| 1. |
- Hallingström, Maria, et al.
(författare)
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The association between selected mid-trimester amniotic fluid candidate proteins and spontaneous preterm delivery
- 2020
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Ingår i: Journal of Maternal-Fetal and Neonatal Medicine. - : Informa UK Limited. - 1476-7058 .- 1476-4954. ; 33:4, s. 583-592
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to explore inflammatory response and identify early potential biomarkers in mid-trimester amniotic fluid associated with subsequent spontaneous preterm delivery (PTD). Methods: A cohort study was performed at Sahlgrenska University Hospital/Östra, Gothenburg, Sweden, between 2008 and 2010. Amniotic fluid was collected from consecutive women undergoing mid-trimester transabdominal genetic amniocentesis at 14–19 gestational weeks. Clinical data and delivery outcome variables were obtained from medical records. The analysis included 19 women with spontaneous PTD and 118 women who delivered at term. A panel of 26 candidate proteins was analyzed using Luminex xMAP technology. Candidate protein concentrations were analyzed with ANCOVA and adjusted for plate effects. Results: The median gestational age at delivery was 35 + 3 weeks in women with spontaneous PTD and 40 + 0 weeks in women who delivered at term. Nominally significantly lower amniotic fluid levels of adiponectin (PTD: median 130,695 pg/mL (IQR 71,852–199,414) vs term: median 185,329 pg/mL (IQR (135,815–290,532)), granulocyte-macrophage colony stimulating factor (PTD: median 137 pg/mL (IQR 74–156) vs term: median 176 pg/mL (IQR 111–262)), and macrophage migration inhibitory factor (PTD: median 3025 pg/mL (IQR 1885–3891) vs term: median 3400 pg/mL (IQR 2181–5231)) were observed in the spontaneous PTD group, compared with the term delivery group, after adjusting for plate effects. No significant differences remained after Bonferroni correction for multiple comparisons. Conclusions: Our results are important in the process of determining the etiology behind spontaneous PTD but due to the non-significance after Bonferroni correction, the results should be interpreted with caution. Further analyses of larger sample size will be required to determine whether these results are cogent and to examine whether microbial invasion of the amniotic cavity or intra-amniotic inflammation occurs in asymptomatic women in the mid-trimester with subsequent spontaneous PTD.
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| 2. |
- Hallingström, Maria
(författare)
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Biomarkers in mid-trimester amniotic fluid in relation to gestational duration and spontaneous preterm delivery
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The biological mechanisms and physiological pathways of pregnancy maintenance and timing of delivery are complex and multifactorial. Pregnancy clocks, partly controlled by timing mechanisms linked to fetal development, which regulate the onset of labor has previously been described. These clocks include inflammatory processes, involving endocrine, mechanical and genetic factors. However, the sequence and timing of events preceding the spontaneous onset of labor, both at term and at preterm, are as yet incompletely identified. Spontaneous preterm delivery, defined as delivery before 37 weeks of gestation, is a serious global health problem accounting for the majority of all perinatal deaths and half of the short- and long-term postnatal morbidity. Identifying women at risk of spontaneous preterm delivery is complicated by its heterogeneous etiology and several different sub-phenotypes. Mid-trimester amniocentesis, clinically performed for prenatal genetic testing, provides a unique opportunity to obtain insight into the intrauterine environment in asymptomatic women early in gestation. However, the complex and dynamic composition of amniotic fluid changes continually as pregnancy progresses, making early identification of factors involved in the process of spontaneous preterm delivery and other pregnancy complications, a major challenge. Objective: The aim of this thesis and its constituent papers was to identify specific biomarkers related to the development of subsequent spontaneous preterm delivery, by examination of mid-trimester amniotic fluid composition in asymptomatic women. During the period of doctoral studies, new data emerged, indicating that a shift to gestational duration as the main outcome might increase the likelihood of finding associations that could assist in the prediction of spontaneous preterm delivery. The aim thus partly shifted toward investigating associations between mid-trimester amniotic fluid composition and gestational duration. Material and methods: All constituent papers in this thesis are based on subsets of a single cohort of 1,240 amniotic fluid samples collected from asymptomatic women aged over 18 years with a singleton viable pregnancy, intact membranes, without preterm labor or signs of infection, undergoing genetic amniocentesis at gestational weeks 14-19 at Sahlgrenska University Hospital/Östra, Gothenburg, Sweden during September 2008 to December 2017. Demographics and clinical data were obtained from medical records at inclusion and after delivery. Studies investigating inflammatory, immunological and cellular-metabolic markers were designed to contribute to early identification of women with subsequent spontaneous preterm delivery and to study associations with gestational duration. Amniotic fluid samples were analyzed with targeted hypothesis-driven approaches using multiplex technologies such as Luminex xMAP and Meso-Scale Discovery, as well as with broad, untargeted hypothesis-generating approaches such as proteomics and metabolomics. The proteomics analyses were followed by validation/replication with Enzyme-Linked Immunosorbent Assay, a singleplex technology. Results: No mid-trimester amniotic fluid biomarkers associated with spontaneous preterm delivery were identified. Thrombospondin-1, macrophage inflammatory protein-1 beta and S100 calcium-binding protein A8, two alarmins and one chemokine, were found to be significantly associated with gestational duration in women with a spontaneous onset of labor at term. Gestational age at sampling was strongly associated with protein concentrations in several of the constituent studies. Conclusions: I) Biological signals in early mid-trimester amniotic fluid may be of insufficient strength for accurate risk prediction of spontaneous PTD, or the condition may result from acute events not detectable in amniotic fluid as early as at mid-trimester; II) Alarmins and chemokines, which seem to play an essential role in the inflammatory processes preceding the spontaneous onset of labor at term, can be detected in amniotic fluid as early as in the mid-trimester; III) The concept of a pregnancy clock is strengthened by our findings, which also suggest that this is reflected in the amniotic fluid, where deviations from the clock may precede spontaneous preterm delivery; and IV) The results emphasize the importance of adjusting for gestational age at sampling when performing amniotic fluid biomarker studies.
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| 3. |
- Hallingström, Maria, et al.
(författare)
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Mid-trimester amniotic fluid proteome’s association with spontaneous preterm delivery and gestational duration
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Amniotic fluid is clinically accessible via amniocentesis and its protein composition may correspond to birth timing. Early changes in the amniotic fluid proteome could therefore be associated with the subsequent development of spontaneous preterm delivery. Objective The main objective of this study was to perform unbiased proteomics analysis of the association between mid-trimester amniotic fluid proteome and spontaneous preterm delivery and gestational duration, respectively. A secondary objective was to validate and replicate the findings by enzyme-linked immunosorbent assay using a second independent cohort. Methods Women undergoing a mid-trimester genetic amniocentesis at Sahlgrenska University Hospital/Östra between September 2008 and September 2011 were enrolled in this study, designed in three analytical stages; 1) an unbiased proteomic discovery phase using LC-MS analysis of 22 women with subsequent spontaneous preterm delivery (cases) and 37 women who delivered at term (controls), 2) a validation phase of proteins of interest identified in stage 1, and 3) a replication phase of the proteins that passed validation using a second independent cohort consisting of 20 cases and 40 matched controls. Results Nine proteins were nominally significantly associated with both spontaneous preterm delivery and gestational duration, after adjustment for gestational age at sampling, but none of the proteins were significant after correction for multiple testing. Several of these proteins have previously been described as being associated with spontaneous PTD etiology and six of them were thus validated using enzyme linked immunosorbent assay. Two of the proteins passed validation; Neutrophil gelatinase-associated lipocalin and plasminogen activator inhibitor 1, but the results could not be replicated in a second cohort. Conclusions Neutrophil gelatinase-associated lipocalin and Plasminogen activator inhibitor 1 are potential biomarkers of spontaneous preterm delivery and gestational duration but the findings could not be replicated. The negative findings are supported by the fact that none of the nine proteins from the exploratory phase were significant after correction for multiple testing.
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| 4. |
- Stinson, Lisa, et al.
(författare)
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Comparison of Bacterial DNA Profiles in Mid-Trimester Amniotic Fluid Samples From Preterm and Term Deliveries
- 2020
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Infection and inflammation are well recognized causes of spontaneous preterm delivery (PTD) (<37 gestational weeks) and adverse infant outcomes. To date, there has been very little investigation into bacterial communities in amniotic fluid using next generation sequencing technology. In particular, it is important to characterize amniotic fluid bacterial profiles in complicated pregnancies as well as in asymptomatic women to identify predictive bacterial DNA signatures. Here, 1198 mid-trimester amniotic fluid samples from a cohort of Swedish women undergoing mid-trimester genetic amniocentesis were screened for bacterial DNA using qPCR protocols specifically designed to reduce the impacts of reagent contamination and human DNA mispriming. The majority of samples were devoid of detectable bacterial DNA; however, approximately a fifth of the cohort (19.9%) were 16S rRNA gene positive in duplicate screening. Among these, nine women had a spontaneous PTD. These nine women were matched with 18 healthy women with a delivery at term. We used PacBio SMRT technology, coupled with appropriate negative extraction and PCR controls, to sequence the full-length 16S rRNA gene in this subset of 27 women. The amniotic fluid samples contained low-abundance and low-diversity bacterial DNA profiles. Species typically associated with spontaneous PTD were absent. We were not able to identify any differences in the amniotic fluid bacterial DNA profiles of women with a subsequent spontaneous PTD compared to women who delivered at term. The findings suggest that, in a minor proportion of pregnancies, DNA from non-pathogenic bacteria may be present in the amniotic fluid far earlier than previously reported. Early detection of bacterial DNA in the amniotic fluid was, in this study, not associated with spontaneous PTD.
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| 5. |
- Thorell, Anna, et al.
(författare)
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Microbial invasion of the amniotic cavity is associated with impaired cognitive and motor function at school age in preterm children.
- 2020
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Ingår i: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 87:5, s. 924-931
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Tidskriftsartikel (refereegranskat)abstract
- Chorioamnionitis is an important cause of preterm delivery. Data on neurodevelopmental outcome in exposed infants are inconsistent due to difficulties in diagnosing intrauterine infection/inflammation and lack of detailed long-term follow-up. We investigate cognitive and motor function in preterm infants at early school age and relate the findings to bacteria in amniotic fluid obtained by amniocentesis (microbial invasion of the amniotic cavity (MIAC)) or placenta findings of histological chorioamnionitis (HCA) or fetal inflammatory response syndrome (FIRS).Sixty-six infants with gestational age <34 weeks at birth and without major disabilities were assessed using WISC-III and the Bruininks-Oseretsky Test of Motor Proficiency. Results were corrected for gestational age and sex.Children exposed to MIAC had significantly lower scores for full-scale IQ and verbal IQ compared to the non-MIAC group and the difference in full-scale IQ remained after correction for confounding factors. The MIAC group had also significantly lower motor scores after correction. In contrast, motor function was not affected in infants exposed to HCA or FIRS and differences between groups for cognitive scores were lost after corrections.Exposure to bacteria in amniotic fluid is associated with lower motor and cognitive scores in school age preterm infants without major disabilities.
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| 6. |
- Viklund, Felicia, et al.
(författare)
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Protein Concentrations of Thrombospondin-1, MIP-1β, and S100A8 Suggest the Reflection of a Pregnancy Clock in Mid-Trimester Amniotic Fluid
- 2020
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Ingår i: Reproductive Sciences. - : Springer Science and Business Media LLC. - 1933-7205 .- 1933-7191. ; 27:12, s. 2146-2157
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Tidskriftsartikel (refereegranskat)abstract
- The development of immunoassays enables more sophisticated studies of the associations between protein concentrations and pregnancy outcomes, allowing early biomarker identification that can improve neonatal outcomes. The aim of this study was to explore associations between selected mid-trimester amniotic fluid proteins and (1) overall gestational duration and (2) spontaneous preterm delivery. A prospective cohort study, including women undergoing mid-trimester transabdominal genetic amniocentesis, was performed in Gothenburg, Sweden, 2008–2016 (n = 1072). A panel of 27 proteins related to inflammation was analyzed using Meso-Scale multiplex technology. Concentrations were adjusted for gestational age at sampling, experimental factors, year of sampling, and covariates (maternal age at sampling, parity (nulliparous/multiparous), smoking at first prenatal visit, and in vitro fertilization). Cox regression analysis of the entire cohort was performed to explore possible associations between protein concentrations and gestational duration. This was followed by Cox regression analysis censored at 259 days or longer, to investigate whether associations were detectable in women with spontaneous preterm delivery (n = 47). Finally, linear regression models were performed to analyze associations between protein concentrations and gestational duration in women with spontaneous onset of labor at term (n = 784). HMG-1, IGFBP-1, IL-18, MIP-1α, MIP-1β, S100A8, and thrombospondin-1 were significantly associated with gestational duration at term, but not preterm. Increased concentrations of thrombospondin-1, MIP-1β, and S100A8, respectively, were significantly associated with decreased gestational duration after the Holm-Bonferroni correction in women with spontaneous onset of labor at term. This adds to the concept of a pregnancy clock, where our findings suggest that such a clock is also reflected in the amniotic fluid at early mid-trimester, but further research is needed to confirm this.
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