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1.
Am J Obstet Gynecol ; 225(1): 43-50, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34215353

RESUMO

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.


Assuntos
Desenvolvimento de Medicamentos , Mortalidade Infantil , Mortalidade Materna , Obstetrícia/métodos , Complicações na Gravidez/tratamento farmacológico , Animais , Desenvolvimento de Medicamentos/ética , Desenvolvimento de Medicamentos/legislação & jurisprudência , Desenvolvimento de Medicamentos/estatística & dados numéricos , Feminino , Feto/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Troca Materno-Fetal , Pesquisa Farmacêutica/ética , Pesquisa Farmacêutica/legislação & jurisprudência , Pesquisa Farmacêutica/estatística & dados numéricos , Gravidez
2.
FASEB J ; 35(8): e21754, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34191338

RESUMO

To obtain a successful pregnancy, the establishment of maternal-fetal tolerance and successful placentation are required to be established. Disruption of this immune balance and/or inadequate placental perfusion is believed to be associated with a lot of pregnancy-related complications, such as recurrent spontaneous abortion, pre-eclampsia, and fetal intrauterine growth restriction. Extravillous trophoblasts (EVTs) have the unique ability to instruct decidual immune cells (DICs) to develop a regulatory phenotype for fetal tolerance. Utilizing immortalized human first trimester extravillous trophoblast cells and primary EVTs, we found that DICs promote EVT function and placental development. We have previously shown that checkpoints T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are important for DIC function. In the present study, we showed that blockade of Tim-3 and CTLA-4 pathways leaded to the abnormal DICs-EVTs interaction, poor placental development, and increased fetal loss. Treatment with IL-4 and IL-10 could rescue the adverse effects of targeting Tim-3 and CTLA-4 on the pregnancy outcome. Hence, the reproductive safety must be a criterion considered in the assessment of immuno-therapeutic agents. In addition, IL-4 and IL-10 may represent novel therapeutic strategies to prevent pregnancy loss induced by checkpoint inhibition.


Assuntos
Antígeno CTLA-4/imunologia , Decídua/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Trofoblastos/imunologia , Animais , Antígeno CTLA-4/antagonistas & inibidores , Comunicação Celular/imunologia , Células Cultivadas , Decídua/citologia , Perda do Embrião/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Humanos , Tolerância Imunológica , Interleucina-10/administração & dosagem , Interleucina-4/administração & dosagem , Masculino , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Modelos Imunológicos , Placentação/imunologia , Gravidez , Resultado da Gravidez , Transdução de Sinais/imunologia , Trofoblastos/citologia
3.
BMC Pregnancy Childbirth ; 21(1): 427, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134652

RESUMO

BACKGROUND: Euglycaemic ketoacidosis (EKA) is an infrequent but serious condition which usually follows a period of starvation, severe vomiting or illness in individuals with or without diabetes. Ketoacidosis is associated with materno-fetal morbidity and mortality necessitating prompt diagnosis and management. Physiological increases in insulin resistance render pregnancy a diabetogenic state with increased susceptibility to ketosis. COVID-19 is associated with worse clinical outcomes in patients with diabetes and is an independent risk factor for ketoacidosis in normoglycaemic individuals. CASE PRESENTATIONS: We describe two cases of SARS-CoV-2 positive pregnant women presenting with normoglycaemic metabolic ketoacidosis. Both cases were associated with maternal and fetal compromise, requiring aggressive fluid and insulin resuscitation and early delivery. CONCLUSION: We discuss possible physiology and propose a management strategy for euglycaemic ketoacidosis in pregnancy.


Assuntos
COVID-19/diagnóstico , Cetose/diagnóstico , Complicações na Gravidez/diagnóstico , Inanição/complicações , COVID-19/complicações , Feminino , Hidratação/métodos , Humanos , Resistência à Insulina , Cetose/complicações , Cetose/terapia , Troca Materno-Fetal , Gravidez , Complicações na Gravidez/terapia , SARS-CoV-2 , Inanição/terapia
4.
Nutr Metab Cardiovasc Dis ; 31(7): 2151-2155, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34039507

RESUMO

AIM: To discuss available information on the opportunity for pregnant women affected by diabetes/obesity to receive COVID-19 vaccine. DATA SYNTHESIS: Pregnant women with SARS-CoV-2 (COVID-19) infection are at high risk for severe acute respiratory syndrome and adverse outcomes. Pregnant women with severe COVID-19 present increased rates of preterm delivery (<37 gestational weeks), cesarean delivery and neonatal admissions to the intensive care unit. Comorbidity such as diabetes (pregestational or gestational) or obesity further increased maternal and fetal complications. It is known that diabetic or obese patients with COVID-19 present an unfavorable course and a worse prognosis, with a direct association between worse outcome and suboptimal glycol-metabolic control or body mass index (BMI) levels. Critical COVID-19 infection prevention is important for both mother and fetus. Vaccination during pregnancy is a common practice. Vaccines against COVID-19 are distributed across the world with some population considered to have a priority. Since pregnant women are excluded from clinical trials very little information are available on safety and efficacy of COVD-19 vaccines during pregnancy. However, it is well known the concept of passive immunization of the newborn obtained with transplacental passage of protective antibodies into the fetal/neonatal circulation after maternal infection or vaccination. Moreover, it has been reported that COVID-19 vaccine-induced IgG pass to the neonates through breastmilk. Therefore, maternal vaccination can protect mother, fetus and baby. CONCLUSIONS: After an individual risk/benefit evaluation pregnant and lactating women should be counselled to receive COVID-19 vaccines.


Assuntos
Glicemia/metabolismo , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Diabetes Gestacional/sangue , Lactação , Complicações Infecciosas na Gravidez/prevenção & controle , Gravidez em Diabéticas/sangue , SARS-CoV-2/patogenicidade , Vacinação , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Índice de Massa Corporal , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Tomada de Decisão Clínica , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/terapia , Feminino , Controle Glicêmico , Humanos , Imunidade Materno-Adquirida , Troca Materno-Fetal , Leite Humano/imunologia , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Gravidez em Diabéticas/diagnóstico , Gravidez em Diabéticas/terapia , Cuidado Pré-Natal , Medição de Risco , Fatores de Risco , SARS-CoV-2/imunologia , Vacinação/efeitos adversos
5.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34014840

RESUMO

BACKGROUNDThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , Troca Materno-Fetal/imunologia , SARS-CoV-2/imunologia , Adulto , Estudos de Coortes , Feminino , Sangue Fetal/imunologia , Humanos , Imunização Passiva , Imunoglobulina G/sangue , Recém-Nascido , Masculino , Gravidez , Adulto Jovem
6.
Nutr Metab Cardiovasc Dis ; 31(6): 1791-1797, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34023181

RESUMO

BACKGROUND AND AIMS: Gestational diabetes mellitus (GDM), hyperglycemia diagnosed during pregnancy, is one of the most common medical complications of pregnancy, treated primarily by diet and pharmacotherapy, if indicated. It is well-established that GDM increases the risk of adverse pregnancy outcomes and long-term complications in mothers and infants. Galectin-3 (Gal-3) is important in processes of cell growth, differentiation, inflammation, and fibrosis. We evaluated Gal-3 expression in pregnancies complicated by GDM as a parameter that might explain how GDM influences early onset of future complications. METHODS AND RESULTS: Forty-four women with GDM and 40 with normal pregnancy (NP) were recruited during delivery admission. Blood samples were obtained from parturients and umbilical cords blood, as well as placental tissue for analysis. Gal-3 mRNA expression was increased in maternal blood samples and placental tissue of women with GDM compared to NP. In GDM, Gal-3 mRNA was decreased in cord blood compared to maternal blood and placental tissue. Gal-3 GDM placental protein expression was increased compared to NP. Immunostaining revealed that Gal-3 is upregulated in GDM placental extravillous trophoblast. ELISA of Gal-3 maternal serum levels between GDM and NP were similar. CONCLUSION: Gal-3 is strongly expressed at molecular levels (mRNA and protein expression) in GDM maternal blood and placental tissue, and decreased in cord blood. These findings highlight the role of the placenta in protecting the fetus from potential Gal-3 damage. Gal-3 expression at mRNA and protein levels might be influenced by diabetes, even if blood glucose is balanced by medication or diet.


Assuntos
Proteínas Sanguíneas/metabolismo , Diabetes Gestacional/metabolismo , Galectinas/metabolismo , Placenta/metabolismo , Adulto , Biomarcadores/metabolismo , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Feminino , Sangue Fetal/metabolismo , Galectinas/sangue , Galectinas/genética , Humanos , Troca Materno-Fetal , Gravidez , Regulação para Cima
7.
Obstet Gynecol ; 138(2): 189-197, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33910220

RESUMO

OBJECTIVE: To characterize maternal immune response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and quantify the efficiency of transplacental antibody transfer. METHODS: We conducted a prospective cohort study of pregnant patients who tested positive for SARS CoV-2 infection at any point in pregnancy and collected paired maternal and cord blood samples at the time of delivery. An enzyme-linked immunosorbent assay (ELISA) and neutralization assays were performed to measure maternal plasma and cord blood concentrations and neutralizing potency of immunoglobulin (Ig)G, IgA, and IgM antibodies directed against the SARS-CoV-2 spike protein. Differences in concentrations according to symptomatic compared with asymptomatic infection and time from positive polymerase chain reaction (PCR) test result to delivery were analyzed using nonparametric tests of significance. The ratio of cord to maternal anti-receptor-binding domain IgG titers was analyzed to assess transplacental transfer efficiency. RESULTS: Thirty-two paired samples were analyzed. Detectable anti-receptor-binding domain IgG was detected in 100% (n=32) of maternal and 91% (n=29) of cord blood samples. Functional neutralizing antibody was present in 94% (n=30) of the maternal and 25% (n=8) of cord blood samples. Symptomatic infection was associated with a significant difference in median (interquartile range) maternal anti-receptor-binding domain IgG titers compared with asymptomatic infection (log 3.2 [3.5-2.4] vs log 2.7 [2.9-1.4], P=.03). Median (interquartile range) maternal anti-receptor-binding domain IgG titers were not significantly higher in patients who delivered more than 14 days after a positive PCR test result compared with those who delivered within 14 days (log 3.3 [3.5-2.4] vs log 2.67 [2.8-1.6], P=.05). Median (range) cord/maternal antibody ratio was 0.81 (0.67-0.88). CONCLUSIONS: These results demonstrate robust maternal neutralizing and anti-receptor-binding domain IgG response after SARS-CoV-2 infection, yet a lower-than-expected efficiency of transplacental antibody transfer and a significant reduction in neutralization between maternal blood and cord blood. Maternal infection does confer some degree of neonatal antibody protection, but the robustness and durability of protection require further study.


Assuntos
Formação de Anticorpos , COVID-19/imunologia , Troca Materno-Fetal , Complicações Infecciosas na Gravidez/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Neutralizantes , Infecções Assintomáticas , Feminino , Humanos , Gravidez , Estudos Prospectivos , Adulto Jovem
8.
Sci Rep ; 11(1): 8021, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850202

RESUMO

At present, there are still ambiguous reports about the perinatal infection of infants born to mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The dynamic characteristics of infantile serum antibodies born to mother with SARS-CoV-2 has not been well described. In this study, we analyzed the seroconversion of 27 newborns born to 26 pregnant women infected with SARS-CoV-2. The SARS-CoV-2 IgG positive rate of parturient was 80.8%, and half of their infants obtained maternal IgG. IgG transfer rates were 18.8% and 81.8% in those infants whose mother infected less and more than 2 weeks before delivery. In the first two months of life, the IgG level of infants dropped sharply to one tenth of that at birth. These results suggest that maternal SARS-CoV-2 IgG provides limited protection for infants.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/diagnóstico , Imunoglobulina G/sangue , Troca Materno-Fetal , SARS-CoV-2/imunologia , Adulto , COVID-19/virologia , Feminino , Idade Gestacional , Humanos , Imunoensaio , Lactente , Recém-Nascido , Masculino , Gravidez , RNA Viral/análise , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação
9.
BMC Pregnancy Childbirth ; 21(1): 267, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789610

RESUMO

BACKGROUND: The effect of maternal amino acid (AA) infusion before and during cesarean delivery on neonatal temperature remains unknown. We hypothesized that thermogenic effects of AA metabolism would help maintain body temperature of newborn babies and their mothers. METHODS: Seventy-six parturients scheduled for elective singleton term cesarean delivery were equally randomized to receive intravenous 200 ml of AA or placebo approximately 1 h before subarachnoid block (infusion rate:100 ml/h). The primary outcome was the newborn rectal temperature at 0, 5 and 10 min after birth. The secondary outcomes included the maternal rectal temperature at six time-points: T0 = before starting study solution infusion, T1 = 30 min after starting infusion, T2 = one hour after starting infusion, T3 = during spinal block, T4 = half an hour after spinal block, T5 = at the time of birth and T6 = at the end of infusion, as well as maternal thermal discomfort and shivering episodes. RESULTS: There were no differences in newborn temperature between the two groups at any of the time-points (intervention-time-interaction effect, P = 0.206). The newborn temperature (mean [95%CI] °C) at birth was 37.5 [37.43-37.66] in the AA and 37.4 [37.34-37.55] in the placebo group. It showed a significant (P < 0.001) downward trend at 5 and 10 min after birth (time effect) in both groups. One neonate in the AA and five in the placebo group were hypothermic (temperature < 36.5 °C) (P = 0.20). There was a significant difference in the maternal temperature at all time points between the two groups (Intervention-time interaction effect, P < 0.001). However, after adjustment for multiplicity, the difference was significant only at T6 (P = 0.001). The mean difference [95%CI] in temperature decline from baseline (T0) till the end of infusion (T6) between the two groups was - 0.39 [- 0.55;- 0.22] °C (P < 0.0001). Six mothers receiving placebo and none receiving AA developed hypothermia (temperature < 36 °C) (P = 0.025). Maternal thermal discomfort and shivering episodes were unaffected by AA therapy. CONCLUSIONS: Under the conditions of this study, maternal AA infusion before and during spinal anesthesia for cesarean delivery did not influence the neonatal temperature within 10 min after birth. In addition, the maternal temperature was only maintained at two hours of AA infusion. TRIAL REGISTRATION: ClinicalTrials.government, Identifier NCT02575170 . Registered on 10th April, 2015 - Retrospectively registered.


Assuntos
Aminoácidos/administração & dosagem , Temperatura Corporal/fisiologia , Cesárea/efeitos adversos , Hipotermia/prevenção & controle , Recém-Nascido/fisiologia , Complicações Intraoperatórias/prevenção & controle , Adulto , Temperatura Corporal/efeitos dos fármacos , Feminino , Humanos , Hipotermia/diagnóstico , Hipotermia/etiologia , Infusões Intravenosas , Cuidados Intraoperatórios/métodos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/etiologia , Troca Materno-Fetal/fisiologia , Gravidez , Estudos Prospectivos , Lactato de Ringer/administração & dosagem , Resultado do Tratamento , Adulto Jovem
10.
Nutrients ; 13(4)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918517

RESUMO

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.


Assuntos
Encéfalo/crescimento & desenvolvimento , Ácidos Graxos Ômega-3/farmacocinética , Ácidos Graxos Ômega-6/farmacocinética , Fenômenos Fisiológicos da Nutrição Materna , Transtornos do Neurodesenvolvimento/etiologia , Adulto , Disponibilidade Biológica , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Troca Materno-Fetal , Polimorfismo Genético , Gravidez , Fatores Sexuais
11.
Am J Hematol ; 96(6): 659-670, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33684239

RESUMO

The demand for iron is high in pregnancy to meet the increased requirements for erythropoiesis. Even pregnant females with initially iron-replete stores develop iron-deficiency anemia, due to inadequate iron absorption. In anemic females, the maternal iron supply is dedicated to maintaining iron metabolism in the fetus and placenta. Here, using a mouse model of iron deficiency in pregnancy, we show that iron recycled from senescent erythrocytes becomes a predominant source of this microelement that can be transferred to the placenta in females with depleted iron stores. Ferroportin is a key protein in the molecular machinery of cellular iron egress. We demonstrate that under iron deficiency in pregnancy, levels of ferroportin are greatly reduced in the duodenum, placenta and fetal liver, but not in maternal liver macrophages and in the spleen. Although low expression of both maternal and fetal hepcidin predicted ferroportin up-regulation in examined locations, its final expression level was very likely correlated with tissue iron status. Our results argue that iron released into the circulation of anemic females is taken up by the placenta, as evidenced by high expression of iron importers on syncytiotrophoblasts. Then, a substantial decrease in levels of ferroportin on the basolateral side of syncytiotrophoblasts, may be responsible for the reduced transfer of iron to the fetus. As attested by the lowest decrease in iron content among analyzed tissues, some part is retained in the placenta. These findings confirm the key role played by ferroportin in tuning iron turnover in iron-deficient pregnant mouse females and their fetuses.


Assuntos
Proteínas de Transporte de Cátions/fisiologia , Ferro na Dieta/administração & dosagem , Ferro/deficiência , Fígado/metabolismo , Complicações na Gravidez/metabolismo , Baço/metabolismo , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Proteínas de Transporte de Cátions/biossíntese , Proteínas de Transporte de Cátions/genética , Citocinas/sangue , Duodeno/metabolismo , Envelhecimento Eritrocítico , Índices de Eritrócitos , Feminino , Feto/metabolismo , Hemoglobinas/metabolismo , Hepcidinas/biossíntese , Hepcidinas/genética , Ferro/metabolismo , Fígado/embriologia , Macrófagos/metabolismo , Troca Materno-Fetal , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos da Linhagem 129 , Proteínas Musculares/sangue , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos , Fagocitose , Placenta/metabolismo , Gravidez , Regulação para Cima
12.
Front Immunol ; 12: 614246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746958

RESUMO

Transplacental transfer of antibodies is essential for conferring protection in newborns against infectious diseases. We assessed the impact of different factors, including gestational age and maternal infections such as HIV and malaria, on the efficiency of cord blood levels and placental transfer of IgG subclasses. We measured total IgG and IgG subclasses by quantitative suspension array technology against 14 pathogens and vaccine antigens, including targets of maternal immunization, in 341 delivering HIV-uninfected and HIV-infected mother-infant pairs from southern Mozambique. We analyzed the association of maternal HIV infection, Plasmodium falciparum exposure, maternal variables and pregnancy outcomes on cord antibody levels and transplacental transfer. Our results show that maternal antibody levels were the main determinant of cord antibody levels. Univariable and multivariable analysis showed that HIV reduced the placental transfer and cord levels of IgG and IgG1 principally, but also IgG2 to half of the antigens tested. P. falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer, but this was antigen-subclass dependent. Our findings suggest that lower maternally transferred antibodies may underlie increased susceptibility to infections of HIV-exposed infants. This could affect efficacy of maternal vaccination, especially in sub-Saharan Africa, where there is a high prevalence of HIV, malaria and unfavorable environmental factors.


Assuntos
Anticorpos/imunologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Adulto , Antígenos/imunologia , Terapia Antirretroviral de Alta Atividade , Feminino , Sangue Fetal/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunidade Materno-Adquirida , Imunoglobulina G/imunologia , Moçambique , Placenta/metabolismo , Gravidez , Transporte Proteico , Fatores Sexuais , Vacinas/imunologia , Adulto Jovem
13.
Sheng Li Xue Bao ; 73(1): 103-114, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33665665

RESUMO

Natural killer (NK) cells are the main immune cells at the maternal-fetal interface and accumulate in the uterine decidua in early pregnancy. Many studies have shown that NK cells at the maternal-fetal interface have unique phenotypes and play critical roles in various processes, including immune tolerance during pregnancy, decidualization, invasion of trophoblasts, remodeling of the uterine spiral artery, formation of the placenta and growth of embryo. However, specific functions of NK cells and their mechanism remain to be fully elucidated. This review summarizes the research progress of NK cells at the maternal-fetal interface and their roles in the pregnancy-related disorders in recent years. The aims of this review are to gain deep insight of the function of NK cells at the maternal-fetal interface and provide new ideas for intervention of pregnancy-related diseases.


Assuntos
Decídua , Células Matadoras Naturais , Feminino , Humanos , Troca Materno-Fetal , Placenta , Gravidez , Trofoblastos , Útero
14.
BMC Pregnancy Childbirth ; 21(1): 260, 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33773574

RESUMO

BACKGROUND: In monochorionic twin (MC) gestations with selective fetal growth restriction (FGR), the discordant fetal growth usually is due to unequal placental sharing. Glucose, which is essential for oxidative metabolism in the growing placenta and fetus, is transferred from maternal blood by facilitated carrier-mediated diffusion via glucose transporters (GLUTs). How the GLUTs expression varies in the two placenta territories manifests discordant perfusion in MC twin pregnancy with selective FGR is unknown. This study evaluates the human placental GLUT1 and GLUT3 gene expression in MC twin gestations with selective FGR. METHODS: MC twin pregnancy with selective FGR was defined as the presence of inter-twin birth weight discordance of > 25% and the smaller twin with a birth weight less than the 10th percentile in third trimester. Fetal umbilical artery Doppler was checked within 1 week before delivery in the two fetuses. An abnormal umbilical artery Doppler was defined as persistently absent or reverse end-diastolic flow (UA-AREDF). GLUT1, GLUT3 and HIF-1α gene expression were assayed in each twin's placental territories. The inter-twin placental gene expression ratio was calculated as the placenta GLUTs or HIF-1α expression level of the selective FGR twin divided by expression level of the appropriate-for-gestational-age (AGA) cotwin. Higher gene expression ratio means elevated gene expression in the selective FGR twin's placenta territory compared to AGA twin's placenta territory. RESULTS: 15 MC twin gestations with selective FGR including nine with normal (group 1) and six with abnormal selective FGR twin UA Doppler (group 2) were included into this study. The GLUT3 and HIF-1α gene expression are significantly elevated in selective FGR twin's placenta territory in group 2 twin pregnancies (mean gene expression ratio as 2.23 and 1.65, p values as 0.015 and 0.045, respectively), but not in in group 1 twin pregnancies. CONCLUSION: The upregulation of placental GLUT3 gene expression in selective FGR fetus with abnormal UA Doppler may be due to hypo-perfusion which is mediated by up -regulation of HIF-1α gene expression.


Assuntos
Retardo do Crescimento Fetal/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 3/genética , Placenta/patologia , Gravidez de Gêmeos/metabolismo , Adulto , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Perfilação da Expressão Gênica , Idade Gestacional , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Recém-Nascido , Idade Materna , Troca Materno-Fetal/genética , Placenta/irrigação sanguínea , Gravidez , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Regulação para Cima
15.
Nat Commun ; 12(1): 1064, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594056

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.


Assuntos
Síndrome do Ovário Policístico/patologia , Adiposidade , Animais , Animais Recém-Nascidos , Peso Corporal , Análise Discriminante , Modelos Animais de Doenças , Dislipidemias/patologia , Sistema Endócrino/patologia , Ciclo Estral , Feminino , Teste de Tolerância a Glucose , Gonadotropinas/farmacologia , Hormônios/sangue , Humanos , Secreção de Insulina , Análise dos Mínimos Quadrados , Lipídeos/química , Masculino , Troca Materno-Fetal , Análise Multivariada , Ovário/patologia , Ovário/fisiopatologia , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Ratos Wistar , Reprodução , Maturidade Sexual
16.
Placenta ; 106: 25-29, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33610934

RESUMO

INTRODUCTION: The possibility of vertical transmission of SARS-CoV-2 from the mother to the fetus is one of the most crucial issues regarding the COVID-19 effects on pregnancy. In this study, we aimed to explore the risk of maternal-fetal transmission before 24 weeks of gestation, through analysis of abortion materials collected from PCR-positive women with pregnancy loss. To the best of our knowledge, apart from case reports, this study is the first prospective work on the vertical transmission of SARS-CoV-2 in early pregnancy. METHODS: The patients who had attended our clinic with the diagnosis of pregnancy loss before 24 weeks of gestation were screened for COVID-19. Vertical transmission in PCR-positive women was assessed through the presence of SARS-CoV-2 RNA in fetal-placental tissues by rt-PCR test. RESULTS: 24 of 210 (%11,4) pregnant women participating in the study had positive rt-PCR results. Placenta and curettage material samples of these PCR-positive patients were analyzed and all valid test results (21 samples) were negative for SARS CoV-2 RNA. In three cases, the rt-PCR results were invalid due to failed internal controls. DISCUSSION: In the literature, the possibility of intrauterine vertical transmission of SARS-CoV-2 is still controversial. The findings of the present study did not reveal any evidence of vertical transmission of SARS-CoV-2 in early pregnancy.


Assuntos
COVID-19/diagnóstico , COVID-19/transmissão , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez/diagnóstico , SARS-CoV-2/fisiologia , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Aborto Espontâneo/virologia , Adulto , COVID-19/epidemiologia , COVID-19/terapia , Feminino , Feto/patologia , Feto/virologia , Idade Gestacional , Humanos , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Troca Materno-Fetal/fisiologia , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/terapia , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos , RNA Viral/isolamento & purificação , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Turquia/epidemiologia , Adulto Jovem
17.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33402432

RESUMO

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal-fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto-maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.


Assuntos
Adaptação Fisiológica , Retardo do Crescimento Fetal/metabolismo , Troca Materno-Fetal/fisiologia , Pinocitose/genética , Proteínas da Gravidez/genética , Serina-Treonina Quinases TOR/genética , Trofoblastos/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoácidos/deficiência , Animais , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Vilosidades Coriônicas/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Regulação da Expressão Gênica , Humanos , Camundongos , Gravidez , Proteínas da Gravidez/metabolismo , Cultura Primária de Células , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Trofoblastos/citologia
18.
Cell ; 184(3): 628-642.e10, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33476549

RESUMO

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Complicações Infecciosas na Gravidez/imunologia , SARS-CoV-2/imunologia , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Terceiro Trimestre da Gravidez/imunologia , Receptores de IgG/imunologia , Células THP-1
19.
Sci Rep ; 11(1): 23, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420078

RESUMO

Valproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause neurodevelopmental disorders in offspring, such as autism spectrum disorder. Understanding the negative action of VPA may help to prevent VPA-induced neurodevelopmental disorders. Astrocytes play a vital role in neurodevelopment and synapse function; however, the impact of VPA on astrocyte involvement in neurodevelopment and synapse function has not been examined. In this study, we examined whether exposure of cultured astrocytes to VPA alters neuronal morphology and synapse function of co-cultured neurons. We show that synaptic transmission by inhibitory neurons was small because VPA-exposed astrocytes reduced the number of inhibitory synapses. However, synaptic transmission by excitatory neurons and the number of excitatory synapses were normal with VPA-exposed astrocytes. VPA-exposed astrocytes did not affect the morphology of inhibitory neurons. These data indicate that VPA-exposed astrocytes impair synaptogenesis specifically of inhibitory neurons. Our results indicate that maternal use of VPA would affect not only neurons but also astrocytes and would result in perturbed astrocyte-mediated neurodevelopment.


Assuntos
Anticonvulsivantes/toxicidade , Astrócitos/efeitos dos fármacos , Ácido Valproico/toxicidade , Animais , Anticonvulsivantes/administração & dosagem , Astrócitos/patologia , Astrócitos/fisiologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Neurônios GABAérgicos/fisiologia , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ácido Valproico/administração & dosagem
20.
Nat Commun ; 12(1): 132, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420104

RESUMO

The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.


Assuntos
Poluentes Ambientais/efeitos adversos , Feto/imunologia , Exposição Materna/efeitos adversos , Sarampo/sangue , Praguicidas/efeitos adversos , Adulto , Anticorpos Antivirais/sangue , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Feminino , Sangue Fetal/química , Seguimentos , Humanos , Sistema Imunitário/efeitos dos fármacos , Imunogenicidade da Vacina , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Malária/prevenção & controle , Troca Materno-Fetal/imunologia , Sarampo/imunologia , Sarampo/prevenção & controle , Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/imunologia , Controle de Mosquitos/métodos , Praguicidas/análise , Fenilcarbamatos/efeitos adversos , Fenilcarbamatos/análise , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
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