. Portanto, um entendimento comum do exame macroscópico básico e dos padrões histológicos da lesão é importante para maximizar o benefício diagnóstico, prognóstico e terapêutico do exame da placenta e, consequentemente, reduzir os riscos para a mãe e o feto.

Placental Sampling for Understanding Viral Infections - A Simplified Protocol for the COVID-19 Pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) is a pandemic viral disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of the disease among the obstetric population remains unclear, and the study of the placenta can provide valuable information. Adequate sampling of the placental tissue can help characterize the pathways of viral infections. METHODS: A protocol of placental sampling is proposed, aiming at guaranteeing representativity of the placenta and describing the adequate conservation of samples and their integrity for future analysis. The protocol is presented in its complete and simplified versions, allowing its implementation in different complexity settings. RESULTS: Sampling with the minimum possible interval from childbirth is the key for adequate sampling and storage. This protocol has already been implemented during the Zika virus outbreak. CONCLUSION: A protocol for adequate sampling and storage of placental tissue is fundamental for adequate evaluation of viral infections on the placenta. During the COVID-19 pandemic, implementation of this protocol may help to elucidate critical aspects of the SARS-CoV-2 infection.

OBJETIVO: A doença do novo coronavírus (COVID-19) é uma doença viral pandêmica causada pelo coronavírus da síndrome respiratória aguda 2 (SARS-CoV-2). O impacto da doença entre a população obstétrica ainda é incerto, e o estudo da placenta pode fornecer informações valiosas. Assim, a coleta adequada do tecido placentário pode ajudar a caracterizar algumas propriedades das infecções virais. MéTODOS: Um protocolo de coleta placentária é proposto, objetivando a garantia de representatividade da placenta, descrevendo a maneira de conservação adequada das amostras, e visando garantir sua integridade para análises futuras. O protocolo é apresentado em suas versões completa e simplificada, permitindo sua implementação em diferentes configurações de infraestrutura. RESULTADOS: A amostragem com o intervalo mínimo possível do parto é essencial para coleta e armazenamento adequados. Esse protocolo já foi implementado durante a epidemia de vírus Zika. CONCLUSãO: Um protocolo para coleta e armazenamento adequados de tecido placentário é fundamental para a avaliação adequada de infecções virais na placenta. Durante a pandemia de COVID-19, a implementação deste protocolo pode ajudar a elucidar aspectos críticos da infecção por SARS-CoV-2.

Placental Sampling for Understanding Viral Infections - A Simplified Protocol for the COVID-19 Pandemic / Coleta placentária para entender infecções virais - Um protocolo simplificado para a pandemia de COVID-19

Abstract Objective The coronavirus disease 2019 (COVID-19) is a pandemic viral disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of the disease among the obstetric population remains unclear, and the study of the placenta can provide valuable information. Adequate sampling of the placental tissue can help characterize the pathways of viral infections. Methods A protocol of placental sampling is proposed, aiming at guaranteeing representativity of the placenta and describing the adequate conservation of samples and their integrity for future analysis. The protocol is presented in its complete and simplified versions, allowing its implementation in different complexity settings. Results Sampling with the minimum possible interval from childbirth is the key for adequate sampling and storage. This protocol has already been implemented during the Zika virus outbreak. Conclusion A protocol for adequate sampling and storage of placental tissue is fundamental for adequate evaluation of viral infections on the placenta. During the COVID-19 pandemic, implementation of this protocol may help to elucidate critical aspects of the SARS-CoV-2 infection.

Resumo Objetivo A doença do novo coronavírus (COVID-19) é uma doença viral pandêmica causada pelo coronavírus da síndrome respiratória aguda 2 (SARS-CoV-2). O impacto da doença entre a população obstétrica ainda é incerto, e o estudo da placenta pode fornecer informações valiosas. Assim, a coleta adequada do tecido placentário pode ajudar a caracterizar algumas propriedades das infecções virais. Métodos Um protocolo de coleta placentária é proposto, objetivando a garantia de representatividade da placenta, descrevendo a maneira de conservação adequada das amostras, e visando garantir sua integridade para análises futuras. O protocolo é apresentado em suas versões completa e simplificada, permitindo sua implementação em diferentes configurações de infraestrutura. Resultados A amostragem com o intervalo mínimo possível do parto é essencial para coleta e armazenamento adequados. Esse protocolo já foi implementado durante a epidemia de vírus Zika. Conclusão Um protocolo para coleta e armazenamento adequados de tecido placentário é fundamental para a avaliação adequada de infecções virais na placenta. Durante a pandemia de COVID-19, a implementação deste protocolo pode ajudar a elucidar aspectos críticos da infecção por SARS-CoV-2.

Adequate Placental Sampling for the Diagnosis and Characterization of Placental Infection by Zika Virus.

The detection of Zika virus (ZIKV) in immunoprivileged anatomical sites, potential sites for viral persistence, may guide the confirmation of undefined cases of ZIKV infection and also bring to light unknown pathways of viral transmission. Thus, this study aimed to characterize ZIKV infection in stratified, standardized placental samples in women with exanthematic febrile manifestations during pregnancy and compare findings to the standard investigation protocol of official health agencies. To this end, a case series of placental findings within a prospective cohort study was conducted over a period of 24 months. Serum/urine were obtained at the time of clinical case identification. Placental sampling was performed following standard investigation protocol (samples of 1.0 cm sent to a reference laboratory) and in a systematic way at various regions, such as chorionic plate, chorionic villi, basal plate, amniotic membrane, and umbilical cord, for subsequent ZIKV identification and quantification. Clinical information was obtained and histological preparation with hematoxylin-eosin staining for morphological evaluation was performed. This case series included 17 placentas systematically collected. Of these, 14 were positive by qRT-PCR for ZIKV, 5 in the umbilical cord, 7 in the amniotic membrane, 7 in the chorionic plate, 13 in the chorionic villi, and 7 in the basal plate, whereas none were reported by the reference laboratory. The most common morphological and anatomopathological findings were increased stromal cellularity, villitis, calcification, maternal vascular malperfusion, placental hypoplasia, and maternal-fetal hemorrhage (intervillous thrombi). Seven women presented positive testing for ZIKV in serological and/or molecular tests during gestation in urine. While viral quantification in urine ranged from 101 to 103 FFU eq/ml, that in different placental regions ranged from 103 to 108 FFU eq/g. Thus, ZIKV can infect different regions of the placenta and umbilical cord of pregnant women, showing that the systematic collection and adequate storage of the placenta is fundamental for the detection of ZIKV in this organ. The detection of ZIKV in the placenta after several months of initial symptoms suggests that this tissue may be a site for viral persistence during pregnancy.

Key Infections in the Placenta.

Congenital infections are an important cause of morbidity and mortality worldwide, especially in low-income settings. This review discusses the main pathways of infections and associated adverse maternal and fetal outcomes, considering the TORCH pathogens, including Zika virus; the acronym stands for Toxoplasma gondii infection, other (Listeria monocytogenes, Treponema pallidum, and parvovirus B19, among others, including Zika virus), rubella virus, cytomegalovirus, and herpes simplex viruses type 1 and type 2.