BACKGROUNDDespite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODSWe performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 −8 ) or an association with suggestive significance (P<1.0×10 −6 ) in the discovery set. RESULTSIn the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONSIn this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2–4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.

IMPORTANCE Maternal infection has been implicated in the pathogenesis of preterm birth through intrauterine inflammatory response. Chlamydia, gonorrhea, and syphilis are among the most common sexually transmitted infections worldwide, but studies on their association with preterm birth are sparse. OBJECTIVETo examine the association between maternal chlamydia, gonorrhea, and syphilis infections in pregnancy and the risk of preterm birth in a large population-based study in the US. DESIGN, SETTING, AND PARTICIPANTSThis population-based retrospective cohort study examined nationwide birth certificate data from the US National Vital Statistics System between 2016 and 2019. All mothers who had a singleton live birth and available data on chlamydia, gonorrhea, or syphilis infection before or during pregnancy and gestational age at birth were included in analysis. EXPOSURES Sexually transmitted infection (chlamydia, gonorrhea, or syphilis) occurring before or during pregnancy. MAIN OUTCOMES AND MEASURES Preterm birth, defined as gestational age less than 37 weeks. RESULTS This study included 14 373 023 mothers (mean [SD] age 29 [5.8] years; Hispanic, 3 435 333 [23.9%]; non-Hispanic Asian, 912 425 [6.3%]; non-Hispanic Black, 2 058 006 [14.3%]; and non-Hispanic White, 7 386 568 [51.4% ]). Among the mothers, 267 260 (1.9%) had chlamydia, 43 147 (0.3%) had gonorrhea, and 16 321 (0.1%) had syphilis. Among the newborns, 1 146 800 (8.0%) were preterm births. The rate of preterm birth was 9.9%, 12.2%, and 13.3% among women with chlamydia, gonorrhea, and syphilis infection, respectively. After adjustment for sociodemographic and medical and/or health factors, the adjusted odds ratio of preterm birth was 1.03 (95% CI, 1.02-1.04) for chlamydia, 1.11 (95% CI, 1.08-1.15) for gonorrhea, 1.17 (95% CI, 1.11-1.22) for syphilis, and 1.06 (95% CI, 1.05-1.07) for any of these sexually transmitted infections comparing mothers with these conditions and those without. CONCLUSIONS AND RELEVANCEMaternal sexually transmitted infections (gonorrhea, syphilis, or chlamydia) were associated with an increased risk of preterm birth. Pregnant women with sexually transmitted infections before or during pregnancy might benefit from targeted prevention for preterm birth.

Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal–fetal tolerance and promote labor.

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BackgroundSelenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations.MethodsGestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis.FindingsIn all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi.InterpretationWhile our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

Background Babies born early and/or small for gestational age in Low and Middle-income countries (LMICs) contribute substantially to global neonatal and infant mortality. Tracking this metric is critical at a population level for informed policy, advocacy, resources allocation and program evaluation and at an individual level for targeted care. Early prenatal ultrasound examination is not available in these settings, gestational age (GA) is estimated using new-born assessment, last menstrual period (LMP) recalls and birth weight, which are unreliable. Algorithms in developed settings, using metabolic screen data, provided GA estimates within 1–2 weeks of ultrasonography-based GA. We sought to leverage machine learning algorithms to improve accuracy and applicability of this approach to LMICs settings. Methods This study uses data from AMANHI-ACT, a prospective pregnancy cohorts in Asia and Africa where early pregnancy ultrasonography estimated GA and birth weight are available and metabolite screening data in a subset of 1318 new-borns were also available. We utilized this opportunity to develop machine learning (ML) algorithms. Random Forest Regressor was used where data was randomly split into model-building and model-testing dataset. Mean absolute error (MAE) and root mean square error (RMSE) were used to evaluate performance. Bootstrap procedures were used to estimate confidence intervals (CI) for RMSE and MAE. For pre-term birth identification ROC analysis with bootstrap and exact estimation of CI for area under curve (AUC) were performed. Results Overall model estimated GA had MAE of 5.2 days (95% CI 4.6–6.8), which was similar to performance in SGA, MAE 5.3 days (95% CI 4.6–6.2). GA was correctly estimated to within 1 week for 85.21% (95% CI 72.31–94.65). For preterm birth classification, AUC in ROC analysis was 98.1% (95% CI 96.0–99.0; p < 0.001). This model performed better than Iowa regression, AUC Difference 14.4% (95% CI 5–23.7; p = 0.002). Conclusions Machine learning algorithms and models applied to metabolomic gestational age dating offer a ladder of opportunity for providing accurate population-level gestational age estimates in LMICs settings. These findings also point to an opportunity for investigation of region-specific models, more focused feasible analyte models, and broad untargeted metabolome investigation.

Background-Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR). Endogenous nitric oxide is critical for regulation of PVR . Nitric oxide is generated from L -arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN.Methods-Family based candidate gene analysis to study 48 single nucleotide polymorphisms in 6 UC enzyme genes. Genotyping was done on 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify the association between amino acid levels on initial newborn screening and PPHN.Results-Three SNPs in carbamoyl phosphate synthetase 1 gene (CPS1) showed significant association with PPHN (p=0.02). Tyrosine levels were significantly lower (p=0.003) and phenylalanine levels were significantly higher (p=0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups.Conclusions-This study suggests a potential association between SNPs in the CPS1 and PPHN. Tyrosine level was significantly lower and phenylalanine level was significantly higher in cases with PPHN. These findings warrant further replication in larger cohorts of patients.