RESUMO
BACKGROUND: Maternal anticoagulation use may increase indeterminate result rates on cell-free DNA-based screening, but existing studies are confounded by inclusion of individuals with autoimmune disease, which alone is associated with indeterminate results. Changes in chromosome level Z-scores are proposed by others as a reason for indeterminate results, but the etiology of this is uncertain. OBJECTIVE: This study aimed to evaluate differences in fetal fraction, indeterminate result rate, and total cell-free DNA concentration in individuals on anticoagulation without autoimmune disease compared with controls undergoing noninvasive prenatal screening. Secondly, using a nested case-control design, we evaluated differences in fragment size, GC-content, and Z-scores to evaluate laboratory-level test characteristics. STUDY DESIGN: This was a retrospective single-institution study of pregnant individuals undergoing cell-free DNA-based noninvasive prenatal screening using low-pass whole-genome sequencing between 2017 and 2021. Individuals with autoimmune disease, suspected aneuploidy, and cases where fetal fraction was not reported were excluded. Anticoagulation included heparin-derived products (unfractionated heparin, low-molecular-weight heparin), clopidogrel, and fondaparinux, with a separate group for those on aspirin alone. An indeterminate result was defined as fetal fraction <4%. We evaluated the association between maternal anticoagulation or aspirin use, and fetal fraction, indeterminate results, and total cell-free DNA concentration using univariate and multivariate analyses, controlling for body mass index, gestational age at sample collection, and fetal sex. For the anticoagulation cohort, we compared laboratory-level test characteristics among cases (on anticoagulation) and a subset of controls. Lastly, we evaluated for differences in chromosome level Z-scores among those on anticoagulation with and without indeterminate results. RESULTS: A total of 1707 pregnant individuals met the inclusion criteria. Of those, 29 were on anticoagulation and 81 were on aspirin alone. For those on anticoagulation, the fetal fraction was significantly lower (9.3% vs 11.7%; P<.01), the indeterminate result rate was significantly higher (17.2% vs 2.7%; P<.001), and the total cell-free DNA concentration was significantly higher (218 pg/µL vs 83.7 pg/µL; P<.001). Among those on aspirin alone, the fetal fraction was lower (10.6% vs 11.8%; P=.04); however, there were no differences in the rate of indeterminate results (3.7% vs 2.7%; P=.57) or total cell-free DNA concentration (90.1 pg/µL vs 83.8 pg/µL; P=.31). After controlling for maternal body mass index, gestational age at sample collection, and fetal sex, anticoagulation was associated with an >8-fold increase in the likelihood of an indeterminate result (adjusted odds ratio, 8.7; 95% confidence interval, 3.1-24.9; P<.001), but not aspirin (adjusted odds ratio, 1.2; 95% confidence interval, 0.3-4.1; P=.8). Anticoagulation was not associated with appreciable differences in cell-free DNA fragment size or GC-content. Although differences in chromosome 13 Z-scores were observed, none were observed for chromosomes 18 or 21, and this difference did not contribute to the indeterminate result call. CONCLUSION: In the absence of autoimmune disease, anticoagulation use, but not aspirin, is associated with lower fetal fraction, higher total cell-free DNA concentration, and higher rates of indeterminate results. Anticoagulation use was not accompanied by differences in cell-free DNA fragment size or GC-content. Statistical differences in chromosome level Z-scores did not clinically affect aneuploidy detection. This suggests a likely dilutional effect by anticoagulation on cell-free DNA-based noninvasive prenatal screening assays contributing to low fetal fraction and indeterminate results, and not laboratory or sequencing-level changes.
Assuntos
Doenças Autoimunes , Ácidos Nucleicos Livres , Gravidez , Feminino , Humanos , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Heparina , Aneuploidia , Aspirina/uso terapêutico , Anticoagulantes/uso terapêuticoRESUMO
BACKGROUND: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. OBJECTIVE: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. STUDY DESIGN: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. RESULTS: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4-4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4-4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04-1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5-8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5-4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. CONCLUSION: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.
Assuntos
Ácidos Nucleicos Livres , Síndrome de Down , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Estatura Cabeça-Cóccix , Resultado da Gravidez , Peso ao Nascer , Estudos Retrospectivos , Nascimento Prematuro/etiologia , Primeiro Trimestre da Gravidez , Ultrassonografia Pré-Natal/efeitos adversos , Gêmeos Dizigóticos , Gravidez de Gêmeos , TrissomiaRESUMO
BACKGROUND: Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE: This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13. STUDY DESIGN: This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. RESULTS: A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. CONCLUSION: Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.
Assuntos
Ácidos Nucleicos Livres , Síndrome de Down , Recém-Nascido , Gravidez , Feminino , Humanos , Adulto , Lactente , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Gravidez de Gêmeos , Trissomia/diagnóstico , Trissomia/genética , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Estudos RetrospectivosRESUMO
Pregnancy in individuals with a mechanical heart valve has been classified as very high risk because of a substantially increased risk of maternal mortality or severe morbidity. Lifelong therapeutic anticoagulation is a principal component of the medical management of mechanical heart valves to prevent valve thrombosis. Anticoagulation regimens indicated outside of pregnancy for patients with mechanical valves should be continued during pregnancy with the possibility of modifications based on the type of valve, the trimester of pregnancy, individual risk tolerance, and circumstances around the time of delivery. The purpose of this document is to provide recommendations regarding the management of anticoagulation for common cardiac conditions complicating pregnancy, including mechanical heart valves, atrial fibrillation, systolic heart failure, and congenital heart disease.
Assuntos
Complicações Cardiovasculares na Gravidez , Tromboembolia , Anticoagulantes/uso terapêutico , Arritmias Cardíacas , Feminino , Humanos , Perinatologia , Gravidez , Complicações Cardiovasculares na Gravidez/induzido quimicamente , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/prevenção & controle , Tromboembolia/prevenção & controleRESUMO
OBJECTIVE: Reasons for first trimester noninvasive prenatal screening (NIPS) test failure in obese women remain elusive. As dilution from maternal sources may be explanatory, we determined the relationship between obesity, fetal fraction (FF), and total cell-free DNA (cfDNA) using our NIPS platform. METHODS: We assessed differences in first trimester (≤14 weeks) FF, indeterminate rate, and total cfDNA between obese (n = 518) and normal-weight women (n = 237) after exclusion of confounders (anticoagulation, autoimmunity, aneuploidy) and controlling for covariates. RESULTS: Fetal fraction was lower, and the indeterminate rate higher, in obese compared to controls (9.2% ± 4.4 vs. 12.5% ± 4.5, p < 0.001 and 8.4 vs. 1.7%, p < 0.001, respectively), but total cfDNA was not different (92.0 vs. 82.1 pg/µl, p = 0.10). For each week, the FF remained lower in obese women (all p < 0.01) but did not increase across the first trimester for either group. Obesity increased the likelihood of indeterminate result (OR 6.1, 95% CI 2.5, 14.8; p < 0.001) and maternal body mass index correlated with FF (ß -0.27, 95% CI -0.3, -0.22; p < 0.001), but not with total cfDNA (ß 0.49, 95% CI -0.55, 1.53; p = 0.3). CONCLUSIONS: First trimester obese women have persistently low FF and higher indeterminate rates, without differences in total cfDNA, suggesting placental-specific mechanisms versus dilution from maternal sources as a potential etiology.
Assuntos
Ácidos Nucleicos Livres/análise , Obesidade/genética , Primeiro Trimestre da Gravidez/fisiologia , Adulto , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Feminino , Humanos , Obesidade/complicações , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricosRESUMO
BACKGROUND: Incorporation of the patient voice is urgently needed in a broad array of health care settings, but it is particularly lacking in the obstetrical literature. Systematically derived information about patients' experience with hypertensive disorders of pregnancy (HDP), most notably preeclampsia, is necessary to improve patient-provider communication and ultimately inform patient-centered care and research. We sought to examine the information needs and experiences of individuals with pregnancies complicated by hypertensive disorders. METHODS: We conducted a qualitative content analysis of narrative-responses to an open-ended question from the Preeclampsia Registry (TPR), an online registry hosted by the Preeclampsia Foundation. Individuals were invited to enroll in TPR via social media, web searches, and newsletters. We restricted our analysis to participants who self-reported a history of HDP and responded to the open-ended question, "Is there any information that you could have had at the time of this pregnancy that would have been helpful?". Available responses from July 2013 to March 2017 were included. Narrative responses were coded, reconciled, and thematically analyzed by multiple coders using an inductive approach. Our main outcome measures included participants' expressed needs and additional concerns with respect to their HDP pregnancy. RESULTS: Of 3202 enrolled participants, 1850 completed the survey and self-reported having at least one pregnancy complicated by HDP, of which 895 (48.4%) responded to the open-ended question. Participants delivered in the United States (83%) and 27 other countries. Compared to non-responders, responders reported more severe HDP phenotypes and adverse offspring outcomes. We identified three principal themes from responses: patient-identified needs, management and counseling, and potential action. Responses revealed that participants' baseline understanding of HDP, including symptoms, management, therapeutic strategies, and postpartum complications, was demonstrably lacking. Responders strongly desired improved counseling so that both they and their providers could collaboratively diagnose, appropriately manage, and robustly and continuously communicate to facilitate a partnership to address any HDP complications. CONCLUSIONS: Participants' responses regarding their HDP experience provide indispensable insight into the patient's perspectives. Our study suggests that improved education regarding possible HDP complications and transparency about the consideration of HDP and its associated outcomes during an evaluation are needed, and efforts to implement these strategies should be sought. TRIAL REGISTRATION: The Preeclampsia Registry: NCT02020174.
Assuntos
Atitude Frente a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Hipertensão Induzida pela Gravidez/psicologia , Pré-Eclâmpsia/psicologia , Sistema de Registros , Adulto , Comunicação , Aconselhamento , Feminino , Humanos , Narração , Gravidez , Pesquisa QualitativaRESUMO
BACKGROUND: Preeclampsia is associated with diastolic dysfunction, peripartum cardiomyopathy, and both pre-existing and subsequent maternal cardiovascular disease. Gene mutations causing idiopathic cardiomyopathy were recently implicated in peripartum cardiomyopathy. We sought to determine whether cardiomyopathy gene mutations are also a contributory factor in preeclampsia. METHODS: Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of preeclampsia completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with cardiomyopathy. Missense variants were deemed damaging missense if so classified by any of 7 standard function prediction algorithms. Variants were defined as loss-of-function if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from 2 control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33 000 subjects in the Exome Aggregation Consortium. Preeclampsia was not excluded in control groups. RESULTS: Of 181 subjects with confirmed preeclampsia, 96% were white. Seventy-two percent had ≥1 preterm preeclampsia delivery <37 weeks. Among preeclampsia subjects, whole exome sequencing demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 cardiomyopathy genes considered. The prevalence of these loss-of-function variants was significantly higher in preeclampsia subjects (5.5%) compared with the local control (2.5%) population ( P=0.014). Sixty-eight percent of women with preeclampsia carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum cardiomyopathy, most mutations (55%) were found in the TTN gene. Seventy-three percent of preeclampsia subjects had TTN mutations in the preeclampsia cohort versus 48% in local controls ( P=1.36E-11). DISCUSSION: Women who develop preeclampsia are more likely to carry protein-altering mutations in genes associated with cardiomyopathy, particularly in TTN. Mutations promoting cardiomyopathy are prevalent in preeclampsia, idiopathic cardiomyopathy, and peripartum cardiomyopathy, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
Assuntos
Cardiomiopatias/patologia , Conectina/genética , Pré-Eclâmpsia/patologia , Adulto , Bancos de Espécimes Biológicos , Cardiomiopatias/genética , Conectina/química , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Feminino , Idade Gestacional , Humanos , Mutação de Sentido Incorreto , Pré-Eclâmpsia/genética , Gravidez , Sistema de Registros , Saliva/metabolismo , Sequenciamento do ExomaRESUMO
CONCLUSIONS: Maternal red blood cell (RBC) alloantibodies can cause hemolytic disease of the fetus and newborn (HDFN). Although much is described about common antibodies associated with HDFN, management of a pregnancy complicated by a maternal rare antibody presents several challenges related to assessment of fetal anemia risk, availability of blood for transfusion to the mother and/or the fetus or newborn if needed, and planning for delivery in the case of maternal hemorrhage. Here we report the laboratory medicine workup of a patient who presented for obstetrical care in the United States in the third trimester and had a rare antibody (anti-Inb). Prenatal antibody detection testing demonstrated maternal anti-Inb in a 28-year-old woman (gravida 4 para 1021). Ultrasound could not rule out fetal anemia. Monocyte monolayer assay was performed to assess for the clinical significance of the anti-Inb and revealed that the antibody may be capable of causing accelerated clearance of antigen-positive RBCs. A local and national query revealed that no appropriate units of RBCs were available for either the mother or neonate. Given this information, serial maternal autologous blood donations were performed, and a comprehensive care plan with a multidisciplinary approach for delivery, neonatal management, and preparation for hemorrhage was developed. Published data and our experience suggest that maternal blood donation appears to be a safe and effective way to manage mothers who cannot safely use the community blood supply. Involvement of obstetric, transfusion medicine, anesthesia, and neonatology providers was imperative for a favorable outcome. The antibody did not cause clinically significant anemia in this infant.
Assuntos
Doadores de Sangue , Eritroblastose Fetal , Adulto , Eritrócitos , Feminino , Humanos , Recém-Nascido , Isoanticorpos , Monócitos , GravidezRESUMO
OBJECTIVE: This study aims to identify risk factors for cesarean delivery (CD) surgical site infection (SSI). study design: Retrospective analysis of 2,739 CDs performed at the University of Pittsburgh in 2011. CD SSIs were defined using National Healthcare Safety Network (NHSN) criteria. Chi-square test and t-test were used for bivariate analyses and multivariate logistic regression was used to identify SSI risk factors. RESULTS: Of 2,739 CDs, 178 (6.5%) were complicated by SSI. Patients with a SSI were more likely to have Medicaid, have resident physicians perform the CD, an American Society of Anesthesiologists (ASA) class of ≥ 3, chorioamnionitis, tobacco use, and labor before CD. In multivariable analysis, labor (odds ratio [OR], 2.35; 95% confidence interval [95% CI], 1.65-3.38), chorioamnionitis (OR, 2.24; 95% CI, 1.25-3.83), resident teaching service (OR, 2.15; 95% CI, 1.54-3.00), tobacco use (OR, 1.70; 95% CI, 1.04-2.70), ASA class ≥ 3 (OR, 1.61; 95% CI, 1.06-2.39), and CDs performed for nonreassuring fetal status (OR, 0.43; 95% CI, 0.26-0.67) were significantly associated with CD SSI. CONCLUSION: Multiple patient, provider, and procedure-specific risk factors contribute to CD SSI risk which may be targeted in infection-control efforts.
Assuntos
Cesárea , Corioamnionite/epidemiologia , Sofrimento Fetal/epidemiologia , Trabalho de Parto , Medicaid/estatística & dados numéricos , Infecção da Ferida Cirúrgica/epidemiologia , Uso de Tabaco/epidemiologia , Adulto , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Feminino , Humanos , Seguro Saúde/estatística & dados numéricos , Internato e Residência/estatística & dados numéricos , Modelos Logísticos , Análise Multivariada , Obstetrícia/educação , Razão de Chances , Gravidez , Prática Privada/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Hemorragia Uterina/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Both history of spontaneous preterm birth (sPTB) and shorter interpregnancy intervals (IPIs) increase the risk of recurrent sPTB. Mechanisms underlying the association between IPI and recurrent sPTB are unknown. We have previously demonstrated that higher concentrations of cervical anti-inflammatory cytokines are a risk factor for sPTB and upper genital tract inflammation. Here, we examine the association between IPI and cervical anti-inflammatory cytokines among women with previous sPTB. PATIENTS AND METHODS: A prospective cohort of 73 women with previous sPTB and cervical interleukins (IL-4, IL-10, and IL-13) measured at < 16 weeks. Using the published principal factor analysis, the anti-inflammatory (ANTI) score was calculated. From our previous work, higher ANTI scores increase the subsequent risk of sPTB. IPI was the time from the previous birth to the conception of current pregnancy. Confounders included education level, marital status, gonorrhea, chlamydia, body mass index, race, and cigarette smoking. IPI and ANTI score were analyzed using univariable and multivariable analyses. RESULTS: There was a significant negative linear relation between IPI and ANTI score (ß = -0.075, p = 0.017). This persisted after adjustment for confounders (p = 0.02). As IPI decreases by 1 month, the ANTI-score-associated risk of sPTB increases approximately by 4%. CONCLUSION: Among women with previous sPTB, there was a significant negative linear relation between IPI and ANTI score.
Assuntos
Intervalo entre Nascimentos , Secreções Corporais/química , Colo do Útero/química , Interleucinas/análise , Nascimento Prematuro/metabolismo , Adulto , Quimiocina CCL2/análise , Feminino , Humanos , Interleucina-10/análise , Interleucina-13/análise , Interleucina-4/análise , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Segundo Trimestre da Gravidez/metabolismo , Estudos Prospectivos , Medição de Risco , Adulto JovemRESUMO
Uterine leiomyomas may affect the performance of cell-free DNA (cfDNA)-based noninvasive prenatal testing (NIPT). We conducted a retrospective cohort study of pregnant individuals with and without leiomyomas undergoing first-trimester cfDNA-based NIPT. Characteristics of NIPT in patients with leiomyomas (n=122) were compared with those in patients without leiomyomas (n=937). Mean fetal fraction was lower in patients with leiomyomas compared with patients without (10.0% vs 11.5%; P =.001); however, the rate of indeterminate results was different only in patients without obesity (body mass index [BMI] lower than 30) (5.3% vs 1.5%; P =0.03). Total cfDNA concentration was higher in patients with leiomyomas ( P =.002), suggesting possible dilution of the fetal fraction. Leiomyoma size did not affect NIPT metrics. In conclusion, uterine leiomyomas are associated with lower fetal fraction and, in patients without obesity, with a higher rate of indeterminate results independent of leiomyoma size.
Assuntos
Ácidos Nucleicos Livres , Leiomioma , Teste Pré-Natal não Invasivo , Gravidez , Feminino , Humanos , Primeiro Trimestre da Gravidez , Estudos Retrospectivos , Leiomioma/diagnóstico , Obesidade , Diagnóstico Pré-Natal/métodosRESUMO
Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-ß1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.
RESUMO
Pediatric Bipolar Disorder (BD) is a serious mental illness that affects children and adolescents, characterized by episodes of mania, depression, and mixed episodes. Recent studies have suggested that abnormalities in the white matter (WM) may be a contributing factor. The neuropathogenesis of BD in children is not well-described, and research in this area is limited. Euthymic phase is a period in which clinical symptoms are present but not severe enough to significantly impact mood and daily behavior. In order to better understand the WM changes associated with BD in children, this study utilized Diffusion Tensor Imaging (DTI), to investigate alterations in WM microstructure. 20 confirmed euthymic BD children (aged 7-16) and 20 typically developing children were included in the study. DTI scans were obtained using a 3 T Magnetom Skyra and were analyzed using tract-based spatial statistics (TBSS) to examine changes in fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Results showed that compared to the healthy control group, the euthymic BD group exhibited increased FA, AD, RD, and MD values in several brain regions, including the thalamus, precentral corticospinal tract, and superior longitudinal fasciculus. Conversely, decreased values were observed in the body of the corpus callosum and inferior fronto-occipital fasciculus. These findings suggest that alterations in WM microstructure are a hallmark of pediatric bipolar disorder. These findings provide important insights into the brain changes associated with pediatric bipolar disorder and open the door for new avenues of research.
Assuntos
Transtorno Bipolar , Substância Branca , Adolescente , Criança , Humanos , Transtorno Bipolar/diagnóstico por imagem , Imagem de Tensor de Difusão , Substância Branca/diagnóstico por imagem , Transtorno Ciclotímico , Encéfalo/diagnóstico por imagemRESUMO
PROBLEM: Preeclampsia (PE) is associated with an increased risk of maternal cardiovascular disease (CVD), however, it is unclear whether this is due to shared underlying physiology or changes which occur during the disease process. Fetal microchimerism (FMc) within the maternal circulation can durably persist decades after pregnancy, is known to occur at greater frequency in PE, and can potentially affect local and systemic immune programming, thus changes in cellular FMc may provide a mechanism for long-term health outcomes associated with PE. METHOD OF STUDY: We investigated whether PE is associated with alterations in FMc immune and stem cell populations. We analyzed maternal peripheral blood mononuclear cells (PBMC) from PE cases (n = 16) and matched controls from normal pregnancies (n = 16), from which immune and stem cell subsets were isolated by flow cytometry. Genomic DNA was extracted from total PMBC and individual cell subsets, and FMc frequency was quantified by quantitative polymerase chain reaction assays targeting a fetal-specific non-shared polymorphism identified from family genotyping. RESULTS: There was a significant increase in FMc concentration in immune cell subsets in PE cases compared to controls, predominantly in B cell, and NK cell lymphocyte populations. There was no significant difference in FMc frequency or concentration within the stem cell population between PE and controls. CONCLUSIONS: The altered concentrations of immune cells within FMc in the maternal blood provides a potential mechanism for the inflammation which occurs during PE to induce long-lasting changes to the maternal immune system and may potentially promote chronic maternal disease.
Assuntos
Leucócitos Mononucleares , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Quimerismo , Feto , Células-TroncoRESUMO
Bidirectional exchange of cells between mother and fetus establishes microchimerism (Mc). Mc can persist for decades and is associated with later-life health and disease. Greater fetal Mc is detected in the maternal compartment in preeclampsia (PE), but whether maternal Mc (MMC) in umbilical cord blood (CB) is altered in PE is unknown. We evaluated MMc in CB from normal and PE pregnancies. DNA from CB mononuclear cells following placental delivery (n = 36 PE, n = 37 controls) and maternal blood was extracted and genotyped. MMc, quantified by qPCR assays targeting maternal-specific nonshared polymorphisms in CB, was compared using logistic and negative binomial regression models. Clinically and statistically relevant confounders were included, and included the total number of cell equivalents tested, gravidity, mode of delivery, birthweight, and fetal sex. PE participants delivered at earlier gestational ages, with higher Cesarean rates, and lower infant birthweights. CB MMc detection was similar between PE and controls (52.8% vs. 51.3%, respectively, p = 0.90) and unchanged after adjustment for confounders. MMc concentration was not different between groups (mean 73.7 gEq/105 gEq in PE vs. mean 22.8 gEq/105 in controls, p = 0.56), including after controlling for confounders (p = 0.64). There was no difference in CB MMc detection or concentration between PE and normal pregnancies, despite previously noted greater fetal Mc in the maternal compartment. This suggests possible differential transfer of cells at the maternal fetal interface in PE. Phenotypic evaluation of Mc cells may uncover underlying mechanisms for differential cellular exchange between mother and fetus in PE.
Assuntos
Placenta , Pré-Eclâmpsia , Gravidez , Humanos , Feminino , Quimerismo , Mães , Cordão Umbilical , Sangue FetalRESUMO
Bipolar disorder (BPD) is a psychiatric condition driving frequent mood swings between periodic extremes of happiness and depression in patients. In this study, a source-based morphometry (SBM) and voxel-based morphometry (VBM) analysis was utilized to measure the differences in the white matter (WM) and grey matter (GM) between euthymic children with BPD and typically developing (TD) children. We adapted both multivariate (SBM) and univariate (VBM) analysis in 20 children with BPD euthymia /remission and compared to the same number of TD age-matched children. The VBM did not reveal any increase in GM and WM voxel values in children with BPD. However, a decrease in the GM voxel values in the bilateral middle frontal and WM voxels in the left hippocampus, left caudate, left orbitofrontal and right inferior parietal cortices was identified. Conversely, SBM analysis in BPD displayed a high GM value in bilateral angular gyrus, bilateral inferior temporal, left supplementary motor area and left middle temporal region, while a low value was observed in left inferior and middle occipital, cerebellum, thalamus, left premotor area and left lingual gyrus. These findings suggested a crucial GM and WM alteration in multiple neural regions in BPD children even during sustained and substantial remission.
Assuntos
Transtorno Bipolar , Substância Branca , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Córtex Cerebral , Criança , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND: Hypertensive disorders of pregnancy contribute to maternal and offspring morbidity and mortality. Studies suggest that a lower early pregnancy fetal fraction is associated with an increased risk of hypertensive disorders of pregnancy. However, maternal obesity significantly affects fetal fraction and is a risk factor for hypertensive disorders of pregnancy. OBJECTIVE: We determined the association between fetal fraction (using a standardized single-institution platform, including male and female fetuses) and hypertensive disorders of pregnancy, stratified by obesity status. Second, we evaluated differences in total cell-free DNA concentration and correlation of fetal fraction with clinical markers of hypertensive disorders of pregnancy severity. STUDY DESIGN: This was a retrospective, single-institution study of a previously validated cell-free DNA-based noninvasive prenatal screening assay of 1058 samples. Maternal body mass index at the time of noninvasive prenatal screening was assessed, and hypertensive disorders of pregnancy were confirmed by a detailed medical record review. Differences in fetal fraction and total cell-free DNA concentration between the groups were assessed with univariate analyses. Multivariable regression was used to evaluate the association between fetal fraction and hypertensive disorders of pregnancy, adjusted for body mass index, maternal age, gestational age at noninvasive prenatal screening, and fetal sex. The association between fetal fraction and hypertensive disorders of pregnancy among individuals with obesity (body mass index, ≥30 kg/m2) and individuals without obesity (body mass index, <30 kg/m2) was investigated while controlling for the aforementioned covariates. Lastly, multivariable linear regression was used to evaluate the association between fetal fraction and clinical markers of hypertensive disorders of pregnancy severity. RESULTS: We identified individuals with (n=117) and without (n=941) hypertensive disorders of pregnancy with noninvasive prenatal screening drawn before 20 weeks of gestation and with fetal fraction and body mass index data available. Those with hypertensive disorders of pregnancy had a lower fetal fraction (10.2%±4.2% vs 11.6%±4.7%; P<.01), without differences in total cell-free DNA concentration (P=.14). When groups were stratified by obesity status, this relationship was only valid for individuals without obesity (P=.02). Only when logistic regression analysis was restricted to individuals without obesity did the likelihood of hypertensive disorders of pregnancy rise with decreasing fetal fraction (odds ratio, 0.93; 95% confidence interval, 0.88-0.99; P=.02). In addition, fetal fraction was inversely associated with maximum systolic blood pressure at the time of hypertensive disorders of pregnancy only in the population without obesity (ß, -0.08; 95% confidence interval, -0.147 to -0.01; P=.02). CONCLUSION: Although a lower fetal fraction is associated with the development of hypertensive disorders of pregnancy, the use of this parameter for the prediction may be problematic in individuals with obesity, as obesity has such a profound effect on fetal fraction. However, we uniquely noted that among individuals without obesity, fetal fraction is lower for those that develop hypertensive disorders of pregnancy and lower fetal fraction increases the odds of hypertensive disorders of pregnancy development. Lastly, low fetal fraction in the population without obesity that developed hypertensive disorders of pregnancy was associated with higher systolic blood pressure at the time of hypertensive disorders of pregnancy, an important clinical marker of hypertensive disorders of pregnancy severity. As analytical approaches of cell-free DNA interrogation advance, the prediction of placental-mediated disorders with first-trimester sampling is likely to improve, although this may remain challenging in gravidas with obesity, a cohort at high risk of developing hypertensive disorders of pregnancy.
Assuntos
Ácidos Nucleicos Livres , Hipertensão Induzida pela Gravidez , Biomarcadores , Feminino , Humanos , Hipertensão Induzida pela Gravidez/diagnóstico , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/etiologia , Incidência , Masculino , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Placenta , Gravidez , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Nepal has substantial potential to generate electricity through hydropower projects. Most of the hydropower projects in Nepal are Run-off-River (ROR) types. Significant seasonal variation can be pronounced on its river basins resulting in higher streamflow & higher hydropower generation during the wet/summer season and just reverse scenario in case of the dry/winter season. Thus, ROR-type hydropower in Nepal is more susceptible to Climate Change. This study assesses the impact of variation in climatic parameters on the hydropower generation by implementing WEAP model using the meteorological and hydrological data from 1976 to 2004 under Reference & Climatic Scenarios. The results reveal that the streamflow of Dordi River of Nepal is in increasing trends and can be more pronounced during April, May, June & July of the season under climatic scenarios. The generation of hydropower plant is likely to increase up to 15%, 1%-32% & 1%-51% over the study period under climatic scenario-1, 2 & 3, respectively, as compared to baseline scenario and the increments are observed to be more prominent during April & May of the season which is very crucial finding in current context of Nepal as there is power deficit during the dry season. Therefore, detailed technical and policy level planning can enhance the power generating capability of the future hydropower projects that will be developed in this corridor. This will significantly impacts the national energy planning and implementation.
RESUMO
OBJECTIVES: To gain insight into the patient journey through a pre-eclampsia-complicated pregnancy. DESIGN: Cross-sectional patient registry study. SETTING: Online patient registry initiated by the Preeclampsia Foundation. PARTICIPANTS: Women with a history of pre-eclampsia enrolled in The Preeclampsia Registry (TPR). PRIMARY AND SECONDARY OUTCOME MEASURES: Retrospective patient-reported experience measures concerning awareness of pre-eclampsia, timing and type of information on pre-eclampsia received, involvement in decision making regarding medical care, mental/emotional impact of the pre-eclampsia-complicated pregnancy and impact on future pregnancy planning. RESULTS: Of 3618 TPR-participants invited to complete the Patient Journey questionnaire, data from 833 (23%) responders were available for analysis. Most responders were white (n=795, 95.4%) and lived in the USA (n=728, 87.4%). Before their pre-eclampsia diagnosis, 599 (73.9%) responders were aware of the term 'pre-eclampsia', but only 348 (43.7%) were aware of its associated symptoms. Women with a lower level of education were less likely to have heard of pre-eclampsia (OR 0.36, 95% CI 0.21 to 0.62). Around the time of diagnosis, 29.2% of responders did not feel involved in the decision making, which was associated with reporting a serious mental/emotional impact of the pre-eclampsia experience (OR 2.46, 95% CI 1.58 to 3.84). Over time, there was an increase in the proportion of women who were aware of the symptoms of pre-eclampsia (32.2% before 2011 to 52.5% after 2016; p<0.001) and in the proportion of responders stating they received counselling about the later-life health risks associated with pre-eclampsia (14.2% before 2011 to 25.6% after 2016; p=0.005). CONCLUSIONS: This study demonstrates that improved patient education regarding pre-eclampsia is needed, that shared decision making is of great importance to patients to enhance their healthcare experience, and that healthcare providers should make efforts to routinely incorporate counselling about the later-life health risks associated with pre-eclampsia. TRIAL REGISTRATION NUMBER: NCT02020174.
Assuntos
Pré-Eclâmpsia , Aconselhamento , Estudos Transversais , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Gravidez , Sistema de Registros , Estudos RetrospectivosRESUMO
Background Placental derived cell-free DNA (cfDNA), widely utilized for prenatal screening, may serve as a biomarker for preeclampsia. To determine whether cfDNA parameters are altered in preeclampsia, we conducted a case-control study using prospectively collected maternal plasma (n=20 preeclampsia, n=22 normal) using our in-house validated prenatal screening assay. Methods and Results Isolated cfDNA was quantified, sequenced using Illumina NextSeq 500, and the placental-derived fraction was determined. Clinical and test characteristics were compared between preeclampsia and controls, followed by comparisons within the preeclampsia cohort dichotomized by cfDNA concentration. Lastly, cfDNA parameters in preeclampsia were correlated with markers of disease severity. Maternal age, body mass index, gestational age at delivery, cesarean rate, and neonatal birthweight were expectedly different between groups (P≤0.05). The placental-derived cfDNA fraction did not differ between groups (21.4% versus 16.9%, P=0.06); however, total cfDNA was more than 10 times higher in preeclampsia (1235 versus 106.5 pg/µL, P<0.001). This relationship persisted when controlling for important confounders (OR 1.22, 95% CI 1.04-1.43, P=0.01). The dichotomized preeclampsia group with the highest cfDNA concentration delivered earlier (33.2 versus 36.6 weeks, P=0.02) and had lower placental-derived fractions (9.1% versus 21.4%, P=0.04). Among preeclampsia cases, higher total cfDNA correlated with earlier gestational age at delivery (P=0.01) and higher maximum systolic blood pressure (P=0.04). Conclusions At diagnosis, total cfDNA is notably higher in preeclampsia, whereas the placental derived fraction remains similar to healthy pregnancies. In preeclampsia, higher total cfDNA correlates with earlier gestational age at delivery and higher systolic blood pressure. These findings may indicate increased release of cfDNA from maternal tissue injury.