Cervical microRNA expression and spontaneous preterm birth.

2023

100783

01/2023

2589-9333

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.

10.1016/j.ajogmf.2022.100783

Am J Obstet Gynecol MFM

36280145

Association of Prenatal Acetaminophen Exposure Measured in Meconium With Adverse Birth Outcomes in a Canadian Birth Cohort.

2022

828089

2022

2296-2360

<p><strong>Background: </strong>The small number of studies examining the association of prenatal acetaminophen with birth outcomes have all relied on maternal self-report. It remains unknown whether prenatal acetaminophen exposure measured in a biological specimen is associated with birth outcomes.</p>

<p><strong>Objectives: </strong>To investigate the association of acetaminophen measured in meconium with birthweight, gestational age, preterm birth, size for gestational age, gestational diabetes, preeclampsia, and high blood pressure.</p>

<p><strong>Methods: </strong>This birth cohort from Sherbrooke, QC, Canada, included 773 live births. Mothers with no thyroid disease enrolled at their first prenatal care visit or delivery. Acetaminophen was measured in meconium for 393 children at delivery. We tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, small and large for gestational age, gestational diabetes, preeclampsia, and high blood pressure. We imputed missing data multiple imputation and used inverse probability weighting to account for confounding and selection bias.</p>

<p><strong>Results: </strong>Acetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 g (β = -136; 95% CI [-229, -43]), 20% increased weekly hazard of delivery (hazard ratio = 1.20; 95% CI [1.00, 1.43]), and over 60% decreased odds of being born large for gestational age (odds ratio = 0.38; 95% CI [0.20, 0.75]). Prenatal acetaminophen was not associated with small for gestational age, preterm birth, or any pregnancy complications.</p>

<p><strong>Conclusion: </strong>Prenatal acetaminophen was associated with adverse birth outcomes. Although unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.</p>

10.3389/fped.2022.828089

Front Pediatr

35450103

Pregnancy-associated changes in cervical noncoding RNA.

2020

1013-1025

2020 06

1750-192X

<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>

10.2217/epi-2019-0231

Epigenomics

32808540

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

2020

2020 Nov 20

1750-192X

<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>

10.2217/epi-2020-0022

Epigenomics

33215541

Prenatal lead exposure and fetal growth: Smaller infants have heightened susceptibility.

2017

228-233

2017 Feb

1873-6750

<p><strong>BACKGROUND: </strong>As population lead levels decrease, the toxic effects of lead may be distributed to more sensitive populations, such as infants with poor fetal growth.</p>

<p><strong>OBJECTIVES: </strong>To determine the association of prenatal lead exposure and fetal growth; and to evaluate whether infants with poor fetal growth are more susceptible to lead toxicity than those with normal fetal growth.</p>

<p><strong>METHODS: </strong>We examined the association of second trimester maternal blood lead levels (BLL) with birthweight-for-gestational age (BWGA) z-score in 944 mother-infant participants of the PROGRESS cohort. We determined the association between maternal BLL and BWGA z-score by using both linear and quantile regression. We estimated odds ratios for small-for-gestational age (SGA) infants between maternal BLL quartiles using logistic regression. Maternal age, body mass index, socioeconomic status, parity, household smoking exposure, hemoglobin levels, and infant sex were included as confounders.</p>

<p><strong>RESULTS: </strong>While linear regression showed a negative association between maternal BLL and BWGA z-score (β=-0.06 z-score units per log BLL increase; 95% CI: -0.13, 0.003; P=0.06), quantile regression revealed larger magnitudes of this association in the &lt;30th percentiles of BWGA z-score (β range [-0.08, -0.13] z-score units per log BLL increase; all P values&lt;0.05). Mothers in the highest BLL quartile had an odds ratio of 1.62 (95% CI: 0.99-2.65) for having a SGA infant compared to the lowest BLL quartile.</p>

<p><strong>CONCLUSIONS: </strong>While both linear and quantile regression showed a negative association between prenatal lead exposure and birthweight, quantile regression revealed that smaller infants may represent a more susceptible subpopulation.</p>

10.1016/j.envint.2016.11.023

Environ Int

27923585

Bacterial and cytokine mixtures predict the length of gestation and are associated with miRNA expression in the cervix.

2017

33-45

2017 01

1750-192X

<p><strong>AIM: </strong>Bacterial vaginosis may lead to preterm birth through epigenetic programming of the inflammatory response, specifically via miRNA expression.</p>

<p><strong>METHODS: </strong>We quantified bacterial 16S rRNA, cytokine mRNA and 800 miRNA from cervical swabs obtained from 80 women at 16-19 weeks' gestation. We generated bacterial and cytokine indices using weighted quantile sum regression and examined associations with miRNA and gestational age at delivery.</p>

<p><strong>RESULTS &amp; DISCUSSION: </strong>Each decile of the bacterial and cytokine indices was associated with shorter gestations (p &lt; 0.005). The bacterial index was associated with miR-494, 371a, 4286, 185, 320e, 888 and 23a (p &lt; 0.05). miR-494 remained significant after false discovery rate correction (q &lt; 0.1). The cytokine index was associated with 27 miRNAs (p &lt; 0.05; q &lt; 0.01).</p>

<p><strong>CONCLUSION: </strong>Future investigation into the role of bacterial vaginosis- and inflammation-associated miRNA and preterm birth is warranted.</p>

10.2217/epi-2016-0095

Epigenomics

27936911

Air pollution and in utero programming of poor fetal growth.

2017

213-216

2017 03

1750-192X

<p>Poor fetal growth is associated with adverse postnatal health outcomes. In the newborn period, compared with well-grown infants, those small-for-gestational age (typically defined as less than 10th percentile are at higher risk of mortality and morbidities including difficulties with glucose homeostasis and thermoregulatory control. They are also more likely to require neonatal intensive care. Subsequently, small-for-gestational age infants are predisposed to hypertension and neurodevelopmental delays and disabilities. The etiology of poor fetal growth is multifactorial. Maternal conditions such as pre-eclampsia, infections such as cytomegalovirus and toxoplasmosis, maternal malnutrition and exposures to environmental pollutants such as lead, can all lead to infants being born smaller than their genetic potential.</p>

<p>Maternal cigarette smoking in pregnancy represents one of the most preventable causes of poor fetal growth. Air pollution, which contains many of the same compounds found in cigarette smoke including fine particulate matter smaller than five microns in diameter (PM_2.5), has been shown to increase the risk of many of the same conditions caused by smoking including lung cancer and cardiovascular disease. Further, air pollution exposure in pregnancy is associated with lower birth weight for gestational age. How air pollution affects fetal growth is incompletely understood, but new insights into how the fetal epigenome responds to cigarette smoke may provide clues as to how air pollution may affect the developing fetus.</p>

10.2217/epi-2017-0008

Epigenomics

28234022

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.

2018

34-41

2018 01

1534-7796

<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>

10.1097/PSY.0000000000000517

Psychosom Med

28787364

Prenatal salivary sex hormone levels and birth-weight-for-gestational age.

2019

2019 May 20

1476-5543

<p><strong>OBJECTIVE: </strong>To determine whether prenatal sex hormones from maternal saliva are associated with birth-weight-for-gestational age.</p>

<p><strong>STUDY DESIGN: </strong>We measured salivary progesterone, testosterone, estradiol, dehydroepiandrosterone (DHEA), and cortisone in 504 pregnant women in a Mexico City cohort. We performed linear and modified Poisson regression to examine associations of log-transformed hormones with birth-weight-for-gestational age z-scores and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA) adjusting for maternal age, sex, BMI, parity, smoking, education, and socioeconomic status.</p>

<p><strong>RESULTS: </strong>In total, 15% of infants were SGA and 2% were LGA. Each interquartile range increment in testosterone/estradiol ratio was associated with a 0.12 decrement in birth-weight-for-gestational age z-score (95% CI: -0.27 to -0.02) and a 50% higher risk of SGA versus appropriate-for-gestational age (AGA) (95% CI: 1.13-1.99).</p>

<p><strong>CONCLUSION: </strong>Higher salivary testosterone/estradiol ratios may affect fetal growth, and identifying the predictors of hormone levels may be important to optimizing fetal growth.</p>

10.1038/s41372-019-0385-y

J Perinatol

31110244

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

2018

742-750

2018

1559-2308

<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>

10.1080/15592294.2018.1503490

Epigenetics

30045669