1. |
- Gravett, Michael G, et al.
(author)
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Assessment of current biomarkers and interventions to identify and treat women at risk of preterm birth.
- 2024
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In: Frontiers in medicine. - 2296-858X. ; 11
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Research review (peer-reviewed)abstract
- Preterm birth remains an important global problem, and an important contributor to under-5 mortality. Reducing spontaneous preterm birth rates at the global level will require the early identification of patients at risk of preterm delivery in order to allow the initiation of appropriate prophylactic management strategies. Ideally these strategies target the underlying pathophysiologic causes of preterm labor. Prevention, however, becomes problematic as the causes of preterm birth are multifactorial and vary by gestational age, ethnicity, and social context. Unfortunately, current screening and diagnostic tests are non-specific, with only moderate clinical risk prediction, relying on the detection of downstream markers of the common end-stage pathway rather than identifying upstream pathway-specific pathophysiology that would help the provider initiate targeted interventions. As a result, the available management options (including cervical cerclage and vaginal progesterone) are used empirically with, at best, ambiguous results in clinical trials. Furthermore, the available screening tests have only modest clinical risk prediction, and fail to identify most patients who will have a preterm birth. Clearly defining preterm birth phenotypes and the biologic pathways leading to preterm birth is key to providing targeted, biomolecular pathway-specific interventions, ideally initiated in early pregnancy Pathway specific biomarker discovery, together with management strategies based on early, mid-, and-late trimester specific markers is integral to this process, which must be addressed in a systematic way through rigorously planned biomarker trials.
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2. |
- Mead, Elyse C, et al.
(author)
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The Role of Genetics in Preterm Birth.
- 2023
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In: Reproductive sciences (Thousand Oaks, Calif.). - 1933-7205. ; 30:12, s. 3410-27
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Research review (peer-reviewed)abstract
- Preterm birth (PTB), defined as the birth of a child before 37 completed weeks gestation, affects approximately 11% of live births and is the leading cause of death in children under 5 years. PTB is a complex disease with multiple risk factors including genetic variation. Much research has aimed to establish the biological mechanisms underlying PTB often through identification of genetic markers for PTB risk. The objective of this review is to present a comprehensive and updated summary of the published data relating to the field of PTB genetics. A literature search in PubMed was conducted and English studies related to PTB genetics were included. Genetic studies have identified genes within inflammatory, immunological, tissue remodeling, endocrine, metabolic, and vascular pathways that may be involved in PTB. However, a substantial proportion of published data have been largely inconclusive and multiple studies had limited power to detect associations. On the contrary, a few large hypothesis-free approaches have identified and replicated multiple novel variants associated with PTB in different cohorts. Overall, attempts to predict PTB using single "-omics" datasets including genomic, transcriptomic, and epigenomic biomarkers have been mostly unsuccessful and have failed to translate to the clinical setting. Integration of data from multiple "-omics" datasets has yielded the most promising results.
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3. |
- Menon, Ramkumar, et al.
(author)
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Ethnic differences in key candidate genes for spontaneous preterm birth: TNF-alpha and its receptors
- 2006
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In: HUMAN HEREDITY. - : S. Karger AG. - 0001-5652 .- 1423-0062. ; 62:2, s. 107-118
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Journal article (peer-reviewed)abstract
- <i>Objectives:</i> Spontaneous preterm birth (PTB) has a significant ethnic disparity with people of African descent having an almost 2-fold higher incidence than those of European descent in the United States. This disparity may be caused by differences in the distribution of genetic risk factors. The objective of this study is to examine genetic differences between African-Americans and European Americans for single nucleotide polymorphisms (SNPs) in candidate genes for PTB. <i>Methods:</i> We examined patterns of variation in 19 SNPs in 3 candidate genes for preterm birth: TNF-α, TNF-receptor 1 and TNF-receptor 2. Allele, genotype and haplotype frequencies were compared between African-Americans (AA) and European-Americans (EA) in cases and controls separately. Both maternal and fetal genotypes were studied, as it is unclear whether one or both of these are important in the etiology of PTB. <i>Results:</i> The vast majority of the SNPs differed significantly between ethnic groups, although there are only a few suggestive results comparing cases and controls within an ethnic group. For TNF-α, four of six SNPs; for TNF-R1, 5/6; and for TNF-R2, 6/7 showed significant differences between ethnic groups in either allele and/or genotype frequency. <i>Conclusions:</i> Our data demonstrate highly significant genetic differences between ethnic groups in genes that may play a role in the risk of PTB.
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4. |
- Menon, Ramkumar, 1967, et al.
(author)
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Increased Bioavailability of TNF-alpha in African Americans During In Vitro Infection: Predisposing Evidence for Immune Imbalance.
- 2007
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In: Placenta. ; 28:8-9, s. 946-50
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The objective of this study is to examine TNF-alpha and its soluble and membrane bound receptors in fetal membranes derived from blacks and whites in response to in vitro infectious stimulus, and the balance between TNF-alpha and the receptors. Fetal membranes collected from black and white women at term were maintained in an organ explant system and stimulated with lipopolysaccharide (LPS). TNF-alpha, soluble TNF receptors (sTNFR1 and sTNFR2) in culture media and membrane bound TNF receptors (TNFR1 and TNFR2) in tissue homogenates were measured. Molar ratio (TNF/sTNFR) was calculated between LPS stimulated and unstimulated (controls) cultures in both races. TNF-alpha was increased in both races after LPS stimulation and showed no difference between races (p=0.7). LPS decreased sTNFR1 in blacks, but increased in whites, showing a significant difference between races (p=0.001). In blacks sTNFR2 also decreased and increased in whites, but the results were not significant between races (p=0.4). Both TNFR1 and TNFR2 were increased in blacks after LPS stimulation whereas no such changes were seen in whites compared to controls that were also significant between races. After LPS stimulation TNF-alpha bioavailability was increased in blacks with a drop in soluble receptors and with an increase in membrane receptors. This was not evident in whites because in whites soluble receptors were increased with no change in membrane receptors. Our data demonstrated that LPS stimulation results in a molar ratio switch favoring TNF-alpha biofunction in blacks, but not in whites.
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5. |
- Musilova, Ivana, et al.
(author)
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Amniotic fluid prostaglandin E2 in pregnancies complicated by preterm prelabor rupture of the membranes.
- 2016
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In: The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. - : Informa UK Limited. - 1476-4954. ; 29:18, s. 2915-2923
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Journal article (peer-reviewed)abstract
- To determine amniotic fluid prostaglandin E2 concentrations in women preterm prelabor rupture of the membranes (PPROM) with respect to microbial invasion of the amniotic cavity (MIAC), intraamniotic inflammation (IAI), microbial-associated IAI, histological chorioamnionitis, and short-term neonatal morbidity.
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6. |
- Plunkett, Jevon, et al.
(author)
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An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing
- 2011
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:4
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Journal article (peer-reviewed)abstract
- Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened.8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.
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7. |
- Plunkett, Jevon, et al.
(author)
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Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth
- 2010
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In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3
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Journal article (peer-reviewed)abstract
- Background: The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods: We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results: Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions: Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
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8. |
- Radochova, Vladimira, et al.
(author)
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Association between periodontal disease and preterm prelabor rupture of membranes.
- 2019
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In: Journal of clinical periodontology. - : Wiley. - 1600-051X .- 0303-6979. ; 46:2, s. 189-196
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Journal article (peer-reviewed)abstract
- Periodontal disease is a possible contributing factor to preterm delivery. The aim of this study was to compare the periodontal status of women with preterm prelabor rupture of membranes (PPROM) and women with uncomplicated singleton pregnancies.Seventy-eight women with PPROM at gestational ages between 24+0 and 36+6 weeks and 77 healthy women with uncomplicated pregnancies, matched for gestational age at sampling without preterm birth, were included in this study. All women underwent evaluation of periodontal and oral hygiene status.Women with PPROM had higher gingival and plaque indexes in crude analysis (gingival index: median 0.80 vs. 0.20; p < 0.0001; plaque index: median 0.80 vs. 0.10; p < 0.0001), even after adjustment for smoking status (p < 0.0001 and p < 0.0001). Mean clinical attachment loss and probing pocket depth values were higher in women with PPROM in the crude analysis (clinical attachment loss: median 2.3 mm vs. 1.8 mm; p < 0.0001; probing pocket depth: median 2.3 mm vs. 1.8; p < 0.0001), as well as after adjustment for smoking status (p < 0.0001 and p < 0.0001).Pregnant women with PPROM residing in central Europe had worse periodontal status than women with uncomplicated pregnancies. This article is protected by copyright. All rights reserved.
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9. |
- Ryckman, Kelli K, et al.
(author)
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Maternal and fetal genetic associations of PTGER3 and PON1 with preterm birth.
- 2010
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:2
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The purpose of this study was to identify associations between maternal and fetal genetic variants in candidate genes and spontaneous preterm birth (PTB) in a Norwegian population and to determine the effect size of those associations that corroborate a previous study of PTB. METHODS: DNA from 434 mother-baby dyads (214 cases and 220 controls) collected from the Norwegian Mother and Child Cohort (MoBa) was examined for association between 1,430 single nucleotide polymorphisms in 143 genes and PTB. These results were compared to a previous study on European Americans (EA) from Centennial Women's Hospital in Nashville, TN, USA. Odds ratios for SNPs that corroborated the Cenntennial study were determined on the combined MoBa and Centennial studies. RESULTS: In maternal samples the strongest results that corroborated the Centennial study were in the prostaglandin E receptor 3 gene (PTGER3; rs977214) (combined genotype p = 3x10(-4)). The best model for rs977214 was the AG/GG genotypes relative to the AA genotype and resulted in an OR of 0.55 (95% CI = 0.37-0.82, p = 0.003), indicating a protective effect. In fetal samples the most significant association in the combined data was rs854552 in the paraoxonase 1 gene (PON1) (combined allele p = 8x10(-4)). The best model was the TT genotype relative to the CC/CT genotypes, and resulted in an OR of 1.32 (95% CI = 1.13-1.53, p = 4x10(-4)). CONCLUSIONS: These studies identify single locus associations with preterm birth for both maternal and fetal genotypes in two populations of European ancestry.
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10. |
- Solé Navais, Pol, et al.
(author)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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In: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Journal article (peer-reviewed)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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11. |
- Stalberg, Cecilia, et al.
(author)
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Anti-inflammatory Elafin in human fetal membranes.
- 2017
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In: Journal of perinatal medicine. - : Walter de Gruyter GmbH. - 1619-3997 .- 0300-5577. ; 45:2, s. 237-244
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Journal article (peer-reviewed)abstract
- Elafin is a low molecular weight protein with antileukoproteinase, anti-inflammatory, antibacterial and immunomodulating properties. The profile of Elafin in fetal membranes is not well characterized. This study determined the changes in Elafin expression and concentration in human fetal membrane from patients with preterm prelabor rupture of membranes (PPROM) and in vitro in response to intra-amniotic polymicrobial pathogens.Elafin messenger RNA (mRNA) expressions were studied in fetal membranes from PPROM, normal term as well as in normal term not in labor membranes in an organ explant system treated (24 h) with lipopolysaccharide (LPS), using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) measured Elafin concentrations in culture supernatants from tissues treated with LPS and polybacterial combinations of heat-inactivated Mycoplasma hominis (MH), Ureaplasma urealyticum (UU) and Gardnerella vaginalis (GV).Elafin mRNA expression in fetal membranes from women with PPROM was significantly higher compared to women who delivered at term after normal pregnancy (5.09±3.50 vs. 11.71±2.21; P<0.05). In vitro, LPS-stimulated membranes showed a significantly increased Elafin m-RNA expression (P<0.05). However, the protein levels after LPS stimulation was not changed. Similarly, polymicrobial-treated fetal membranes also showed no changes in Elafin protein concentrations compared to untreated controls.Higher Elafin expression in PPROM fetal membranes suggests a host response to an inflammatory pathology. However, lack of Elafin response to LPS and polymicrobial treatment is indicative of the minimal anti-inflammatory impact of this molecule in fetal membranes.
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