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.

Indirect Effects of Neighbourhood Socioeconomic Status on Preterm Birth Risk in an Argentine Population.

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.

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.

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..

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.

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.

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.

Association of candidate gene polymorphisms with clinical subtypes of preterm birth in a Latin American population.

BackgroundPreterm birth (PTB) is the leading cause of neonatal mortality and morbidity. PTB is often classified according to clinical presentation as follows: idiopathic (PTB-I), preterm premature rupture of membranes (PTB-PPROM), and medically induced (PTB-M). The aim of this study was to evaluate the associations between specific candidate genes and clinical subtypes of PTB.MethodsTwenty-four single-nucleotide polymorphisms (SNPs) were genotyped in 18 candidate genes in 709 infant triads. Of them, 243 were PTB-I, 256 were PTB-PPROM, and 210 were PTB-M. These data were analyzed with a Family-Based Association.ResultsPTB was nominally associated with rs2272365 in PON1, rs883319 in KCNN3, rs4458044 in CRHR1, and rs610277 in F3. Regarding clinical subtypes analysis, three SNPs were associated with PTB-I (rs2272365 in PON1, rs10178458 in COL4A3, and rs4458044 in CRHR1), rs610277 in F3 was associated with PTB-PPROM, and rs883319 in KCNN3 and rs610277 in F3 were associated with PTB-M.ConclusionOur study identified polymorphisms potentially associated with specific clinical subtypes of PTB in this Latin American population. These results could suggest a specific role of such genes in the mechanisms involved in each clinical subtype. Further studies are required to confirm our results and to determine the role of these genes in the pathophysiology of clinical subtypes.

Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.

Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. © 2016 Wiley Periodicals, Inc.

Polymorphisms in NR5A2, gene encoding liver receptor homolog-1 are associated with preterm birth.

BACKGROUND: Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidence of genetic susceptibility. Objective of this study was to identify genetic variants contributing to PTB. METHODS: Genotyping was performed for 24 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NR5A2, FSHR, FOXP3, and SERPINH1). Genotyping was completed on 728 maternal triads (mother and maternal grandparents of a preterm infant). Data were analyzed with Family Based Association Test. RESULTS: For all maternal triads rs2737667 of NR5A2 showed significant association at P = 0.02. When stratifying by gestational age three SNPs in NR5A2 had P values <0.05 in the <32-wk gestational age group (rs12131233, P = 0.007; rs2737667, P = 0.04; rs2816949, P = 0.02). When preterm premature rupture of membranes cases were excluded rs2737667 of NR5A2 showed the strongest association with a P value <0.0002. This association remained significant after correction for multiple testing. CONCLUSION: This study suggests a potential association between intronic SNPs in the NR5A2 gene and PTB. NR5A2 gene encodes for the liver receptor homolog-1 protein, which plays a critical role in regulation of cholesterol metabolism, steroidogenesis, and progesterone synthesis. These findings suggest that NR5A2 may be important in the pathophysiology of PTB and exploring noncoding regulators of NR5A2 is warranted.

Gastroschisis and young mothers: What makes them different from other mothers of the same age?

BACKGROUND: Although young maternal age has been identified as a risk factor for gastroschisis, its role remains undisclosed. To our knowledge, the differences between young mothers of infants with gastroschisis and young mothers of infants with other pregnancy outcomes have not been established. The aim of this work was to compare characteristics of young mothers whose newborn had gastroschisis with same aged mothers of malformed and nonmalformed control infants, diagnosed within the ECLAMC maternity hospital network. METHODS: Data base records of live and stillborn infants of one of three groups (with isolated gastroschisis, with 1 of 5 other isolated birth defects, and nonmalformed), and whose mothers were younger than 20 years, were selected. Secular trends were obtained for all birth defects; frequencies and odds ratios (OR) of demographic and reproductive variables were compared among the 3 groups. Significantly associated variables were adjusted with a multivariate regression. RESULTS: The association was higher with gastroschisis 1) than with other birth defects for African ancestry, smoking, adequate prenatal control and diagnosis 2) than with nonmalformed controls for maternal illnesses and alcohol 3) and than both for previous pregnancy loss and medication, mainly sex hormones. After adjustment, only previous pregnancy loss maintained its significance when compared with malformed (OR = 2.34; 1.37-3.97; P = 0.002), as well as with nonmalformed (OR = 3.43; 2.07-5.66; P < 0.001) controls. CONCLUSION: A previous pregnancy loss was identified as the main risk factor for gastroschisis, while an increased use of sex hormones, perhaps related to the previous loss, could trigger a disruptive mechanism, due to their thrombophilic effect.

Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study.

BACKGROUND: Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. METHODS: To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. RESULTS: Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case-control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. CONCLUSIONS: Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

Environmental risk factors and perinatal outcomes in preterm newborns, according to family recurrence of prematurity.

OBJECTIVE: We analyzed the role of environmental risk factors, sociodemographic characteristics, clinical characteristics, and reproductive history in preterm births and their associated perinatal outcomes in families classified according to their histories of preterm recurrence among siblings. STUDY DESIGN: A retrospective study was conducted at Nuestra Señora de la Merced Maternity Hospital in the city of Tucumán, Argentina. A total of 348 preterm, non-malformed, singleton children born to multipara women were reviewed. The family history score described by Khoury was applied, and families were classified as having no, medium, or high genetic aggregation. RESULTS: Families with no familial aggregation showed a higher rate of short length of cohabitation, maternal urinary tract infections during the current pregnancy, and maternal history of miscarriage during the previous pregnancy. Families with a high level of aggregation had a significantly higher incidence of pregnancy complications, such as diabetes, hypertension, and immunologic disorders. CONCLUSION: Reproductive histories clearly differed between the groups, suggesting both a different response to environmental challenges based on genetic susceptibility and the activation of different pathophysiological pathways to determine the duration of pregnancy in each woman.

Genome-wide analysis of DNA methylation in human amnion.

The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.

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.

Replication of a genome-wide association study of birth weight in preterm neonates.

OBJECTIVE: To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al. STUDY DESIGN: A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis. RESULTS: Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples. CONCLUSIONS: These results indicate the potential importance of this marker on birth weight regardless of gestational age.

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.

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.

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.