Genetic susceptibility for retinopathy of prematurity and its associated comorbidities.

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.

Gene-environment interactions and preterm birth predictors: A Bayesian network approach.

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.

Paternal age and risk for selected birth defects in a large South American sample.

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.

Using a health observance event to raise awareness: An assessment of World Birth Defects Day.

World Birth Defects Day (WorldBDDay), observed annually on March 3, was launched in 2015 to advocate for public health surveillance, research, and prevention of birth defects, along with improved care and treatment for affected individuals. Following its fifth observance in 2019, we assessed WorldBDDay by analyzing: (a) engagement and content of over 2000 WorldBDDay posts on Facebook, Twitter, and Instagram; (b) interview responses from 9 WorldBDDay charter (founding) organizations on their perceptions of strengths and areas for improvement for WorldBDDay; (c) survey responses from 61 WorldBDDay 2019 partner (participating) organizations on their WorldBDDay 2019 activities; and (d) post-2019 social media engagement. Most social media posts (60%) occurred from organizations using Twitter (80% vs. 14% for Instagram and 6% for Facebook), although posts from individuals had higher levels of engagement (e.g., likes and comments). The highest engagement occurred for posts focused on general awareness, prevention, or events. Charter organizations reported the need for existing and new partner engagement, including a designated WorldBDDay contact for regular communication and coordination of activities and prepared prevention-focused messaging. Partner organizations reported using the WorldBDDay toolkit, especially key messages and social media tips, and suggested expanding the toolkit with relevant resources. Post-2019 Twitter engagement was lower than 2019 WorldBDDay (peak event) but showed similar reach to WorldBDDay events prior to 2019. Our assessment identified WorldBDDay health observance events as an important tool to support knowledge dissemination and global community engagement around birth defects. Moving forward, engagement with more individuals and organizations may improve the reach of WorldBDDay.

Lethality of Birth Defects in Live Born Infants Categorized by Gestational Age and Birth Weight.

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..

Diseases during pregnancy in a large unselected South American sample.

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.

Genes, exposures, and interactions on preterm birth risk: an exploratory study in an Argentine population.

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.

Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease.

Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.

Preterm birth etiological pathways: a Bayesian networks and mediation analysis approach.

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.

Diseases during pregnancy in a large unselected South American sample / Prevalência de doenças durante a gravidez em uma grande amostra sul-americana não selecionada

ABSTRACT 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.

RESUMO Objetivo: Descrever a prevalência de doenças durante a gravidez e a associação entre a exposição fetal às doenças maternas mais prevalentes e o risco de recém-nascidos prematuros (PP) e/ou pequenos para a idade gestacional (PIG) em uma amostra não selecionada de mulheres que deram à luz em países da América do Sul. Métodos: Estudo descritivo transversal que incluiu 56.232 mães de crianças não malformadas nascidas entre 2002 e 2016, utilizando dados do Estudo Colaborativo Latino-americano de Malformações Congênitas (ECLAMC). Foram identificadas as doenças com maior número de casos observado/esperado de PP/PIG. O esperado foi obtido dos controles sem doenças. Odds ratios para variáveis de confusão de doença e eventos ao nascimento foram calculadas usando regressão logística multivariada. Resultados: Das 14 doenças mais referidas, hipertensão, infecção geniturinária, epilepsia, hipotireoidismo, diabetes e HIV/AIDS apresentaram maiores frequências de PP e/ou PIG. Idade materna nos dois extremos, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PP, enquanto idade materna avançada, primigravidez, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PIG. Após ajuste para as variáveis associadas, as doenças identificadas mantiveram associação com PP e todas, exceto epilepsia, com PIG. Conclusão: A descrição de uma população não selecionada de gestantes possibilitou identificar as doenças mais frequentes e seu impacto nos resultados adversos na gravidez. Seis doenças foram associadas a PP e duas a recém-nascidos PIG. Até onde sabemos, não há relatos semelhantes sobre mulheres não selecionadas intencionalmente por doenças específicas durante a gravidez em populações sul-americanas.

New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly.

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.

Análisis de anomalías cromosómicas, desbalances genómicos y variantes de secuencia como causa de cardiopatías congénitas / Analysis of chromosomal abnormalities, genomic imbalances, and sequence variants as cause of congenital heart defects

INTRODUCCIÓN: Las cardiopatías congénitas (CC) son causadas por el desarrollo anómalo del corazón durante el período embriofetal. Abarcan un amplio espectro de anomalías estructurales de las cavidades cardíacas o de los grandes vasos, con una prevalencia mundial de 6 a 9 por 1000 nacimientos. En Argentina constituyen un tercio de las anomalías congénitas (AC) al nacimiento. Si bien su etiología es heterogénea, se ha observado recurrencia familiar acorde con la influencia de factores genéticos. El objetivo del estudio fue evaluar la presencia de anomalías cromosómicas, desbalances genómicos o variantes de secuencias en una muestra de niños afectados con CC en Argentina. MÉTODOS: Se incluyó a 289 pacientes con CC de hasta 16 años. Se realizó un cariotipo para pacientes con otras AC y análisis por amplificación múltiple de sondas dependiente de ligación (MLPA) de regiones genómicas asociadas a CC para aquellos con CC conotroncales. En muestras seleccionadas, se analizaron desbalances genómicos por microarreglos de ADN (array-CGH) o variantes de secuencia en el gen NKX2-5. RESULTADOS: Hubo 9 pacientes que presentaron anomalías cromosómicas, 21 desbalances por MLPA y 8 por array-CGH. No se hallaron variantes patogénicas en NKX2-5 en los casos estudiados. DISCUSIÓN: Se halló la causa de la afección en el 13% de los casos analizados. El estudio de pacientes con CC aisladas o asociadas a otras AC no había sido abordado previamente en Argentina mediante este algoritmo

[Social inequities in teenage mothers and the relationship to adverse perinatal outcomes in South American populations]. / Inequidades sociales en madres adolescentes y la relación con resultados perinatales adversos en poblaciones sudamericanas.

The aim was to explain differences in the rates of adverse perinatal events in teenage mothers with low and high schooling. The sample was collected from the Latin American Colaborative Study of Congenital Malformations (ECLAMC) database. From a total of 2,443,747 births in 93 hospitals, 66,755 live newborns without congenital malformations were recruited from 2000 to 2017. Teenage mothers were classified according to low, medium, and high schooling. A multivariate model was used that included reproductive history, access to health services, demographic and socioeconomic variables, and ethnic group. The Fairlie decomposition model was applied to quantify the contribution of explanatory variables to the adverse perinatal event rates. Of the 66,755 newborns analyzed, 21.1% (n = 14,078) were born to teenage mothers. Distribution of maternal schooling was 24.2%, 59.8%, and 16% for low, medium, and high schooling, respectively. The highest rates of adverse perinatal events were seen in teenage mothers with low schooling. The variable "access to health services" explained 35%, 37%, and 23% of the disparities in low birthweight, prematurity, and intrauterine growth restriction, respectively, among teenage mother with low and high schooling. Low number of prenatal visits was the only risk factor for the two levels of schooling and the variable that best explained the differences between the rates of adverse perinatal events. From the public health perspective, prenatal care represents a low-cost intervention with the possibility of increased implementation through adequate information for the population and systematic measures in primary care.

El objetivo fue explicar las diferencias en la frecuencia de eventos perinatales adversos entre madres adolescentes con baja y alta escolaridad. La muestra poblacional se recogió en la base de datos del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Entre 2.443.747 nacimientos ocurridos en 93 hospitales, se reclutaron 66.755 recién nacidos vivos, sin defectos congénitos, durante el período 2000-2017. Las madres adolescentes se clasificaron según su escolaridad en: baja, media y alta. Se utilizó un modelo multivariado, que incluyó efectos reproductivos, acceso a servicios de salud, variables demográficas-socioeconómicas, así como de grupo étnico. El modelo de descomposición de Fairlie se aplicó para cuantificar la contribución de variables explicativas en las frecuencias de eventos perinatales adversos. De los 66.755 recién nacidos investigados, el 21,1% (n = 14.078) fue primigrávida de madres adolescentes. La distribución por escolaridad materna fue de 24,2%, 59,8% y 16% para baja, media y alta escolaridad, respectivamente. Las mayores frecuencias de eventos perinatales adversos se observaron en madres adolescentes con baja escolaridad. La variable "acceso a servicios de salud" explicó un 35%, 37% y 23% de las disparidades en el bajo peso al nacimiento, prematuridad y retardo de crecimiento intrauterino, respectivamente, entre madres adolescentes con baja y alta escolaridad. El bajo número de consultas prenatales fue el único factor de riesgo para los dos niveles de escolaridad y la variable que mejor explica las diferencias entre las frecuencias de eventos perinatales adversos. Desde el punto de vista de la salud pública, ellos representan una intervención de bajo coste, con posibilidad de que se incrementen mediante información adecuada para la población y medidas sistemáticas en los niveles de atención primaria.

O objetivo foi explicar as diferenças na frequência de eventos perinatais adversos entre mães adolescentes com baixa e alta escolaridade. A amostra populacional foi coletada na base de dados do Estudo Colaborativo Latino-Americano de Malformações Congênitas (ECLAMC). Entre 2.443.747 nascimentos ocorridos em 93 hospitais, 66.755 recém-nascidos vivos sem defeitos congênitos foram recrutados no período 2000-2017. As mães adolescentes foram classificadas segundo sua escolaridade em: baixa, média e alta. Foi utilizado um modelo multivariado que incluiu efeitos reprodutivos, acesso a serviços de saúde, variáveis demográficas-socioeconômicas e de grupo étnico. O modelo de decomposição de Fairlie foi aplicado para quantificar a contribuição de variáveis explicativas nas frequências de eventos perinatais adversos. Dos 66.755 recém-nascidos pesquisados, o 21,1% (n = 14.078) foi a mãe adolescente. A distribuição por escolaridade materna foi de 24,2%, 59,8% e 16% para baixa escolaridade, média escolaridade e alta escolaridade, respectivamente. As maiores frequências de eventos perinatais adversos foram observadas em mães adolescentes com baixa escolaridade. A variável "acesso a serviços de saúde"; explicou 35%, 37% e 23% das disparidades no baixo peso ao nascer, prematuridade e retardo de crescimento intrauterino, respectivamente, entre mães adolescentes com baixa e alta escolaridades. O baixo número de consultas pré-natais foi o único fator de risco para os dois níveis de escolaridade e a variável que melhor explica as diferenças entre as frequências de eventos perinatais adversos. Do ponto de vista da saúde pública, eles representam uma intervenção de baixo custo, com possibilidade de ser incrementadas por meio de informações adequadas à população e medidas sistemáticas nos níveis de atenção primária.

Preterm birth and genitourinary tract infections: assessing gene-environment interaction.

BACKGROUND: Preterm birth (PTB) is the leading cause of perinatal morbimortality worldwide. Genetic and environmental factors could raise PTB risk. The aim of this study was to analyze the contribution of the statistical interaction between genes and vaginal-urinary tract infections (VI-UTI) to the risk of PTB by clinical subtype. METHODS: Twenty-four SNPs were genotyped in 18 candidate genes from 352 fetal triads and 106 maternal triads. Statistical interactions were evaluated with conditional logistic regression models based on genotypic transmission/disequilibrium test. RESULTS: In PTB-idiopathic subtype mothers exposed to UTI, fetal SNPs rs11686474 (FSHR), rs4458044 (CRHR1, allele G), rs883319 (KCNN3), and maternal SNP rs1882435 (COL4A3) showed a nominal significant increment in prematurity risk. In preterm premature rupture of membranes (PPROM), fetal SNP rs2277698 (TIMP2) showed a nominal significant risk increment. In mothers exposed to VI, fetal SNP rs5742612 (IGF1) in PTB-PPROM and maternal SNP rs4458044 (CRHR1, allele C) in spontaneous PTB showed nominal significant increment in prematurity risk. CONCLUSIONS: Certain maternal and fetal genes linked to infectious/inflammatory and hormonal regulation processes increase prematurity risk according to clinical subtype when mothers are exposed to UTI or VI. These findings may help in the understanding of PTB etiology and PTB prevention. IMPACT: Preterm birth is a major cause of perinatal morbimortality worldwide and its etiology remains unknown. This work provides evidence on the statistical interaction of six genes with gestational vaginal or urinary infections leading to the occurrence of preterm births. Statistical interactions vary according to infection type, genotype (maternal and fetal), and clinical subtype of prematurity. Certain maternal and fetal genetic variants of genes linked to infectious/inflammatory and hormonal regulation processes would increase the risk of prematurity according to clinical subtype and infection type. Our findings may help in the study of etiology of preterm birth and its prevention.

A graph theory approach to analyze birth defect associations.

Birth defects are prenatal morphological or functional anomalies. Associations among them are studied to identify their etiopathogenesis. The graph theory methods allow analyzing relationships among a complete set of anomalies. A graph consists of nodes which represent the entities (birth defects in the present work), and edges that join nodes indicating the relationships among them. The aim of the present study was to validate the graph theory methods to study birth defect associations. All birth defects monitoring records from the Estudio Colaborativo Latino Americano de Malformaciones Congénitas gathered between 1967 and 2017 were used. From around 5 million live and stillborn infants, 170,430 had one or more birth defects. Volume-adjusted Chi-Square was used to determine the association strength between two birth defects and to weight the graph edges. The complete birth defect graph showed a Log-Normal degree distribution and its characteristics differed from random, scale-free and small-world graphs. The graph comprised 118 nodes and 550 edges. Birth defects with the highest centrality values were nonspecific codes such as Other upper limb anomalies. After partition, the graph yielded 12 groups; most of them were recognizable and included conditions such as VATER and OEIS associations, and Patau syndrome. Our findings validate the graph theory methods to study birth defect associations. This method may contribute to identify underlying etiopathogeneses as well as to improve coding systems.

Inequidades sociales en madres adolescentes y la relación con resultados perinatales adversos en poblaciones sudamericanas / Social inequities in teenage mothers and the relationship to adverse perinatal outcomes in South American populations / Iniquidades sociais em mães adolescentes e sua relação com resultados perinatais adversos em populações sul-americanas

Resumen: El objetivo fue explicar las diferencias en la frecuencia de eventos perinatales adversos entre madres adolescentes con baja y alta escolaridad. La muestra poblacional se recogió en la base de datos del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). Entre 2.443.747 nacimientos ocurridos en 93 hospitales, se reclutaron 66.755 recién nacidos vivos, sin defectos congénitos, durante el período 2000-2017. Las madres adolescentes se clasificaron según su escolaridad en: baja, media y alta. Se utilizó un modelo multivariado, que incluyó efectos reproductivos, acceso a servicios de salud, variables demográficas-socioeconómicas, así como de grupo étnico. El modelo de descomposición de Fairlie se aplicó para cuantificar la contribución de variables explicativas en las frecuencias de eventos perinatales adversos. De los 66.755 recién nacidos investigados, el 21,1% (n = 14.078) fue primigrávida de madres adolescentes. La distribución por escolaridad materna fue de 24,2%, 59,8% y 16% para baja, media y alta escolaridad, respectivamente. Las mayores frecuencias de eventos perinatales adversos se observaron en madres adolescentes con baja escolaridad. La variable "acceso a servicios de salud" explicó un 35%, 37% y 23% de las disparidades en el bajo peso al nacimiento, prematuridad y retardo de crecimiento intrauterino, respectivamente, entre madres adolescentes con baja y alta escolaridad. El bajo número de consultas prenatales fue el único factor de riesgo para los dos niveles de escolaridad y la variable que mejor explica las diferencias entre las frecuencias de eventos perinatales adversos. Desde el punto de vista de la salud pública, ellos representan una intervención de bajo coste, con posibilidad de que se incrementen mediante información adecuada para la población y medidas sistemáticas en los niveles de atención primaria.

Abstract: The aim was to explain differences in the rates of adverse perinatal events in teenage mothers with low and high schooling. The sample was collected from the Latin American Colaborative Study of Congenital Malformations (ECLAMC) database. From a total of 2,443,747 births in 93 hospitals, 66,755 live newborns without congenital malformations were recruited from 2000 to 2017. Teenage mothers were classified according to low, medium, and high schooling. A multivariate model was used that included reproductive history, access to health services, demographic and socioeconomic variables, and ethnic group. The Fairlie decomposition model was applied to quantify the contribution of explanatory variables to the adverse perinatal event rates. Of the 66,755 newborns analyzed, 21.1% (n = 14,078) were born to teenage mothers. Distribution of maternal schooling was 24.2%, 59.8%, and 16% for low, medium, and high schooling, respectively. The highest rates of adverse perinatal events were seen in teenage mothers with low schooling. The variable "access to health services" explained 35%, 37%, and 23% of the disparities in low birthweight, prematurity, and intrauterine growth restriction, respectively, among teenage mother with low and high schooling. Low number of prenatal visits was the only risk factor for the two levels of schooling and the variable that best explained the differences between the rates of adverse perinatal events. From the public health perspective, prenatal care represents a low-cost intervention with the possibility of increased implementation through adequate information for the population and systematic measures in primary care.

Resumo: O objetivo foi explicar as diferenças na frequência de eventos perinatais adversos entre mães adolescentes com baixa e alta escolaridade. A amostra populacional foi coletada na base de dados do Estudo Colaborativo Latino-Americano de Malformações Congênitas (ECLAMC). Entre 2.443.747 nascimentos ocorridos em 93 hospitais, 66.755 recém-nascidos vivos sem defeitos congênitos foram recrutados no período 2000-2017. As mães adolescentes foram classificadas segundo sua escolaridade em: baixa, média e alta. Foi utilizado um modelo multivariado que incluiu efeitos reprodutivos, acesso a serviços de saúde, variáveis demográficas-socioeconômicas e de grupo étnico. O modelo de decomposição de Fairlie foi aplicado para quantificar a contribuição de variáveis explicativas nas frequências de eventos perinatais adversos. Dos 66.755 recém-nascidos pesquisados, o 21,1% (n = 14.078) foi a mãe adolescente. A distribuição por escolaridade materna foi de 24,2%, 59,8% e 16% para baixa escolaridade, média escolaridade e alta escolaridade, respectivamente. As maiores frequências de eventos perinatais adversos foram observadas em mães adolescentes com baixa escolaridade. A variável "acesso a serviços de saúde"; explicou 35%, 37% e 23% das disparidades no baixo peso ao nascer, prematuridade e retardo de crescimento intrauterino, respectivamente, entre mães adolescentes com baixa e alta escolaridades. O baixo número de consultas pré-natais foi o único fator de risco para os dois níveis de escolaridade e a variável que melhor explica as diferenças entre as frequências de eventos perinatais adversos. Do ponto de vista da saúde pública, eles representam uma intervenção de baixo custo, com possibilidade de ser incrementadas por meio de informações adequadas à população e medidas sistemáticas nos níveis de atenção primária.

Limb body wall complex: Its delineation and relationship with amniotic bands using clustering methods.

BACKGROUND: Despite the numerous reports on the limb body wall complex (LBWC), this association has never been adequately defined. Amniotic bands (AB) are frequently present but their role remains unclear. Since most reports were based on clinical and often subjective diagnoses, the aim of this work was to define LBWC and the role of AB, minimizing subjectivity. METHODS: Data were obtained from the ECLAMC maternity hospitals network database. A total of 450 live and stillborn infants, born during 1967-2013, with AB or the LBWC were selected. A hierarchical cluster analysis was used to classify cases into homogeneous groups (sharing similar associated defects); robustness of the classification was confirmed with a discriminant analysis. The frequency of associated defects was compared among groups; those whose frequency differed significantly were included in a logistic regression to establish their association within each group. RESULTS: The cluster analysis identified two groups: a body wall defect (BWD) predominating in one, AB in the other. These groups were further divided into: BWD (cases with only BWD), AB (with only AB), BWD + AB, and NONE (with neither). Association with caudal defects and lower limb amelia was observed for BWD, with cephalic defects and upper limb amputations for BWD + AB. CONCLUSIONS: The results, obtained with the least possible subjectivity, indicated that BWD and BWD + AB are different conditions. Since BWD specifically associates with amelia, we propose that this defect and not any limb deficiency should be considered as inclusion criterium and that it should be included in the BWD acronym as LBWC.

Genetic Imbalances in Argentinean Patients with Congenital Conotruncal Heart Defects.

Congenital conotruncal heart defects (CCHD) are a subset of serious congenital heart defects (CHD) of the cardiac outflow tracts or great arteries. Its frequency is estimated in 1/1000 live births, accounting for approximately 10⁻30% of all CHD cases. Chromosomal abnormalities and copy number variants (CNVs) contribute to the disease risk in patients with syndromic and/or non-syndromic forms. Although largely studied in several populations, their frequencies are barely reported for Latin American countries. The aim of this study was to analyze chromosomal abnormalities, 22q11 deletions, and other genomic imbalances in a group of Argentinean patients with CCHD of unknown etiology. A cohort of 219 patients with isolated CCHD or associated with other major anomalies were referred from different provinces of Argentina. Cytogenetic studies, Multiplex-Ligation-Probe-Amplification (MLPA) and fluorescent in situ hybridization (FISH) analysis were performed. No cytogenetic abnormalities were found. 22q11 deletion was found in 23.5% of the patients from our cohort, 66% only had CHD with no other major anomalies. None of the patients with transposition of the great vessels (TGV) carried the 22q11 deletion. Other 4 clinically relevant CNVs were also observed: a distal low copy repeat (LCR)D-E 22q11 duplication, and 17p13.3, 4q35 and TBX1 deletions. In summary, 25.8% of CCHD patients presented imbalances associated with the disease.

Neural tube defects: Sex ratio changes after fortification with folic acid.

BACKGROUND: Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre- folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries. MATERIALS AND METHODS: With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification. RESULTS AND CONCLUSIONS: In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-thoracic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid.

Individual deprivation, regional deprivation, and risk for oral clefts in Argentina.

OBJECTIVE: The aim of this study was to analyze the effects of individual low socioeconomic status (SES) and deprived geographical area (GA) on the occurrence of isolated cleft lip with or without cleft palate (CL±P) in Argentina. METHODS: This case-control study included 577 newborns with isolated CL±P and 13 344 healthy controls, born between 1992 and 2001, from a total population of 546 129 births in 39 hospitals in Argentina. Census data on unsatisfied basic needs were used to establish the degree of geographical area deprivation. An SES index for each individual was established, using maternal age, gravidity, low paternal and maternal education, and low-level paternal occupation. Logistic regression was used to assess the effects of low SES and of deprived GA on CL±P. RESULTS: A slightly increased risk of CL±P was observed in mothers with a low SES, while a deprived GA showed no effect. Native ancestry, acute maternal illnesses, and poor prenatal care were significant risk factors for CL±P for the mothers with low SES, after using propensity scores to adjust for the demographic characteristics in cases and controls. CONCLUSIONS: Low individual SES slightly increased the risk for CL±P, but a deprived GA did not have that effect. There was no interaction between individual SES and deprived GA. Factors related to low individual SES-including poor prenatal care, low parental education, lack of information, and lifestyle factors-should be primarily targeted as risk factors for CL±P rather than factors related to a deprived place of residence.