First name
Kasey
Middle name
J M
Last name
Brennan

Title

Cervical microRNA expression and spontaneous preterm birth.

Year of Publication

2023

Number of Pages

100783

Date Published

01/2023

ISSN Number

2589-9333

Abstract

BACKGROUND: Preterm birth remains a major public health issue affecting 10% of all pregnancies and increases risks of neonatal morbidity and mortality. Approximately 50% to 60% of preterm births are spontaneous, resulting from preterm premature rupture of membranes or preterm labor. The pathogenesis of spontaneous preterm birth is incompletely understood, and prediction of preterm birth remains elusive. Accurate prediction of preterm birth would reduce infant morbidity and mortality through targeted patient referral to hospitals equipped to care for preterm infants. Two previous studies have analyzed cervical microRNAs in association with spontaneous preterm birth and the length of gestation, but the extent to which microRNAs serve as predictive biomarkers remains unknown.

OBJECTIVE: This study aimed to examine associations between cervical microRNA expression and spontaneous preterm birth, with the specific goal of identifying a subset of microRNAs that predict spontaneous preterm birth.

STUDY DESIGN: We performed a prospective, nested, case-control study of 25 cases with spontaneous preterm birth and 49 term controls. Controls were matched to cases in a 2:1 ratio on the basis of age, parity, and self-identified race. Cervical swabs were collected at a mean gestational age of 17.1 (4.8) weeks of gestation, and microRNAs were analyzed using a quantitative polymerase chain reaction array. Normalized microRNA expression was compared between cases and controls, and a false discovery rate of 0.2 was applied to account for multiple comparisons. Histopathologic analysis of slides of cervical swab samples was performed to quantify leukocyte burden for adjustment in conditional regression models. We explored the use of Relief-based unsupervised identification of top microRNAs and support vector machines to predict spontaneous preterm birth. We performed microRNA enrichment analysis to explore potential biologic targets and pathways in which up-regulated microRNAs might be involved.

RESULTS: Of the 754 microRNAs on the polymerase chain reaction array, 346 were detected in ≥75% of participants' cervical swabs. Average cervical microRNA expression was significantly higher in cases of spontaneous preterm birth than in controls (P=.01). There were 95 significantly up-regulated individual microRNAs (>2-fold change) in cases of subsequent spontaneous preterm birth compared with term controls (P<.05; q<0.2). Notably, miR-143, miR-30e-3p, and miR-199b were all significantly up-regulated, which is consistent with the 1 previous study of cervical microRNA and spontaneous preterm birth. A Relief-based, novel variable (feature) selection machine learning approach had low-to-moderate prediction accuracy, with an area under the receiver operating curve of 0.71. Enrichment analysis revealed that identified microRNAs may modulate inflammatory cell signaling.

CONCLUSION: In this prospective nested case-control study of cervical microRNA expression and spontaneous preterm birth, we identified a global increase in microRNA expression and up-regulation of 95 distinct microRNAs in association with subsequent spontaneous preterm birth. Larger and more diverse studies are required to determine the ability of microRNAs to accurately predict spontaneous preterm birth, and mechanistic work to facilitate development of novel therapeutic interventions to prevent spontaneous preterm birth is warranted.

DOI

10.1016/j.ajogmf.2022.100783

Alternate Title

Am J Obstet Gynecol MFM

PMID

36280145

Title

Pregnancy-associated changes in cervical noncoding RNA.

Year of Publication

2020

Number of Pages

1013-1025

Date Published

2020 06

ISSN Number

1750-192X

Abstract

<p>To identify pregnancy-associated changes in cervical noncoding RNA (ncRNA), including miRNA and long noncoding RNA (lncRNA), and their potential effects on biologic processes. We enrolled 21 pregnant women with term deliveries (≥37&nbsp;weeks' gestation) in a prospective cohort and collected cervical swabs before 28&nbsp;weeks' gestation. We enrolled 21 nonpregnant controls. We analyzed miRNA, lncRNA and mRNA expression, applying a Bonferroni correction. Five miRNA and three lncRNA were significantly differentially (&gt;twofold change) expressed. Putative miRNA targets are enriched in genes mediating organogenesis, glucocorticoid signaling, cell adhesion and ncRNA machinery. Differential cervical ncRNA expression occurs in the setting of pregnancy. Gene ontology classification reveals biological pathways through which miRNA may play a biologic role in normal pregnancy physiology.</p>

DOI

10.2217/epi-2019-0231

Alternate Title

Epigenomics

PMID

32808540

Title

Maternal anxiety and depression in pregnancy and DNA methylation of the glucocorticoid receptor gene.

Year of Publication

2020

Date Published

2020 Nov 20

ISSN Number

1750-192X

Abstract

<p><strong>Aim:&nbsp;</strong>To quantify associations of anxiety and depression during pregnancy with differential cord blood DNA methylation of the glucorticoid receptor (<em>NR3C1</em>). <strong>Materials &amp; methods:&nbsp;</strong>Pregnancy anxiety, trait anxiety and depressive symptoms were collected using the Pregnancy Related Anxiety Scale, State-Trait Anxiety Index and Edinburgh Postnatal Depression Scale, respectively. <em>NR3C1&nbsp;</em>methylation was determined at four methylation sites. <strong>Results:</strong>&nbsp;DNA methylation of CpG 1 in the <em>NR3C1&nbsp;</em>CpG island shore&nbsp;was higher in infants born to women with high pregnancy anxiety (β 2.54, 95% CI: 0.49-4.58) and trait anxiety (β 1.68, 95% CI: 0.14-3.22). No significant association was found between depressive symptoms and <em>NR3C1&nbsp;</em>methylation. <strong>Conclusion:</strong>&nbsp;We found that maternal anxiety was associated with increased <em>NR3C1&nbsp;</em>CpG island shore methylation.</p>

DOI

10.2217/epi-2020-0022

Alternate Title

Epigenomics

PMID

33215541

Title

Prenatal Stress, Methylation in Inflammation-Related Genes, and Adiposity Measures in Early Childhood: the Programming Research in Obesity, Growth Environment and Social Stress Cohort Study.

Year of Publication

2018

Number of Pages

34-41

Date Published

2018 01

ISSN Number

1534-7796

Abstract

<p><strong>OBJECTIVE: </strong>Maternal stress during pregnancy may influence childhood growth and adiposity, possibly through immune/inflammatory programming. We investigated whether exposure to prenatal stress and methylation in inflammation-related genes were associated with childhood adiposity in 424 mother-child pairs in Mexico City, Mexico.</p>

<p><strong>METHODS: </strong>A stress index was created based on four prenatally administered stress-related scales (Exposure to Violence, Crisis in Family Systems, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale). We measured weight, height, body fat mass (BFM), percentage body fat (PBF), and waist circumference in early childhood (age range, 4-6 years). Body mass index (BMI) z scores were calculated according to World Health Organization standards. DNA methylation in gene promoters of tumor necrosis factor α, interleukin 8, and interleukin 6 (IL6) in umbilical cord blood were determined by pyrosequencing.</p>

<p><strong>RESULTS: </strong>An interquartile range increase in stress index (27.3) was associated with decreases of 0.14 unit in BMI z score (95% confidence interval [CI] = -0.28 to -0.005), 5.6% in BFM (95% CI = -9.7 to -1.4), 3.5% in PBF (95% CI = -6.3 to -0.5), and 1.2% in waist circumference (95% CI = -2.4 to -0.04) in multivariable-adjusted models. An interquartile range increase in IL6 methylation (3.9%) was associated with increases of 0.23 unit in BMI z score (95% CI = 0.06-0.40), 8.1% (95% CI = 2.3-14.3) in BFM, 5.5% (95% CI = 1.7-9.5) in PBF, and 1.7% (95% CI = 0.2-3.3) in waist circumference.</p>

<p><strong>CONCLUSIONS: </strong>Prenatal stress was associated with decreased childhood adiposity, whereas cord blood IL6 methylation was associated with increased childhood adiposity in Mexican children.</p>

DOI

10.1097/PSY.0000000000000517

Alternate Title

Psychosom Med

PMID

28787364

Title

Long noncoding RNA expression in the cervix mid-pregnancy is associated with the length of gestation at delivery.

Year of Publication

2018

Number of Pages

742-750

Date Published

2018

ISSN Number

1559-2308

Abstract

<p>Infants born preterm are at increased risk of multiple morbidities and mortality. Why some women deliver preterm remains poorly understood. Prior studies have shown that cervical microRNA expression and DNA methylation are associated with the length of gestation. However, no study has examined the role of long noncoding RNAs (lncRNAs) in the cervix during pregnancy. To determine whether expression of lncRNAs is associated with length of gestation at delivery, we analyzed RNA from cervical swabs obtained from 78 women during pregnancy (mean 15.5, SD 5.0, weeks of gestation) who were participating in the Spontaneous Prematurity and Epigenetics of the Cervix (SPEC) Study in Boston, MA, USA. We used a PCR-based platform and found that 9 lncRNAs were expressed in at least 50% of the participants. Of these, a doubling of the expression of TUG1, TINCR, and FALEC was associated with shorter lengths of gestation at delivery [2.8 (95% CI: 0.31, 5.2); 3.3 (0.22, 6.3); and 4.5 (7.3, 1.6) days shorter respectively]. Of the lncRNAs analyzed, none was statistically associated with preterm birth, but expression of FALEC was 2.6-fold higher in women who delivered preterm vs. term (P&nbsp;=&nbsp;0.051). These findings demonstrate that lncRNAs can be measured in cervical samples obtained during pregnancy and are associated with subsequent length of gestation at delivery. Further, this study supports future work to replicate these findings in other cohorts and perform mechanistic studies to determine the role of lncRNAs in the cervix during pregnancy.</p>

DOI

10.1080/15592294.2018.1503490

Alternate Title

Epigenetics

PMID

30045669

Title

Association between meconium acetaminophen and childhood neurocognitive development in GESTE, a Canadian cohort study.

Year of Publication

2018

Date Published

2018 Sep 07

ISSN Number

1096-0929

Abstract

<p>Acetaminophen is the only over-the-counter pain reliever that is not contraindicated during pregnancy, but recent studies have questioned whether acetaminophen is safe for the fetus, particularly the developing brain. This prospective birth cohort study probed the previously observed association between in utero exposure to acetaminophen and neurodevelopment by using concentrations of acetaminophen measured in meconium, which more objectively captures exposure of the fetus than maternal report. Exposure, measured by liquid chromatography coupled with tandem mass spectrometry, was categorized into non-detection, low detection, and high detection levels. At age six to eight years, children completed a set of subtests from the Wechsler Intelligence Scale for Children, 4th edition. Additionally this study examined potential effect modification by child sex on the association between acetaminophen exposure and neurodevelopment. In fully adjusted models, in utero exposure to acetaminophen was not statistically significantly associated with decreased scores on any of the examined subtests in all children combined (n = 118). The effect of in utero acetaminophen exposure on the Coding subtest was marginally significantly different among boys and girls, with girls performing significantly better on the task with higher levels of acetaminophen compared to girls with undetectable levels of exposure [βgirls, low = 2.83 (0.97, 4.70), βgirls, high = 1.95 (-0.03, 3.93), βboys, low = 0.02 (-1.78, 1.81), βboys, high = -0.39 (-2.09, 1.31), pinteraction = 0.06]. Effect modification by child sex was not observed on other subtests. These results do not support prior reports of adverse neurodevelopmental effects of in utero exposure to acetaminophen.</p>

DOI

10.1093/toxsci/kfy222

Alternate Title

Toxicol. Sci.

PMID

30202886

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