Ongoing effects of preterm birth on the dopaminergic and noradrenergic pathways in the frontal cortex and hippocampus of guinea pigs.

Children born preterm have an increased likelihood of developing neurobehavioral disorders such as attention-deficit hyperactivity disorder (ADHD) and anxiety. These disorders have a sex bias, with males having a higher incidence of ADHD, whereas anxiety disorder tends to be more prevalent in females. Both disorders are underpinned by imbalances to key neurotransmitter systems, with dopamine and noradrenaline in particular having major roles in attention regulation and stress modulation. Preterm birth disturbances to neurodevelopment may affect this neurotransmission in a sexually dimorphic manner. Time-mated guinea pig dams were allocated to deliver by preterm induction of labor (gestational age 62 [GA62]) or spontaneously at term (GA69). The resultant offspring were randomized to endpoints as neonates (24 h after term-equivalence age) or juveniles (corrected postnatal day 40, childhood equivalence). Relative mRNA expressions of key dopamine and noradrenaline pathway genes were examined in the frontal cortex and hippocampus and quantified with real-time PCR. Myelin basic protein and neuronal nuclei immunostaining were performed to characterize the impact of preterm birth. Within the frontal cortex, there were persisting reductions in the expression of dopaminergic pathway components that occurred in preterm males only. Conversely, preterm-born females had increased expression of key noradrenergic receptors and a reduction of the noradrenergic transporter within the hippocampus. This study demonstrated that preterm birth results in major changes in dopaminergic and noradrenergic receptor, transporter, and synthesis enzyme gene expression in a sex- and region-based manner that may contribute to the sex differences in susceptibility to neurobehavioral disorders. These findings highlight the need for the development of sex-based treatments for improving these conditions.

Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.

AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.

Transcriptomic analysis delineates preterm prelabor rupture of membranes from preterm labor in preterm fetal membranes.

BACKGROUND: Globally, preterm birth remains the leading cause of death in children younger than 5 years old. Spontaneous preterm birth is comprised of two events that may or may not occur simultaneously: preterm labor and preterm prelabor rupture of membranes (PPROM). To further explore the concept that spontaneous preterm birth can result from the initializing of two separate but overlapping pathological events, we compared fetal membrane tissue from preterm labor deliveries to fetal tissue from preterm labor with PPROM deliveries. We hypothesized that the fetal membrane tissue from preterm labor with PPROM cases will have an RNA-seq profile divergent from the fetal membrane tissue from preterm labor controls. METHODS: Chorioamnion, separated into amnion and chorion, was collected from eight gestationally age-matched cases and controls within 15 min of birth, and analyzed using RNA sequencing. Pathway enrichment analyses and functional annotations of differentially expressed genes were performed using KEGG and Gene Ontogeny Pathway enrichment analyses. RESULTS: A total of 1466 genes were differentially expressed in the amnion, and 484 genes were differentially expressed in the chorion (log2 fold change > 1, FDR < 0.05) in cases (preterm labor with PPROM), versus controls (preterm labor only). In the amnion, the most significantly enriched (FDR < 0.01) KEGG pathway among down-regulated genes was the extracellular matrix receptor interaction pathway. Seven of the most significantly enriched pathways were comprised of multiple genes from the COL family, including COL1A, COL3A1, COL4A4, and COL4A6. In the chorion, the most significantly enriched KEGG pathways in up-regulated genes were chemokine, NOD receptor, Toll-like receptor, and cytokine-cytokine receptor signaling pathways. Similarly, KEGG pathway enrichment analysis for up-regulated genes in the amnion included three inflammatory pathways: cytokine-cytokine interaction, TNF signaling and the CXCL family. Six genes were significantly up regulated in chorionic tissue discriminated between cases (preterm labor with PPROM) and controls (preterm labor only) including GBP5, CXCL9, ALPL, S100A8, CASP5 and MMP25. CONCLUSIONS: In our study, transcriptome analysis of preterm fetal membranes revealed distinct differentially expressed genes for PPROM, separate from preterm labor. This study is the first to report transcriptome data that reflects the individual pathophysiology of amnion and chorion tissue from PPROM deliveries.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

INTRODUCTION: The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. METHODS: This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. RESULTS: Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. DISCUSSION: Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

The impact of DNA methylation as a factor of Adverse Pregnancy and Birth Outcomes (APBOs): a systematic review protocol.

BACKGROUND: Deoxyribonucleic acid (DNA) methylation is one of the epigenetic modifications that has gained a lot of interest as a factor influencing fetal programming and as a biomarker for adverse pregnancy and birth outcomes (APBOs). Epidemiological studies have demonstrated that DNA methylation can result in adverse pregnancy and birth outcomes (APBOs) including miscarriage, intrauterine growth restriction (IUGR), low birth weight (LBW), sepsis, and preterm birth (PTB), which may later result in diseases in adulthood. However, the mechanism by which DNA methylation influences these APBOs remains unclear. The systematic review will assess the association between global and gene-specific DNA methylation with adverse pregnancy outcomes. METHOD: The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 checklist will be followed when conducting this systematic review. To develop the search strategy the PI(E)COS (population, intervention/exposure, comparator/control, outcome, and study designs) framework will be followed. Thus far, the research team has retrieved 4721 from Cochrane Library, PubMed, Web of Sciences, and MEDLINE. Out of these, 584 studies have been screened for eligibility, and approximately 124 studies meet the inclusion criteria. Pending the search results identified from the grey literature. For identification of unpublished studies in journals indexed in electronic databases, Google Scholar will be used. I.M and A.S will separately extract data from the articles and screen them, if there are any disagreements between I.M and A.S, then the L.M will resolve them. The methodological quality and bias risk of the included studies will be evaluated using the Critical Appraisal Skill Programme CASP) checklist. [Formula: see text] and [Formula: see text] alpha = 0.10 statistic will be used for assessing statistical heterogeneity between studies. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to assess and grade the overall quality of extracted data. ETHICS AND DISSEMINATION: Ethical approval is not required. The systematic review will assess available literature on possible associations between DNA methylation with adverse pregnancy and birth outcomes (APBOs) including LBW, IUGR, miscarriage, sepsis, and PTB. The findings could help guide future research assessing DNA methylation and other APBOs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRCRD42022370647.

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Leptin and Leptin Receptor Polymorphisms in Infants and Their Parents: Correlation with Preterm Birth.

It has been proven that single-nucleotide polymorphisms (SNPs) in LEP and LEPR genes could predispose individuals to an increased risk of pregnancy adverse outcomes (PAOs) such as recurrent pregnancy loss (RPL) and pre-eclampsia. Preterm birth (PTB) is the leading cause of infant mortality. We decided to investigate the correlation between PTB and LEP and LEPR SNPs. The study cohort included families who underwent spontaneous PTB and control samples of families who had at-term-born (≥37 weeks of gestational age) children. Swabs were performed by rubbing the sticky end for about 30 s on the gum and on the inside of the cheek, allowing us to collect the flaking cells of the oral mucosa. Genotyping of the three SNPs-LEPRA668G, LEPG2548A and A19G-was carried out via an ARMS-MAMA real-time PCR procedure, as previously described. Regarding LEPG2548A, we found that the most expressed genotype in infants both in the preterm and the at-term group was AG; however, we did not discover any statistically significant difference (p = 0.97). Considering LEPA19G, none among the infants and parents were found to carry the AA genotype. No statistically significant differences were found between children, mothers and fathers belonging to preterm and at-term groups. We did not find a statistically significant association in newborns and their mother, but our results show a statistical correlation with the LEPRA668G genotype GG of the father. This fact can contribute to defining genetic risk factors for PTB. Further studies are certainly needed to better clarify the role of genetics in influencing preterm delivery.

MiRNA-26a-5p inhibits preterm labor initiation by targeting and regulating TRPC3 ion channel protein expression.

The incidence of preterm birth (PTB) is increasing annually worldwide, leading to various health problems or even fetal deaths. Our previous work demonstrated the activation of transient receptor potential cation channel subfamily C 3 (TRPC3) in mice with PTB, and its activation could promote inward flow of calcium ions and uterine smooth muscle (USM) contraction via regulation of Cav3.2, Cav3.1, and Cav1.2. However, the upstream regulators of TRPC3 and its mechanisms remain unknown. In the present study, the binding of miR-26a-5p to the 3' untranslated region of TRPC3 was predicted by bioinformatics databases (TargetScanHuman and starBase v3.0) and confirmed by a dual-luciferase assay. MiR-26a-5p was downregulated, while TRPC3 was upregulated in the USM tissues of patients with PTB compared to people without PTB. The results showed that miR-26a-5p mimic transfection markedly reduced TRPC3 expression in LPS-stimulated USM cells. Additionally, miR-26a-5p regulated intracellular Ca2+ levels in USM cells by targeting TRPC3. Furthermore, miR-26a-5p inhibited the CPI17/PKC/PLCγ signaling pathway and reduced the expression of Cav3.2, Cav3.1, and Cav1.2. In conclusion, miR-26a-5p regulated the initiation of PTB by targeting TRPC3 and regulating intracellular Ca2+ levels. This study provides a promising diagnostic biomarker and therapeutic target for PTB.

LncRNA PSMA3-AS1 promotes preterm delivery by inducing ferroptosis via miR-224-3p/Nrf2 axis.

Long non-coding RNAs (lncRNAs) have a vital potential in premature delivery. This research was intended to explore PSMA3-AS1's role in premature delivery as well as its possible molecular mechanism. We enrolled 100 premature delivery patients and 100 term patients. Fetal membranes were collected. RT-qPCR was adopted for evaluating PSMA3-AS1, miRNA-224-3p, along with Nrf2 expression. Cell function experiments were implemented to clarify PSMA3-AS1 functions in human trophoblast HTR-8/SVneo cells. Rescue together with mechanistic experiments were implemented for assessing the regulatory function and interaction between miR-224-3p and PSMA3-AS1 or Nrf2 axis in human trophoblast cells. The results uncovered that PSMA3-AS1 level presented downregulation in the fetal membrane tissues and human trophoblast cells. Overexpressed PSMA3-AS1 enhanced cell proliferation but suppressed ferroptosis in human trophoblast cells. Besides, PSMA3-AS1 elevation also attenuated the LPS-induced inflammatory response and restored the LPS-induced upregulation of 20α-HSD and downregulation of progesterone (P4). Mechanistically, miR-224-3p could bind to PSMA3-AS1 and present upregulation in fetal membranes and human trophoblast cells. Notably, overexpressed miR-224-3p offset the influences of PSMA3-AS1 on human trophoblast cell proliferation and ferroptosis. Furthermore, Nrf2 was targeted by miR-224-3p. Downregulated Nrf2 offset the influences of the miR-224-3p inhibitor and induced HTR-8/SVneo dysfunction. Additionally, Nrf2 transcriptionally activated PSMA3-AS1 and GPX4. In conclusion, PSMA3-AS1 expression is low during premature delivery and overexpressing PSMA3-AS1 promotes proliferation and suppresses ferroptosis of human trophoblast cells by interacting with miR-224-3p to downregulate Nrf2. Therefore, enhancing PSMA3-AS1 expression may be a promising therapeutic strategy to prevent premature delivery.

Hofbauer cell function in the term placenta associates with adult cardiovascular and depressive outcomes.

Pathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an inflammation-related expression signature, primarily expressed in Hofbauer cells of the term placenta and use expression quantitative trait loci to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we conduct a phenome-wide association study, followed by Mendelian randomization and identify protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth are over-represented within the module. We also identify aspirin as a putative modulator of this inflammation-related signature. Our data support a model where disruption of placental Hofbauer cell function, due to preterm birth or prenatal infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals.

Interferon-stimulated gene 15 polymorphisms are associated with spontaneous preterm birth in Taiwanese women.

PROBLEM: Immune and inflammatory responses are known to be major causes of preterm birth (PTB). The maternal genetic background plays an important role in the development of PTB. Interferon-stimulated gene 15 (ISG15) is an interferon-induced protein which can modulate immune cell activation and function. We aim to study if polymorphisms in the ISG15 gene are associated with spontaneous PTB (sPTB) risk in Taiwanese women. METHOD OF STUDY: ISG15 rs4615788 C/G, rs1921 G/A, and rs8997 A/G polymorphisms were genotyped in a hospital-based study of 112 women with sPTB and 1120 term controls. The plasma concentrations of ISG15 were determined by enzyme-linked immunosorbent assay. RESULTS: We found the ISG15 rs1921 G-rs8997 A haplotype was associated with decreased risk for PTB (χ2  = 6.26, p = .01, pc  = .04). The A/G genotype of ISG15 rs8997 polymorphism might have the potential to confer reduced risk of PTB women (χ2  = 4.09, p = .04, pc  = .08). Spontaneous PTB women displayed higher plasma ISG15 levels compared to term controls (p < .001). The plasma ISG15 levels among pregnant women with rs8997 A/G genotype were found significantly lower compared to G/G genotype (p = .03). CONCLUSIONS: Women with the ISG15 rs1921 G-rs8997 A haplotype may associate with spontaneous PTB. These findings provide new insights into the etiology of preterm birth.

Interleukin-2 gene methylation levels and interleukin-2 levels associated with environmental exposure as risk biomarkers for preterm birth.

AIM: To compare interleukin-2 levels (IL-2) and IL-2 gene site 1 methylation levels between preterm newborns (PN) and full-term newborns (FN) and investigate their association with the environmental exposure of their mothers during pregnancy. METHODS: IL-2 and IL-2 gene site 1 methylation levels were assessed in 50 PN and 56 FN. Newborns' mothers filled in questionnaires about their living and occupational environments, habits, diets, and hobbies. RESULTS: The mothers of PN were significantly more frequently agrarian/rural residents than the mothers of FN. PN had significantly higher IL-2 levels, and significantly lower methylation of IL-2 gene site 1 levels than FN. CONCLUSION: IL-2 levels, hypomethylation of the IL-2 gene site 1, and the mother's rural residence (probably due to pesticide exposure) were predictive biomarkers for preterm birth. For the first time, we present the reference values for the methylation of IL-2 gene site 1 in PN and FN, which can be used in the clinical setting and biomonitoring.

A genome-wide and candidate gene association study of preterm birth in Korean pregnant women.

Preterm birth (PTB) refers to delivery before 37 weeks of gestation. Premature neonates exhibit higher neonatal morbidity and mortality rates than term neonates; therefore, it is crucial to predict and prevent PTB. Advancements enable the prediction and prevention of PTB using genetic approaches, especially by investigating its correlation with single nucleotide polymorphisms (SNPs). We aimed to identify impactive and relevant SNPs for the prediction of PTB via whole-genome sequencing analyses of the blood of 31 pregnant women with PTB (n = 13) and term birth (n = 18) who visited the Ewha Womans University Mokdong Hospital from November 1, 2018 to February 29, 2020. A genome-wide association study was performed using PLINK 1.9 software and 256 SNPs were selected and traced through protein-protein interactions. Moreover, a validation study by genotyping was performed on 60 other participants (preterm birth, n = 30; term birth, n = 30) for 25 SNPs related to ion channel binding and receptor complex pathways. Odds ratios were calculated using additive, dominant, and recessive genetic models. The risk of PTB in women with the AG allele of rs2485579 (gene name: RYR2) was significantly 4.82-fold increase, and the risk of PTB in women with the AG allele of rs7903957 (gene name: TBX5) was significantly 0.25-fold reduce. Our results suggest that rs2485579 (in RYR2) can be a genetic marker of PTB, which is considered through the association with abnormal cytoplasmic Ca2+ concentration and dysfunctional uterine contraction due to differences of RYR2 in the sarcoplasmic reticulum.

Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci.

BACKGROUND: Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome. METHODS: We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively. RESULTS: The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action. CONCLUSION: We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.

Identification and prediction model of placenta-brain axis genes associated with neurodevelopmental delay in moderate and late preterm children.

BACKGROUND: Moderate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and neurobehavioral developmental delays in children and the underlying biological mechanisms need to be further revealed. The "placenta-brain axis" (PBA) provides a new perspective for gene regulation and risk prediction of neurodevelopmental delays in MLPT children. METHODS: The authors performed multivariate logistic regression models between MLPT and children's neurodevelopmental outcomes, using data from 129 MLPT infants and 3136 full-term controls from the Ma'anshan Birth Cohort (MABC). Furthermore, the authors identified the abnormally regulated PBA-related genes in MLPT placenta by bioinformatics analysis of RNA-seq data and RT-qPCR verification on independent samples. Finally, the authors established the prediction model of neurodevelopmental delay in children with MLPT using multiple machine learning models. RESULTS: The authors found an increased risk of neurodevelopmental delay in children with MLPT at 6 months, 18 months, and 48 months, especially in boys. Further verification showed that APOE and CST3 genes were significantly correlated with the developmental levels of gross-motor domain, fine-motor domain, and personal social domain in 6-month-old male MLPT children. CONCLUSIONS: These findings suggested that there was a sex-specific association between MLPT and neurodevelopmental delays. Moreover, APOE and CST3 were identified as placental biomarkers. The results provided guidance for the etiology investigation, risk prediction, and early intervention of neurodevelopmental delays in children with MLPT.

Association of 25-Hydroxyvitamin D with Preterm Birth and Premature Rupture of Membranes: A Mendelian Randomization Study.

Low vitamin D (VitD) level is a risk factor for preterm birth (PTB), but the results of previous studies remained inconsistent, which may be influenced by the confounding factors and different types of PTB. We performed Mendelian randomization (MR) to uncover the association of 25-hydroxyvitamin D (25(OH)D) with PTB, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). This study was conducted in Zhoushan Maternal and Child Health Hospital, Zhejiang, from August 2011 to March 2022. Plasma 25(OH)D levels in three trimesters of pregnancy were measured. We conducted an MR analysis utilizing a genetic risk score (GRS) approach, which was based on VitD-associated single-nucleotide polymorphisms. The prospective cohort study included 3923 pregnant women. The prevalence of PTB, PROM, and PPROM were 6.09%, 13.18%, and 1.33%, respectively. Compared to those without vitamin D deficiency (VDD), only vaginally delivering pregnant women with VDD had a 2.69 (1.08-6.68) times risk of PTB. However, MR analysis did not support the association. One-unit higher GRS was not associated with an increased risk of PTB, regardless of the trimesters (OR [95% CI]: 1.01 [0.93-1.10], 1.06 [0.96-1.18], and 0.95 [0.82-1.10], respectively). When further taking PROM and PPROM as the outcomes, the MR analysis also showed no consistent evidence of a causal effect of VitD levels on the risk of them. Our MR analyses did not support a causal effect of 25(OH)D concentrations in the three trimesters on PTB, PROM, and PPROM.

Intronic variants of LGALS13 gene encoding placental protein (PP13) are linked with increased risk of infection-associated spontaneous preterm birth.

PROBLEM: Spontaneous preterm birth (sPTB) is a global health issue. Studies suggest infection and infection-based inflammatory responses are major risk factors for sPTB. Considering the important role of anti-inflammatory proteins in pregnancy, the study aimed to find the association between anti-inflammatory LGALS13 gene variants IVS2-22 A/G (rs2233706) and IVS3+72 T/A (rs2233708) and the risk of sPTB during Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum infection in Indian population. METHOD OF STUDY: Placental samples of 160 sPTB and 160 term women were collected. Pathogens were detected by PCR. The genotyping of LGALS13 gene variants IVS2-22 A/G (rs2233706) and IVS3+72 T/A (rs2233708) was done by qualitative real-time PCR using allelic discrimination method (VIC- and FAM-labeled). RESULTS: The frequency of AG or GG genotype of LGALS13 IVS2-22A/G polymorphism (rs2233706) was 75.5% in infected sPTB cases and 14.4% in uninfected sPTB cases and 7.3% in term birth controls (p < .0001), while the frequency of TA or AA genotype of LGALS13 IVS3+72T/A polymorphism (rs2233708) was 83.6% in infected sPTB cases and 18% in uninfected sPTB cases and 12.7% in term birth controls (p < .0001). The genotypic frequencies for both the variants of LGALS13 were statistically significant (p < .0001) in the infected sPTB versus uninfected sPTB and term birth controls. CONCLUSIONS: Study reveals strong association between the presence of immunological gene variants LGALS13 IVS2-22 A/G (rs2233706) and LGALS13 IVS3+72 T/A (rs2233708) and risk of sPTB during C. trachomatis, M. hominis and U. urealyticum infection.

Microdiversity of the vaginal microbiome is associated with preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The vaginal microbiome has been associated with PTB, yet the mechanisms underlying this association are not fully understood. Understanding microbial genetic adaptations to selective pressures, especially those related to the host, may yield insights into these associations. Here, we analyze metagenomic data from 705 vaginal samples collected during pregnancy from 40 women who delivered preterm spontaneously and 135 term controls from the Multi-Omic Microbiome Study-Pregnancy Initiative. We find that the vaginal microbiome of pregnancies that ended preterm exhibited unique genetic profiles. It was more genetically diverse at the species level, a result which we validate in an additional cohort, and harbored a higher richness and diversity of antimicrobial resistance genes, likely promoted by transduction. Interestingly, we find that Gardnerella species drove this higher genetic diversity, particularly during the first half of the pregnancy. We further present evidence that Gardnerella spp. underwent more frequent recombination and stronger purifying selection in genes involved in lipid metabolism. Overall, our population genetics analyses reveal associations between the vaginal microbiome and PTB and suggest that evolutionary processes acting on vaginal microbes may play a role in adverse pregnancy outcomes such as PTB.