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1.
Medicine (Baltimore) ; 103(20): e38188, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758859

RESUMO

BACKGROUND: To assess the predictive capabilities of serum exosomal levels of micro-RNA-520a-5p (miR-520a-5p) concerning the occurrence of severe preeclampsia (sPE) and fetal growth restriction (FGR) during the first trimester of pregnancy. METHODS: During the period spanning from October 2020 to October 2021, serum samples were procured from the first trimester and subsequently preserved by freezing at -80 ℃. These samples were obtained from 105 pregnant women in a nested case-control study. This cohort consisted of individuals who later developed sPE (sPE group, n = 35) and FGR (FGR group, n = 35) during the third trimester. Additionally, 35 women with normal blood pressure were denoted as normal pregnancy group. Serum samples from the first trimester were retrieved from all groups for further analysis after thawing. Exosomes were extracted from the serum samples collected during the first trimester and examined using transmission electron microscopy, western blot, and nanoparticle tracking analysis. Additionally, the determination of their placental origin was also established during the course of the study. Exosome miR-520a-5p levels were measured using real-time quantitative polymerase chain reaction assays, primarily involving quantitative reverse transcription polymerase chain reactions. Fetal placental tissues from the 3 groups were collected shortly after birth, and miR-520a-5p expression was measured using real-time quantitative polymerase chain reaction. Serum placental exosomes and fetal placental tissues were compared for miR-520a-5p levels. Placental trophoblasts were identified as the source of serum exosomes in all 3 groups. RESULTS: It was found that serum placental exosomes exhibited lower levels of miR-520a-5p in both the sPE and FGR groups when compared to the normal pregnancy group. This finding was consistent with observations made in postpartum placental tissues. The predictive accuracy for sPE using miR-520a-5p levels in serum placental exosomes during the first trimester was notably higher (area under the receiver operating characteristic curve = 0.806, P <.05) compared to the prediction of FGR (area under the receiver operating characteristic curve = 0.628, P <.05). CONCLUSION: Placenta-derived exosomes can be extracted from maternal serum during the first trimester of pregnancy and miR-520a-5p detected from the exosomes. The downregulation of miR-520a-5p serves as a more predictive indicator for the subsequent development of sPE compared to predicting FGR.


Assuntos
Exossomos , Retardo do Crescimento Fetal , MicroRNAs , Placenta , Pré-Eclâmpsia , Primeiro Trimestre da Gravidez , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Retardo do Crescimento Fetal/sangue , MicroRNAs/sangue , Exossomos/metabolismo , Adulto , Estudos de Casos e Controles , Primeiro Trimestre da Gravidez/sangue , Placenta/metabolismo , Biomarcadores/sangue , Valor Preditivo dos Testes
2.
Am J Reprod Immunol ; 91(5): e13858, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38762781

RESUMO

PROBLEM: In the current study we aimed to investigate Syndecan 1 (SDC1) levels in pregnant women diagnosed with fetal growth restriction (FGR) and the relationship between SDC1 levels and clinical and doppler parameters in FGR cases associated with endothelial dysfunction, angiogenesis and uteroplacental insufficiency METHOD OF STUDY: A total of 90 pregnant women included in the study, (45 with FGR, 45 healthy control) matched by week of gestation and maternal age. Venous blood samples were collected and plasma concentrations of SDC1 were determined by a specific immunoassay. Doppler examination was performed to evaluate the relationship between the SDC1 levels and placental blood supply. RESULTS: Doppler parameters; mean UtA-PI (p < .001), CPR (p = .002) and CPUR (p < .001) were different between the groups, however MCA PI, umbilical artery PI and umbilical artery S/D were not (p > .05). While gestational age at delivery, birth weight, APGAR score at 1 and 5 min were significantly lower (all, p < .001) in the study group, non-reassure fetal heart rate tracing (p = .09) and NICU admission (p = .02) were significantly higher. SDC 1 level was 2,00 ± 1,47 ng/mL and 2,34 ± 1,12 ng/mL in the FGR and control groups, respectively (p = .008). In the study group SDC 1 level was 1,69 ± 2,00 in those with gestational age below 32 weeks and 2,13 ± 1,18 in those with gestational age above 32 weeks and there was a statistically significant difference between the groups (p = .015). Plasma SDC 1 concentration of 2,1850 ng/mL or less had a sensitivity of 70%, a specificity of 72%, area under the ROC curve .65 (p < .005). CONCLUSIONS: Low maternal plasma SDC1 level may be associated with placental insufficiency and FGR. Low levels of SDC1 may be helpful as a predictor for the development of FGR during gestation.


Assuntos
Biomarcadores , Retardo do Crescimento Fetal , Sindecana-1 , Humanos , Sindecana-1/sangue , Retardo do Crescimento Fetal/sangue , Feminino , Gravidez , Adulto , Biomarcadores/sangue , Idade Gestacional , Recém-Nascido , Artérias Umbilicais/diagnóstico por imagem , Placenta/metabolismo , Endotélio Vascular/fisiopatologia
3.
Hum Reprod ; 39(5): 912-922, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38498837

RESUMO

STUDY QUESTION: What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? SUMMARY ANSWER: Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. WHAT IS KNOWN ALREADY: The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. STUDY DESIGN, SIZE, DURATION: This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: ß = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: ß = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). LIMITATIONS, REASONS FOR CAUTION: Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. WIDER IMPLICATIONS OF THE FINDINGS: The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Desenvolvimento Fetal , Cinurenina , Primeiro Trimestre da Gravidez , Triptofano , Humanos , Feminino , Gravidez , Triptofano/metabolismo , Triptofano/sangue , Adulto , Primeiro Trimestre da Gravidez/sangue , Estudos Prospectivos , Cinurenina/sangue , Cinurenina/metabolismo , Países Baixos , Desenvolvimento Embrionário , Recém-Nascido Pequeno para a Idade Gestacional , Recém-Nascido , 5-Hidroxitriptofano , Estudos de Coortes , Ultrassonografia Pré-Natal , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/sangue
4.
Acta Obstet Gynecol Scand ; 103(6): 1112-1119, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38483020

RESUMO

INTRODUCTION: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. MATERIAL AND METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68). CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.


Assuntos
Biomarcadores , Retardo do Crescimento Fetal , Fator de Crescimento Placentário , Nascimento Prematuro , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Feminino , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico , Nascimento Prematuro/sangue , Fator de Crescimento Placentário/sangue , Adulto , Estudos Prospectivos , Biomarcadores/sangue , Valor Preditivo dos Testes , Estudos de Coortes , Recém-Nascido
5.
J Obstet Gynaecol Res ; 50(3): 430-437, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38148278

RESUMO

PURPOSE: This study aimed to determine fatty acid binding protein-4 (FABP-4) concentrations in maternal serum of fetal growth restriction (FGR) pregnancies and controls of normal pregnancies. Furthermore, we hypothesized that the alterations in FABP-4 levels might correlate with FGR severity. METHODS: We performed this prospective case-control study with 83 pregnant women. The study groups included 26 FGR pregnancies without abnormal fetal Doppler flow patterns and 25 pregnancies complicated with FGR accompanied by abnormal fetal Doppler flow patterns. RESULTS: The median serum FABP-4 concentrations were significantly higher in the FGR cases with abnormal Doppler flow pattern group (2.09 ng/mL) than in the FGR cases without abnormal Doppler flow pattern group (1.62 ng/mL) and the control group (1.20 ng/mL, p < 0.001). A significant negative correlation was observed between maternal serum FABP-4 levels and time to birth from blood sample collection (r = -0.356 and p = 0.001), gestational week at birth (r = -0.386 and p < 0.001), and birth weight (r = -0.394 and p < 0.001). A 1.35 ng/mL cut-off value of serum FABP-4 level could be used to discriminate FGR cases with a 78.4% sensitivity and 60.6% specificity. The optimal cut-off value of FABP-4 levels as an indicator for the diagnosis of FGR with abnormal Doppler flow pattern was estimated to be 1.76 ng/mL, which yielded a sensitivity of 84.0% and a specificity of 75.8%. CONCLUSION: FABP-4 is a crucial biomarker in the diagnosis and determining the severity of pregnancies with restricted fetal growth. We consider that FABP-4 is a powerful, reliable, and unique biomarker to diagnose FGR pregnancies.


Assuntos
Proteínas de Ligação a Ácido Graxo , Retardo do Crescimento Fetal , Ultrassonografia Pré-Natal , Feminino , Humanos , Recém-Nascido , Gravidez , Biomarcadores/sangue , Estudos de Casos e Controles , Proteínas de Ligação a Ácido Graxo/sangue , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico por imagem
6.
Pediatr Res ; 94(3): 1189-1194, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37031297

RESUMO

BACKGROUND: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. We longitudinally assessed PGRN concentrations in infants born appropriate (AGA) or small for gestational age (SGA), the latter being at risk for obesity and type 2 diabetes, especially if they experience an excessive postnatal catch-up in weight and are formula-fed (FF). METHODS: The study population consisted of 183 infants who were exclusively breast-fed [(BF), AGA, n = 66; SGA, n = 40], or FF (AGA, n = 31; SGA, n = 46) over the first 4 months. Assessments included auxology, fasting glucose, insulin, IGF-1, high-molecular-weight adiponectin, PGRN and body composition (by DXA), at birth, and at age 4 and 12 months. RESULTS: PGRN levels were low at birth and unaffected by prenatal growth. PGRN increased at 4 and 12 months, although to a lesser extent in SGA infants, and was unrelated to the mode of feeding. PGRN correlated with markers of adiposity, inflammation and insulin resistance in both AGA and SGA infants, especially in those FF. CONCLUSIONS: The attenuated increase of PGRN levels in SGA infants over the first year of life, along with the association to markers of unhealthy metabolic profile, might point to a role of PGRN in future disease risks. IMPACT: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. In healthy infants, PGRN concentrations are low at birth and experience a significant and progressive increase up to age 12 months, which is less marked in infants born small for gestational age (SGA) and is unrelated to the mode of feeding. Circulating PGRN is related to markers of adiposity, inflammation, and insulin sensitivity, especially in formula-fed SGA infants. PGRN may play a role in the metabolic adaptations of SGA infants during early life, potentially contributing to the risk for obesity and type 2 diabetes in this population.


Assuntos
Diabetes Mellitus Tipo 2 , Retardo do Crescimento Fetal , Recém-Nascido Pequeno para a Idade Gestacional , Obesidade , Progranulinas , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Diabetes Mellitus Tipo 2/epidemiologia , Retardo do Crescimento Fetal/sangue , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Inflamação , Resistência à Insulina , Obesidade/epidemiologia , Progranulinas/sangue
7.
Rev Bras Ginecol Obstet ; 45(3): 127-133, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-37105196

RESUMO

OBJECTIVE: To assess the maternal blood levels of fatty acids (FAs) in pregnancies with fetal growth restriction (FGR). METHODS: This prospective cross-sectional study included pregnant women with gestational age between 26 and 37 + 6 weeks with FGR and appropriate for gestational age (AGA) fetuses. The levels of saturated, trans, monounsaturated, and polyunsaturated FAs were measured using centrifugation and liquid chromatography. The Student's t-test, Mann-Whitney test, and general linear model, with gestational age and maternal weight as covariants, were used to compare FA levels and the FGR and AGA groups. The Chi-square was used to evaluate the association between groups and studied variables. RESULTS: Maternal blood sample was collected from 64 pregnant women, being 24 FGR and 40 AGA. A weak positive correlation was found between the palmitoleic acid level and maternal weight (r = 0.285, p = 0.036). A weak negative correlation was found between the gamma-linoleic acid level and gestational age (r = - 0.277, p = 0.026). The median of the elaidic acid level (2.3 vs. 4.7 ng/ml, p = 0.045) and gamma-linoleic acid (6.3 vs. 6.6 ng/ml, p = 0.024) was significantly lower in the FGR than the AGA group. The palmitoleic acid level was significantly higher in the FGR than AGA group (50.5 vs. 47.6 ng/ml, p = 0.033). CONCLUSION: Pregnant women with FGR had lower elaidic acid and gamma-linoleic acid levels and higher palmitoleic acid levels than AGA fetuses.


OBJETIVO: Avaliar os níveis sanguíneos maternos de ácidos graxos (AGs) em gestações com restrição de crescimento fetal (RCF). MéTODOS:: Este estudo prospectivo transversal incluiu gestantes com idade gestacional entre 26 e 37 semanas e 6 dias com RCF e fetos adequados para a idade gestacional (AIG). Os níveis de ácidos graxos saturados, trans, monoinsaturados e poliinsaturados foram medidos usando centrifugação e cromatografia líquida. O teste t-Student, o teste de Mann-Whitney e o modelo linear geral, com idade gestacional e peso materno como covariantes, foram utilizados para comparar os níveis de AGs e os grupos RCF e AIG. O teste Qui-quadrado foi utilizado para avaliar a associação entre os grupos e as variáveis estudadas. RESULTADOS: Amostra de sangue materno foi coletada de 64 gestantes, sendo 24 RCF e 40 AIG. Uma correlação positiva fraca foi encontrada entre o nível de ácido palmitoleico e o peso materno (r = 0,285, p = 0,036). Uma correlação negativa fraca foi encontrada entre o nível de ácido gama-linoleico e a idade gestacional (r = − 0,277, p = 0,026). A mediana do nível de ácido elaídico (2,3 vs. 4,7 ng/ml, p = 0,045) e ácido gama-linoleico (6,3 vs. 6,6 ng/ml, p = 0,024) foram significativamente menores no grupo RCF do que no grupo AIG. O nível de ácido palmitoleico foi significativamente maior no grupo RCF do que no grupo AIG (50,5 vs. 47,6 ng/ml, p = 0,033). CONCLUSãO:: Gestantes com RCF apresentaram níveis mais baixos de ácido elaídico e ácido gama-linoleico e níveis mais elevados de ácido palmitoleico do que os fetos AIG.


Assuntos
Ácidos Graxos , Retardo do Crescimento Fetal , Feminino , Humanos , Lactente , Gravidez , Estudos Transversais , Ácidos Graxos/sangue , Retardo do Crescimento Fetal/sangue , Idade Gestacional , Ácidos Linoleicos/sangue , Estudos Prospectivos , Ultrassonografia Pré-Natal
8.
Int J Mol Sci ; 24(3)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36768287

RESUMO

The aim of the study was to determine whether early-onset and late-onset fetal growth restriction (FGR) differentially affects the blood-brain barrier integrity. Furthermore, the purpose of the study was to investigate the relationship between the blood-brain barrier breakdown and neurological disorders in FGR newborns. To evaluate the serum tight junction (TJ) proteins and the placental TJ proteins expression, an ELISA method was used. A significant difference in serum OCLN concentrations was noticed in pregnancies complicated by the early-onset FGR, in relation to the intraventricular hemorrhage (IVH) occurrence in newborns. No significant differences in concentrations of the NR1 subunit of the N-methyl-d-aspartate receptor (NR1), nucleoside diphosphate kinase A (NME1), S100 calcium-binding protein B (S100B), occludin (OCLN), claudin-5 (CLN5), zonula occludens-1 (zo-1), the CLN5/zo-1 ratio, and the placental expression of OCLN, CLN5, claudin-4 (CLN4), zo-1 were noticed between groups. The early-onset FGR was associated with a higher release of NME1 into the maternal circulation in relation to the brain-sparing effect and premature delivery. Additionally, in late-onset FGR, the higher release of the S100B into the maternal serum in regard to fetal distress was observed. Furthermore, there was a higher release of zo-1 into the maternal circulation in relation to newborns' moderate acidosis in late-onset FGR. Blood-brain barrier disintegration is not dependent on pregnancy advancement at the time of FGR diagnosis. NME1 may serve as a biomarker useful in the prediction of fetal circulatory centralization and extremely low birth weight in pregnancies complicated by the early-onset FGR. Moreover, the serum zo-1 concentration may have prognostic value for moderate neonatal acidosis in late-onset FGR pregnancies.


Assuntos
Barreira Hematoencefálica , Retardo do Crescimento Fetal , Doenças do Sistema Nervoso , Placenta , Feminino , Humanos , Recém-Nascido , Gravidez , Barreira Hematoencefálica/metabolismo , Encéfalo , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Placenta/metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Biomarcadores/análise , Biomarcadores/sangue
9.
Fertil Steril ; 117(2): 368-375, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34686372

RESUMO

OBJECTIVE: To investigate the association of the maternal serum albumin (MAlb) level with fetal growth and fetal growth restriction (FGR) risk in term-born singletons. DESIGN: Prospective cohort study. SETTING: Four hospital maternity units of the Tongji Maternal and Child Health Cohort study initiated from September 2013 to April 2016 at Wuhan City, in central China. PATIENT(S): A total of 3,065 mother-offspring pairs. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fetal growth was evaluated by birth weight (BW) and birth length. Fetal growth restriction was defined as BW below the 10th percentile. RESULT(S): All MAlb levels were within the upper limit of normal. After adjustment for liver function parameters, inflammatory indicators, and others, a reverse U-shaped relationship between MAlb and fetal growth was observed. Specifically, BW increased significantly with an increasing MAlb level when the MAlb level was <36.1 g/L (per g/L: ß = 36.8; 95% CI, 0.8, 72.7) but decreased with increasing the MAlb level when the MAlb level was >36.1 g/L (per g/L: ß = -15.1; 95% CI, -21.2, -8.9). There was a similar association between MAlb and birth length. Furthermore, the adjusted odd ratios of FGR across increasing tertiles of the MAlb levels were 1.0 (reference), 1.1 (0.7, 1.8), and 1.7 (1.0, 2.6). CONCLUSION(S): There was a reverse U-shaped association between MAlb and fetal growth. A higher MAlb level was associated with an increased risk of FGR. CLINICAL TRIAL REGISTRATION NUMBER: NCT03099837.


Assuntos
Desenvolvimento Fetal , Retardo do Crescimento Fetal/sangue , Saúde Materna , Albumina Sérica Humana/análise , Adulto , Biomarcadores/sangue , Peso ao Nascer , China , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Recém-Nascido , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Regulação para Cima
10.
Am J Reprod Immunol ; 87(1): e13504, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34657322

RESUMO

PROBLEM: Small for gestational age (SGA) neonates are vulnerable to various long and short-term adverse health consequences. The expression of HLA-G in the placenta is crucial for establishment and maintenance of pregnancy. Its aberrant expression could lead to perturbed immunological interactions in the placenta which could be associated with SGA births. The objective of this study was to assess the difference in the trajectories of soluble HLA-G in maternal sera during pregnancy between women delivering SGA and appropriate for gestational age (AGA) neonates. METHOD OF STUDY: Soluble HLA-G was estimated in the maternal sera collected at different time points in pregnancy of North-Indian pregnant females delivering SGA (N = 23) or AGA (N = 17) neonates using sandwich ELISA. Linear mixed models were built and compared to study the association between sHLA-G levels during pregnancy and SGA births. RESULTS: No significant difference was observed in the sHLA-G trajectories during pregnancy in mothers delivering SGA as compared to those delivering AGA (P-value = .5677). A trend towards higher sHLA-G levels at the first trimester of pregnancy (< 14 weeks of gestation) was observed in mothers delivering SGA neonates (Median = 41.71, IQR = 21.31-71.38) as compared to those delivering AGA neonates (Median = 37.58, IQR = 19.05-73.57). CONCLUSION: During pregnancy, sHLA-G trajectories do not differ significantly between mothers delivering SGA and those delivering AGA neonates. However, sHLA-G trends towards higher levels during early pregnancy in mothers delivering SGA neonates.


Assuntos
Antígenos HLA-G/sangue , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Adulto , Estudos de Casos e Controles , Feminino , Retardo do Crescimento Fetal/sangue , Idade Gestacional , Humanos , Índia , Recém-Nascido , Projetos Piloto , Gravidez , Adulto Jovem
11.
Arch Gynecol Obstet ; 305(3): 597-605, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34432111

RESUMO

PURPOSE: The study aimed to assess the course of the soluble Fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio in pregnant women with fetal growth restriction (FGR) and to evaluate potential associations between the sFlt-1/PlGF ratio and feto-maternal Doppler parameters, fetal biometric measurements and the time between study inclusion and birth ("time to delivery"). METHODS: This was a retrospective longitudinal single center study including 52 FGR cases. The serum levels of sFlt-1 and PlGF were measured by using the BRAHMS Kryptor Compact PLUS. Fetal biometric and Doppler parameters, as well as the sFlt-1/PlGF ratio, were obtained both upon study inclusion and upon birth. RESULTS: Various associations between the levels of the biomarkers in maternal blood upon study inclusion and upon birth and sonographic parameters were observed in FGR cases: umbilical artery (p < 0.01), uterine arteries (p < 0.01), ductus venosus (p < 0.05), cerebroplacental ratio (CPR) (p < 0.01), femur length (p < 0.01) and birth weight (p < 0.01). The higher the sFlt-1/PlGF ratio upon study inclusion, the shorter the "time to delivery" (p < 0.01). The multivariate regression analysis showed that the greater the daily percentage increase of the angiogenic markers, the shorter the "time to delivery" (p < 0.01). CONCLUSION: The fetal well-being, as measured by feto-maternal Doppler parameters such as CPR and the severity of the placental dysfunction, as measured by the urgency of birth and birth weight, is reflected by the level of the sFlt-1/PlGF ratio in the maternal serum. A rapid daily increase of the sFlt-1/PlGF ratio is significantly associated with the clinical progression of the disease.


Assuntos
Retardo do Crescimento Fetal , Fator de Crescimento Placentário , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Biomarcadores/sangue , Biometria , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico por imagem , Humanos , Placenta , Fator de Crescimento Placentário/sangue , Gravidez , Estudos Retrospectivos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
12.
Am J Obstet Gynecol ; 226(2S): S1037-S1047.e2, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33892922

RESUMO

BACKGROUND: In routine clinical practice, angiogenic factor measurement can facilitate prediction and diagnosis of preeclampsia and other manifestations of placental dysfunction (eg, intrauterine growth restriction). OBJECTIVE: This real-world data analysis investigated the utility of soluble fms-like tyrosine kinase-1 and placental growth factor for preeclampsia and placental dysfunction. STUDY DESIGN: Blood serum soluble fms-like tyrosine kinase-1 and placental growth factor were measured using Elecsys soluble fms-like tyrosine kinase-1 and placental growth factor immunoassays (cobas e analyzer; Roche Diagnostics). Overall, 283 unselected singleton pregnancies with ≥1 determination of soluble fms-like tyrosine kinase-1-to-placental growth factor ratio were included. Distribution of the ratio at admission was normal (<38 [58.7%]), intermediate (38-85/110 [19.1%]), or pathologic (>85/110 [22.3%]). Overall, 15.5% had preeclampsia or hemolysis, elevated liver enzyme levels, and low platelet count, and 15.5% of women had intrauterine growth restriction. RESULTS: Increasing soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was associated with an increase in priority of delivery (r=0.38; P<.001). The percentage of patients who developed preeclampsia by soluble fms-like tyrosine kinase-1-to-placental growth factor ratio at admission was 5.4% (normal), 7.4% (intermediate), and 49.2% (pathologic). The greatest difference in soluble fms-like tyrosine kinase-1-to-placental growth factor ratio from admission to birth occurred in pathologic pregnancies (171.12 vs 39.84 for normal pregnancies). Soluble fms-like tyrosine kinase-1-to-placental growth factor ratio correlated inversely with gestational age at delivery, birthweight, and prolongation time. There was no significant relation between the prolongation period or the gestational age at first determination to the increase of soluble fms-like tyrosine kinase-1 and placental growth factor between admission and delivery (ΔQ). This analysis used a real-world approach to investigate the clinical utility of the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio in placental dysfunction. CONCLUSIONS: Confirming the results of prospective studies, we observed a positive correlation between soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and severity of placental dysfunction and a negative association with time to delivery. In a real-world setting, the soluble fms-like tyrosine kinase-1-placental growth factor ratio stratifies patients with normal outcome and outcome complicated by placental dysfunction.


Assuntos
Síndrome HELLP/sangue , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Humanos , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
13.
BMC Pregnancy Childbirth ; 21(1): 605, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482843

RESUMO

BACKGROUND: D-dimer and fibrinogen were verified to be altered in preeclampsia. This study was to evaluate the associations of D-dimer and fibrinogen plasma levels with postpartum hemorrhage or intrauterine growth restriction in preeclamptic women. METHODS: This was a retrospective study that recruited 278 preeclamptic women with singleton pregnancy from January 2016 to December 2019. Patients were allocated into five groups: mild preeclampsia (mPE) (n=68), mild preeclampsia with postpartum hemorrhage (mPE+PPH) (n=13), severe preeclampsia (sPE) (n=112), severe preeclampsia with postpartum hemorrhage (sPE+PPH) (n=17) and severe preeclampsia with intrauterine growth restriction (sPE+IUGR) (n=68). The antenatal D-dimer and fibrinogen plasma levels were analyzed among the groups. Logistic regression was used to determine the correlation between serum indexes and PPH or IUGR in preeclampsia. RESULTS: The antenatal D-dimer plasma levels were significantly higher in the sPE+PPH group than that in the sPE group (2.02 µg/ml versus 1.37 µg/ml, P = 0.001), but there was no difference in fibrinogen. Elevated D-dimer was associated with PPH among severe preeclamptic women (adjusted odds ratio (aOR) [95% CI]: 3.093 [1.527-6.264], P = 0.002). No differences in D-dimer and fibrinogen were found between the mPE and mPE+PPH groups or between the sPE and sPE+IUGR groups. CONCLUSIONS: Elevated antenatal plasma D-dimer level may be associated with postpartum hemorrhage in severe preeclampsia, but not with intrauterine growth restriction. Future prospective clinical trials are needed to investigate the predictive value of D-dimer in postpartum hemorrhage in severe preeclampsia.


Assuntos
Retardo do Crescimento Fetal/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Hemorragia Pós-Parto/sangue , Adulto , China/epidemiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Hemorragia Pós-Parto/etiologia , Pré-Eclâmpsia , Gravidez , Estudos Retrospectivos , Adulto Jovem
14.
Placenta ; 115: 87-96, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34583270

RESUMO

INTRODUCTION: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. METHODS: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. RESULTS: Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. DISCUSSION: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.


Assuntos
Biomarcadores/sangue , Retardo do Crescimento Fetal/sangue , Estresse Oxidativo/fisiologia , Pré-Eclâmpsia/sangue , Adulto , Feminino , Humanos , Inflamação/sangue , Leptina/sangue , Projetos Piloto , Placenta/patologia , Placenta/fisiopatologia , Fator de Crescimento Placentário/sangue , Gravidez , Estudos Prospectivos , Receptor para Produtos Finais de Glicação Avançada/sangue , Albumina Sérica Humana , Compostos de Sulfidrila/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
15.
Sci Rep ; 11(1): 16595, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400721

RESUMO

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.


Assuntos
Retardo do Crescimento Fetal/sangue , Metaloproteinases da Matriz/fisiologia , Mitocôndrias/fisiologia , Placenta/metabolismo , Complicações na Gravidez/sangue , Sindecana-1/sangue , Adulto , Área Sob a Curva , Peso ao Nascer , Hipóxia Celular , Parto Obstétrico , Diabetes Gestacional/sangue , Transporte de Elétrons/efeitos dos fármacos , Feminino , Idade Gestacional , Humanos , Hipertensão/sangue , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Tamanho do Órgão , Sobrepeso/sangue , Pré-Eclâmpsia/sangue , Gravidez , Curva ROC , Fumar/sangue , Trofoblastos/enzimologia
16.
Genes (Basel) ; 12(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201957

RESUMO

Preeclampsia (PE) and Intrauterine Growth Restriction (IUGR) are two pregnancy-specific placental disorders with high maternal, fetal, and neonatal morbidity and mortality rates worldwide. The identification biomarkers involved in the dysregulation of PE and IUGR are fundamental for developing new strategies for early detection and management of these pregnancy pathologies. Several studies have demonstrated the importance of long non-coding RNAs (lncRNAs) as essential regulators of many biological processes in cells and tissues, and the placenta is not an exception. In this review, we summarize the importance of lncRNAs in the regulation of trophoblasts during the development of PE and IUGR, and other placental disorders.


Assuntos
Biomarcadores/sangue , Retardo do Crescimento Fetal/sangue , Pré-Eclâmpsia/sangue , RNA Longo não Codificante/sangue , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez , RNA Longo não Codificante/genética , Trofoblastos/metabolismo
17.
Am J Med Genet A ; 185(10): 3042-3047, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34196458

RESUMO

22q11.2 deletion syndrome (22q11.2 DS, MIM #188400) is the most common chromosomal microdeletion with an incidence of 1 in 4000 live births. 22q11.2 DS patients present with varying penetrance and a broad phenotypic spectrum including dysmorphic features, congenital heart defects, hypoplastic thymus and T-cell deficiency, and hypocalcemia. The typical deletion spans 3 Mb between 4 large blocks of repetitive DNA, known as low copy repeats (LCRs), on chromosome 22 (LCR22) A and D. This deletion is found in ~85% of 22q11.2 DS patients, while only 4-5% have central LCR22B-D (1.5 Mb) and LCR22C-D (0.7 Mb) deletions. We report on a prenatally diagnosed, inherited case of central LCR22B-D 22q11.2 DS, born to a 22-year-old female with multiple autoimmune disorders. These include Sjogren's-syndrome-related antigen A (SSA+) severe systemic lupus erythematosus (SLE) with cutaneous and discoid components and seronegative antiphospholipid syndrome. Amniocentesis was performed due to fetal growth restriction (FGR). FISH with TUPLE1 (HIRA) probe was normal; however, chromosomal microarray identified a ~737 kb heterozygous loss between LCR22B-D. Subsequently, the same deletion was identified in the mother, which included CRKL and 19 other genes but excluded HIRA and TBX1, the typical candidate genes for 22q11.2DS pathogenesis. This case explores how loss of CRKL may contribute to immune dysregulation, as seen in the multiple severe autoimmune phenotypes of the mother, and FGR. Our experience confirms the importance of thorough workup in individuals with reduced penetrance of 22q11.2 DS features or atypical clinical presentations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome de DiGeorge/genética , Retardo do Crescimento Fetal/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Anticorpos Antinucleares/sangue , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/patologia , Feto , Testes Genéticos , Haploinsuficiência/genética , Humanos , Hibridização in Situ Fluorescente , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Mães , Penetrância , Sequências Repetitivas de Ácido Nucleico/genética
18.
JAMA Netw Open ; 4(7): e2117409, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279647

RESUMO

Importance: Bile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear. Objective: To investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR. Design, Setting, and Participants: This retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020. Exposures: Maternal sTBA concentration during pregnancy. Main Outcomes and Measures: Fetal birth weight and probability of low birth weight (LBW) and IUGR. Results: This study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 µg/mL, 3290 [3.9] g; and for 4.1 µg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 µg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 µg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 µg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28). Conclusions and Relevance: This study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.


Assuntos
Ácidos e Sais Biliares/sangue , Retardo do Crescimento Fetal/sangue , Recém-Nascido de Baixo Peso , Testes para Triagem do Soro Materno/estatística & dados numéricos , Complicações na Gravidez/sangue , Adulto , Peso ao Nascer , China , Feminino , Peso Fetal , Humanos , Hipertensão Induzida pela Gravidez/sangue , Recém-Nascido , Gravidez , Análise de Regressão , Estudos Retrospectivos
19.
J Gynecol Obstet Hum Reprod ; 50(10): 102198, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34289413

RESUMO

OBJECTIVE: The proprotein convertase furin is known to be involved in the processing of pro-B-type natriuretic peptide (proBNP) and prorenin receptor (PRR), suggesting that it has a potential function in blood pressure regulation. We investigated the role of furin in the etiology of pre-eclampsia and its related disorder, unexplained fetal growth restriction (FGR) without hypertension. METHODS: We evaluated serum and placental furin levels in pre-eclampsia, FGR and uncomplicated pregnancy. Additionally, we investigated the correlation between the serum furin levels and products of furin enzymatic activity or clinical parameters. RESULTS: We demonstrated that the maternal circulation in cases of pre-eclampsia and FGR had lower levels of soluble furin than uncomplicated pregnancies. Both NT-proBNP and soluble PRR were elevated in pre-eclampsia, whereas only soluble PRR was at higher levels in unexplained FGR. Linear regression analysis revealed a negative correlation between the serum furin level and that of NT-proBNP or soluble PRR. While we observed that the serum furin or soluble PRR level correlated with blood pressure, a stronger correlation was observed with birth and placental weights. Further to this, the FURIN mRNA levels were significantly reduced in placental pre-eclamptic placentas as well as in FGR cases. CONCLUSION: These data suggest the possibility that reduced levels of furin may be the result of a negative feedback from the activation of the renin-angiotensin pathway that leads to feto-placental dysfunction with or without maternal hypertension. This may represent an etiologic pathway of pre-eclampsia and unexplained FGR.


Assuntos
Retardo do Crescimento Fetal/sangue , Furina/análise , Pré-Eclâmpsia/sangue , Receptores de Superfície Celular/análise , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/epidemiologia , Furina/sangue , Humanos , Japão/epidemiologia , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Gravidez , Receptores de Superfície Celular/sangue , Receptor de Pró-Renina
20.
Placenta ; 110: 24-28, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34102451

RESUMO

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight <10th centile), compared to 772 controls (p < 0.01) at as early as 26 weeks' gestation. There were no correlations between infant body composition and circulating SPINT1 concentrations at 26 weeks. This provides validation that low maternal SPINT1 concentration is associated with poor fetal growth.


Assuntos
Retardo do Crescimento Fetal/sangue , Insuficiência Placentária/sangue , Proteínas Secretadas Inibidoras de Proteinases/sangue , Adulto , Peso ao Nascer/fisiologia , Estudos de Casos e Controles , Estudos de Coortes , Regulação para Baixo , Feminino , Retardo do Crescimento Fetal/epidemiologia , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Avaliação de Resultados em Cuidados de Saúde , Insuficiência Placentária/epidemiologia , Gravidez , Resultado da Gravidez/epidemiologia , Segundo Trimestre da Gravidez/sangue , Proteínas Secretadas Inibidoras de Proteinases/análise , Singapura/epidemiologia , Natimorto/epidemiologia
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