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BACKGROUND: Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to determine the indirect effects of neighbourhood socioeconomic status (NSES) on the risk of spontaneous PTB. METHODS: We carried out a retrospective case-control study including sociodemographic and obstetric data of multigravid women who gave birth at a maternity hospital in Tucumán, Argentina, between 2005 and 2010: 949 women without previous PTB nor pregnancy loss who delivered at term and 552 who had spontaneous PTB. NSES was estimated from the Unsatisfied Basic Needs index of census data. Variables selected through penalised regressions were used to create a data-driven Bayesian network; then, pathways were identified and mediation analyses performed. RESULTS: Maternal age less than 20 years mediated part of the protective effect of high NSES on spontaneous PTB [natural indirect effect (NIE) -0.0125, 95% confidence interval (CI) (-0.0208, -0.0041)] and on few prenatal visits (< 5) [NIE - 0.0095, 95% CI (-0.0166, -0.0025)]. These pathways showed greater sensitivity to unobserved confounders that affect the variables mediator-outcome in the same direction, and exposure-mediator in the opposite direction. They did not show sensitivity to observed potential confounders, nor to the parameterization used to define NSES. Meanwhile, urinary tract infections showed a trend in mediating the effect of low NSES on spontaneous PTB [NIE 0.0044, 95% CI (-0.0006, 0.0093), P 0.0834]. CONCLUSIONS: High NSES has protective indirect effects on spontaneous PTB risk, mainly associated with a lower frequency of teenage pregnancy.

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Torque Teno Virus (TTV) is a nonpathogenic and ubiquitous ssDNA virus, a member of the Anelloviridae family. TTV has been postulated as a biomarker in transplant patients. This study aimed to determine the TTV species diversity and variability in renal transplant recipients and to associate species diversity with the corresponding TTV viral load. From 27 recipients, 30 plasma samples were selected. Viral load was determined using two real-time PCR assays, followed by RCA-NGS and ORF1 phylogenetic analysis. The TTV diversity was determined in all samples. Variability was determined in three patients with two sequential samples (pre- and post-transplantation). Most of the samples presented multiple TTV species, up to 15 different species were detected. In the pre-transplant samples (n = 12), the most prevalent species were TTV3 (75%) and TTV13 (75%), and the median number of species per sample was 5 (IQR: 4-7.5). TTV3 was also the most prevalent (56%) in the post-transplant samples (n = 18), and the median number of species was 2 (IQR: 1.8-5.5). No significant correlation between the number of species and viral load was found. The number and type of TTV species showed total variability over time. We report high TTV species diversity in Argentinian recipients, especially in pre-transplant period, with total intra-host variability. However, we found no significant correlation between this high diversity and TTV viral load.

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BACKGROUND: Retinopathy of prematurity (ROP) is one of the leading cause of child blindness. Preterm newborns of very low gestational age (GA) and very low birth weight are at the greatest risk. Our objective was to evaluate the role of genetic variants associated with ROP risk and its comorbidities in an Argentinian sample of premature infants. METHODS: A sample of 437 preterm infants <33 weeks GA, born at a maternity hospital in Tucumán, Argentina, 2005-2010, was analyzed. Environmental factors, perinatal outcomes, and fourteen single nucleotide polymorphisms associated with ROP were evaluated, comparing ROP with non-ROP newborns. A lasso logistic regression was performed to select variables; then, a conditional logistic regression was used to identify ROP maternal and perinatal risk factors adjusting by maternal and gestational ages, respectively. RESULTS: ROP maternal risk factors were alcohol intake, periodontal infections, and severe stress. Respiratory distress, sepsis, and intracranial hemorrhage were the ROP perinatal risk factors. Markers rs186085 of EPAS1 and rs427832 of AGTR1 were significantly associated with ROP newborns. CONCLUSION: We identified three maternal and three perinatal risk factors associated with ROP. Genes EPAS1 and AGTR1, involved in angiogenesis and vascularization, were identified to be of risk for ROP. IMPACT: Genetic and environmental risk factors associated with ROP and its comorbidities are evaluated in a Latin American population. Genes EPAS1 and AGTR1, involved in angiogenesis and vascularization, were identified to be of risk for ROP. Three maternal and three perinatal risk factors associated with ROP were also identified. A matrix of significant relationships among genetic markers and comorbidities is presented. Reported data may help develop more effective preventive measures for ROP in the Latin American region.

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Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify gene-environment interactions associated with spontaneous PTB or its predictors. We carried out a retrospective case-control study including parental sociodemographic and obstetric data as well as newborn genetic variants of 69 preterm and 61 at term newborns born at a maternity hospital from Tucumán, Argentina, between 2005 and 2010. A data-driven Bayesian network including the main PTB predictors was created where we identified gene-environment interactions. We used logistic regressions to calculate the odds ratios and confidence intervals of the interactions. From the main PTB predictors (nine exposures and six genetic variants) we identified an interaction between low neighbourhood socioeconomic status and rs2074351 (PON1, genotype GG) variant that was associated with an increased risk of toxoplasmosis (odds ratio 12.51, confidence interval 95%: 1.71 - 91.36). The results of this exploratory study suggest that structural social disparities could influence the PTB risk by increasing the frequency of exposures that potentiate the risk associated with individual characteristics such as genetic traits. Future studies with larger sample sizes are necessary to confirm these findings.

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BACKGROUND: The relationship between maternal age (MA) and birth defects (BD) has been extensively studied while much less research, mostly with discordant results, has focused on the risk of paternal age (PA) for BD. Furthermore, no consensus has been reached on the best way to control the association of PA with MA. OBJECTIVES: The aim of the study was to evaluate the risk of PA increase, at 1-year intervals, for selected BD, especially controlling for the confounding effect of MA. METHODS: The sample comprised of 27,944 liveborns presenting 1 of 18 selected isolated BD. Conditional logistic regressions were applied to evaluate the risk of advanced PA and its yearly increase, adjusting by MA and other variables. RESULTS: Of the 18 analyzed BD, only the risk for preaxial polydactyly (PreP) showed a significant association with increasing PA, while advanced MA was of low risk. For esophageal and anal atresia, associations with both PA and MA increases were observed. CONCLUSIONS: Results support the hypothesis of advanced PA as a risk factor for PreP and helps clarify the so far unexplained nonrandom association between this defect and Down syndrome.

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Identifying the risk factors for carbapenem-resistant Enterobacterales (CRE) bacteremia in cancer and hematopoietic stem cell transplantation (HSCT) patients would allow earlier initiation of an appropriate empirical antibiotic treatment. This is a prospective multicenter observational study in patients from 12 centers in Argentina, who presented with cancer or hematopoietic stem-cell transplant and developed Enterobacterales bacteremia. A multiple logistic regression model identified risk factors for CRE bacteremia, and a score was developed according to the regression coefficient. This was validated by the bootstrap resampling technique. Four hundred and forty-three patients with Enterobacterales bacteremia were included: 59 with CRE and 384 with carbapenem-susceptible Enterobacterales (CSE). The risk factors that were identified and the points assigned to each of them were: ≥10 days of hospitalization until bacteremia: OR 4.03, 95% CI 1.88-8.66 (2 points); previous antibiotics > 7 days: OR 4.65, 95% CI 2.29-9.46 (2 points); current colonization with KPC-carbapenemase-producing Enterobacterales: 33.08, 95% CI 11.74-93.25 (5 points). With a cut-off of 7 points, a sensitivity of 35.59%, specificity of 98.43%, PPV of 77.7%, and NPV of 90.9% were obtained. The overall performance of the score was satisfactory (AUROC of 0.85, 95% CI 0.80-0.91). Finally, the post-test probability of CRE occurrence in patients with none of the risk factors was 1.9%, which would virtually rule out the presence of CRE bacteremia.

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OBJECTIVE: This study aimed to describe lethality of birth defects (BDs) in newborns categorized by gestational age and birth weight and to identify BDs associated with prematurity. STUDY DESIGN: Live born infants (n = 16,452) with isolated BDs classified by severity, and 42,511 healthy controls were assigned to categories: adequate growth, preterm, or small for gestational age (SGA). Proportion of cases and BDs' lethality rates were obtained by category and compared with controls. RESULTS: Overall fewer malformed than nonmalformed infants were of adequate growth, while the opposite occurred in the preterm and SGA categories where gastroschisis and esophageal atresia were among the most outstanding defects. For most severe BDs, the early neonatal death rate was higher than control values in all categories; for mild defects, except cleft lip in the preterm category, they did not differ. Diaphragmatic hernia showed the highest lethality values, while those of spina bifida were among the lowest. Talipes, hypospadias, and septal heart defects were mild defects significantly associated with prematurity. CONCLUSION: Although reasons, such as induced preterm delivery of fetuses with certain anomalies, could partially account for their high prematurity rates, susceptibility to preterm birth might exist through underlying mechanisms related with the defects. The identification of BDs associated with prematurity should serve to improve measures that prevent preterm birth especially of fetuses at risk. KEY POINTS: · Some BDs predispose to prematurity.. · Prematurity is an additional risk factor for mortality in infants with mild defects.. · Lethality values should be adjusted by gestational age and birth weight..

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OBJECTIVE: Our aim was to describe the prevalence of diseases during pregnancy and the association between fetal exposure to the most frequent maternal diseases and the risk of preterm (PTB) and/or small for gestational age (SGA) newborns in an unselected sample of women who gave birth in South American countries. METHODS: We conducted a descriptive, cross-sectional study including 56,232 mothers of non-malformed infants born between 2002 and 2016, using data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC). Diseases with higher- than-expected PTB/SGA frequencies were identified. Odds ratios of confounding variables for diseases and birth outcomes were calculated with a multivariable logistic regression. RESULTS: Of the 14 most reported diseases, hypertension, genitourinary infection, epilepsy, hypothyroidism, diabetes, and HIV/AIDS showed higher PTB and/or SGA frequencies. Advanced and low maternal age, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with PTB, while advanced maternal age, primigravidity, previous fetal loss, low socioeconomic level, and African-American ancestry were associated with SGA. After adjusting for the associated variables, the identified illnesses maintained their association with PTB and all, except epilepsy, with SGA. CONCLUSION: The description of an unselected population of mothers allowed identifying the most frequent diseases occurring during gestation and their impact on pregnancy outcomes. Six diseases were associated with PTB and two with SGA newborns. To the best of our knowledge, there are no similar reports about women not intentionally selected by specific diseases during pregnancy in South American populations.

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Preterm birth (PTB) is the main condition related to perinatal morbimortality worldwide. The aim of this study was to identify associations of spontaneous PTB with genetic variants, exposures, and interactions between and within them. We carried out a retrospective case-control study including parental sociodemographic and obstetric data, and fetal genetic variants. We sequenced the coding and flanking regions of five candidate genes from the placental blood cord of 69 preterm newborns and 61 at term newborns. We identify the characteristics with the greatest predictive power of PTB using penalized regressions, in which we include exposures (E), genetic variants (G), and two-way interactions. Few prenatal visits (< 5) was the main predictor of PTB from 26 G, 35 E, 299 G × G, 564 E × E, and 875 G × E evaluated terms. Within the fetal genetic characteristics, we observed associations of rs4845397 (KCNN3, allele T) variant; G × G interaction between rs12621551 (COL4A3, allele T) and rs73993878 (COL4A3, allele A), which showed sensitivity to anemia; and G × G interaction between rs11680670 (COL4A3, allele T) and rs2074351 (PON1, allele A), which showed sensitivity to vaginal discharge. The results of this exploratory study suggest that social disparities and metabolic pathways linked to uterine relaxation, inflammation/infections, and collagen metabolism would be involved in PTB etiology. Future studies with a larger sample size are necessary to confirm these findings and to analyze a greater number of exposures.

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BACKGROUND: The aim of this study was to determine the mediating effect of spontaneous preterm birth (PTB) main predictors that would allow to suggest etiological pathways. METHODS: We carried out a case-control study, including sociodemographic characteristics, habits, health care, and obstetric data of multiparous women who gave birth at a maternity hospital from Tucumán, Argentina, between 2005 and 2010: 998 women without previous PTB who delivered at term and 562 who delivered preterm. We selected factors with the greatest predictive power using a penalized logistic regression model. A data-driven Bayesian network including the selected factors was created where we identified pathways and performed mediation analyses. RESULTS: We identified three PTB pathways whose natural indirect effect was greater than zero with a 95% confidence interval: maternal age less than 20 years mediated by few prenatal visits, vaginal bleeding in the first trimester mediated by vaginal bleeding in the second trimester, and urinary tract infection mediated by vaginal bleeding in the second trimester. The effect mediated in these pathways showed greater sensitivity to confounders affecting the variables mediator-outcome and exposure-mediator in the same direction. CONCLUSION: The identified pathways suggest PTB etiological lines related to social disparities and exposure to genitourinary tract infections. IMPACT: Few prenatal visits (<5) and vaginal bleeding are two of the main predictors for spontaneous preterm birth in the studied population. Few prenatal visits mediates part of the risk associated with maternal age less than 20 years and vaginal bleeding in the second trimester mediates part of the risk associated with vaginal bleeding in the first trimester and with urinary tract infection. Social disparities and exposure to genitourinary tract infections would be etiological lines of spontaneous preterm birth.

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