Pathogenesis Of Preterm Birth Research Articles

Biomarkers of inflammation and placental dysfunction are associated with subsequent preterm birth

Objective. To assess whether the analysis of high sensitivity C-Reactive Protein (hsCRP), a biomarker of inflammation, and placental growth factor (PlGF), a biomarker of placental dysfunction, could help identify patients at risk for preterm birth (PTB).Methods. We performed a prospective cohort study of women with symptoms of preterm labor (22–33 6/7 weeks). Maternal serum was analyzed for hsCRP and PlGF. Median biomarker values were used as analytic cut-points. We performed chi-square tests of association between biomarkers and PTB, nonparametric tests to compare medians, and logistic regression to determine the odds of PTB associated with biomarker values. Test characteristics of each biomarker were calculated.Results. 56.3% of the cohort (N = 96) delivered preterm. Median hsCRP (N = 78) was 4.34 mg/L, and median PlGF (N = 86) was 558.25 mg/l. In the setting of inflammation (high hsCRP), women with low PlGF had a 6.84-fold (95%CI: 1.57–29.80) increased risk of PTB. In the setting of placental dysfunction (low PlGF), women with high hsCRP had a 5.97-fold (95%CI: 1.52–23.43) increased risk of PTB.Conclusions. Our results suggest an interplay between inflammation and placental dysfunction in the pathogenesis of PTB. Analyzing biomarkers that reflect different pathways of PTB may hold promise for identifying patients at greatest risk.

Association between abnormal vaginal flora and cervical length as risk factors for preterm birth.

AIM.: To study the relationship between abnormal vaginal flora (AVF) in the first trimester as a risk factor for shortening cervix length (CL) at second and third trimester, and to assess the combination of these factors in predicting preterm delivery. METHODS.: 1026 unselected low risk women seen before 16 weeks of pregnancy underwent sampling of vaginal fluid for wet mount microscopy at a central laboratory blinded to clinical data. Disappearance of lactobacilli and bacterial vaginosis (BV) were scored according to standardized definitions. Specific cultures were performed for M hominis, U urealyticum, aerobic vaginitis (AV) and vaginal colonization with Candida. CL was measured by transvaginal ultrasound at 10-14, 20-24 and at 30-34 weeks, and gestational age at delivery was recorded. RESULTS.: Short cervix (CL below the lower quartile) at 10-14 weeks is related to a lower CL at 20-24 and 30-34 weeks of gestation (p=0.01, p=0.005 respectively). Short cervix at 20-24 weeks, but not at 10-14 weeks, was predictive for preterm birth. In patients with M. hominis and/or with severe AV at 10-14 weeks, the cervix appeared shorter at 20-24 and at 30-34 weeks than in other women. Increased risk for preterm birth in women with a shorter cervix at 10-14 weeks and AVF could not be proved by this study. DISCUSSION.: Presence of AV or M. hominis is associated with a shorter cervix at 20-24 and 30-34 weeks. Although a short cervix at 10-14 weeks increases the likelihood of having a short cervix later in pregnancy, it was not a prerequisite for AVF to be associated with preterm delivery. Therefore, in the pathogenesis of preterm birth, certain types of AVF may be involved directly in the process of cervical shortening, rather than being exposed to the intrauterine cavity more readily by a short cervix in the early stages of pregnancy. Copyright (c) 2010 ISUOG. Published by John Wiley & Sons, Ltd.

Association of midgestation paraoxonase 1 activity and pregnancies complicated by preterm birth

The objective of the study was to determine whether an association exists between low paraoxonase 1 activity and dyslipidemia at midgestation and preterm birth. We conducted a case-control study of 30 women with preterm birth and 90 women with uncomplicated term deliveries. Maternal serum collected at 15-20 weeks was used to measure lipid concentrations and paraoxonase 1 activity using 2 substrates: paraoxon and phenylacetate (arylesterase activity). The groups did not differ with respect to maternal demographics. Paraoxonase 1 activity (paraoxon) was significantly lower in women delivering preterm compared with controls (12.9 +/- 6.1 vs 16.6 +/- 7.7 dA/min; P = .02). Arylesterase activity and serum lipid concentrations were similar between women with preterm birth and controls. Midgestation paraoxonase 1 activity is lower in women who later experience spontaneous preterm birth compared with women who have term deliveries. Prospective studies are needed to determine the significance of paraoxonase 1 in the pathogenesis of preterm birth.

136: Heat shock proteins and inflammation-induced preterm birth

Heat shock proteins (HSP) have been suggested to be critical players in inflammatory disease states by binding to Toll-like receptor-4(TLR-4) as endogenous ligands. HSPs are released from cells in response to stress and function as regulators of the innate immune response. Limited obstetrical studies suggest that HSPs may have a mechanistic role in preterm birth (PTB) or may be promising biomarkers. These studies sought to determine 1) the regulation of HSP during pregnancy and in the setting of inflammation-induced PTB and 2) the validity of HSP as a potential non-invasive biomarker using a mouse model of PTB. 2 sets of experiments were performed. 1) Cervical (CX) and uterine (UT) tissue was harvested from CD-1 non-pregnant (NP) and pregnant mice on E15, E17, E19 (n=3-6 mice/group). 2) On E15, dams were randomized to intrauterine infusion of saline or lipopolysaccharide (LPS)(N=5-6/group). 6 hrs later, maternal serum (MS), CX and UT were collected for QPCR and ELISA for evaluatoin of HSP 70. HSP 70 levels were undetectable in saline-exposed dams in maternal serum. While HSP 70 was increased in LPS-exposed, variability between dams was pronounced. SEE TABLETabled 1E15 / NPE15 / NPE15 LPS / E15E15 LPS / E15CervixUterusCervixUterusHSP60−9.4−1.5−1.61.6HSP70−10.22.1−2.51.1HSP90−5.91.7−1.61.3 Open table in a new tab HSPs do not appear to be critically involved in the pathogenesis of PTB. Down-regulation of HSPs in the CX during normal pregnancy could be a protective mechanism against preterm cervical ripening by preventing endogenous ligands from activating TLRs.

The placenta in preterm birth

Rates of preterm birth range from 5% to 13% of deliveries in developed countries. About two-thirds of preterm deliveries are due to spontaneous onset of preterm labour or preterm premature...

Spontaneous preterm birth in African Americans is associated with infection and inflammatory response gene variants

The objective of the study was to study the genetic risk factors of spontaneous preterm birth (PTB) in African Americans. Case-control analyses were performed using maternal and fetal deoxyribonucleic acid from 279 African American birth events (82 PTB and 197 term) and 1432 single-nucleotide polymorphisms from 130 candidate genes. Single-locus association and haplotype analyses were performed. The most significant associations were in the maternal interleukin (IL)-15 (rs10833, allele P = 2.91 x 10(-4), genotype P = 2.00 x 10(-3)) gene and the fetal IL-2 receptor B (IL-2RB) (rs84460, allele P = 1.37 x 10(-4), genotype P = 6.29 x 10(-4)) gene. The best models for these markers were additive (rs10833, odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14-0.62; P = 1.0 x 10(-3); rs84460, OR, 2.32; 95% CI, 1.47-3.67; P < 1.0 x 10(-3)). The largest number of significant associations was found in genes related to infection and inflammation. There were overall a larger number of significant associations in infants than in mothers. These results support a strong role for genes involved in infection and inflammation in the pathogenesis of PTB, particularly IL-12 and IL-12RB, and indicate that in African Americans there may be complementarity of maternal and fetal genetic risks for PTB.

Iron-Dependent Oxidative Stress as a Pathogenesis for Preterm Birth

Preterm birth (PTB) is an oxidative stress-related disease that lacks effective therapies partly because of the poor understanding of disease pathogenesis. The aim of this manuscript was to review molecular pathways that could be responsible for the pathogenesis of PTB. Genomic and proteomic studies have started to delineate the wide array of mediators involved in this disorder. Understanding the mechanisms of the development of PTB and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for this disorder. This article reviews the English language literature for pathogenesis and pathophysiological studies on PTB. Several recent genomic and proteomic studies are discussed in the context of PTB biology. Decidual hemorrhage has been identified histologically in the placentas of patients with PTB, which may result in high levels of free heme and iron. Several important PTB-specific genes and proteins overlap with those known to be regulated by iron. Others were genes involved in oxidative stress and detoxification. Free iron oxidatively modifies lipid and protein, leading to DNA and cell damage. This signaling pathway of PTB will be discussed as it provides new insights into regulation of inflammation, oxidative stress, and detoxification. This review summarizes recent advances in heme/iron-mediated signaling, the target genes thereof, and the potential challenges to the understanding of pathogenesis and pathophysiology of PTB. A novel model is proposed. Collectively, decidual hemorrhage and inflammation are considered to be major contributors to the pathogenesis of PTB. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to paraphrase the role of oxidative stress in pathogenesis of preterm birth, explain the idea of preterm birth as a "syndrome," and summarize the potential role of early uterine bleeding in pathophysiology of preterm birth.

Tubal factor infertility is associated with an increased risk of preterm birth compared with male factor infertility

PRETERM BIRTH COMPARED WITH MALE FACTOR INFERTILITY ALISON STUEBE, MEHMET GENC, THOMAS MCELRATH, Brigham and Women’s Hospital, Harvard Medical School, Department of Obstetrics and Gynecology, Boston, Massachusetts OBJECTIVE: Several studies have documented an association between ART and poor obstetrical outcomes in singleton pregnancies. We hypothesized that the pathophysiology that led to tubal factor infertility (TFI) may increase a woman’s risk of preterm birth compared with women undergoing IVF for male factor infertility (MFI). STUDY DESIGN: We studied singleton IVF pregnancies among women who delivered at Brigham and Women’s Hospital between 1995 and 2000. Univariate analyses were conducted to compare the risk of preterm birth among women diagnosed with TFI vs. MFI. Multivariate logistic regression analysis was performed to control for other confounding factors. RESULTS: Of 495 women who underwent IVF and delivered singleton infants, 111 carried a diagnosis of TFI, and 126, MFI. The risk of birth prior to 37, 32, and 28 weeks of gestation was significantly higher among cases of TFI as compared to those of MFI (Table). We also found a higher rate of spontaneous preterm birth among TFI vs. MFI women at !32 weeks (6.3% vs. 0%, p=0.005) and !28 weeks (4.5% vs. 0%, p=0.02). TFI remained associated with an increased risk of birth at less then 37 (OR 2.16; 95% CI, 1.06-5.44), 32 (OR 5.94; 95% CI, 2.02-17.48), and 28 weeks of gestation (OR 4.81; 95% CI, 1.49-15.49), adjusting for maternal age, parity, ovulation induction, and other concurrent infertility diagnoses. CONCLUSION: Compared with MFI, we observed an increased association between TFI and preterm birth. The higher incidence of spontaneous preterm birth in the TFI group supports our hypothesis that the pathological events that led to TFI may also play a role in the pathogenesis of preterm birth.

Associations between periodontal status and delivery outcomes in pregnant women with a diagnosis of threatened premature labor

To evaluate the association between periodontal conditions and delivery outcomes in pregnant women with a diagnosis of threatened premature labor (TPL). Eighty systemically healthy pregnant women were enrolled in the study. Forty of these were pregnant women hospitalized with the diagnosis of TPL, and 40 normal pregnant women served. TPL was control clarified as TPL-PB (14 women) and TPL-TB (26 women) based on the delivery outcomes. No infants were delivered as PB in the control with non-TPL. Periodontal examinations included assessments of plaque index (PLI), clinical attachment loss (CAL), probing depth (PD), bleeding index (BI) and the percentage of periodontitis sites (PD > 3 mm, CAL >or= 2 mm). The serum level of TNF-alpha was determined using commercially available enzyme-linked immunoassays (ELISA). The mean PLI (0.94 +/- 0.05), percentage of periodontitis sites (2.93%) and TNF-alpha levels [14.81 ng/L (13.40 - 15.64 ng/L)] were significantly higher in the TPL group than in the non-TPL group [0.59 +/- 0.03, 1.32% and 11.47 ng/L (10.82 - 12.86) ng/L] (P < 0.001). The mean PLI (0.96 +/- 0.06), BI (2.99 +/- 0.14), percentage of periodontitis sites (3.61%) and TNF-alpha levels [18.35 ng/L (15.47 - 31.94) ng/L] were significantly higher in the TPL-PB group than in the TPL-TB group [0.66 +/- 0.04, 2.76 +/- 0.12, 2.25% and 13.70 ng/L (12.64 - 14.80 ng/L)]. Significant negative correlations were observed between the gestational age at delivery and percentage of periodontitis sites as well as serum TNF-alpha levels (P < 0.05). And significant positive correlations were observed between percentage of periodontitis site and serum TNF-alpha levels (P < 0.05). Periodontal inflammation might be involved in the pathogenesis of preterm birth.

Problemfeld Frühgeburtlichkeit und Inflammation - Besteht eine genetische Determinierung?

Seit Jahrzehnten unverändert sind spontane vorzeitige Wehentätigkeit und Frühgeburtlichkeit von zentraler Bedeutung für perinatale Morbidität und Mortalität in den westlichen Industrienationen. Im Vergleich zu Reifgeborenen tragen Frühgeborene ein 40fach erhöhtes neonatales Mortalitätsrisiko. Somit ist die Frühgeburtlichkeit für 70 % der neonatalen Mortalität und 50 % der neurologischen Langzeitmorbidität verantwortlich [[1]]. Hierbei stellt die vorzeitige Wehentätigkeit und Frühgeburt die Endstrecke unterschiedlicher ätiologischer Risikofaktoren und Auslöser dar. Dies impliziert, dass durch monozentrische Ansätze immer nur ein Teilaspekt der Problematik Frühgeburtlichkeit bearbeitet werden kann. Es ist an der Zeit das Symptom Frühgeburt als eine syndromale Erkrankung anzuerkennen, die nur die Endstrecke unterschiedlicher und häufig gemeinsam auftretender pathophysiologischer Mechanismen darstellt. In den letzten Jahren hat sich herausgestellt, dass genitale und intrauterine Infektionen zu den bedeutsamen Risikofaktoren für die Entwicklung von vorzeitiger Wehentätigkeit und Frühgeburt zählen [[2]]. In großen Studienkollektiven sind aszendierende genitale Infektionen in 40 % der Fälle von Frühgeburtlichkeit nachweisbar. Daraus entwickelte sich die Hoffnung, die Problematik Frühgeburtlichkeit bald durch großzügigen Einsatz von Antibiotika lösen zu können. Allerdings haben die großen Interventionsstudien der letzten Jahre widersprüchliche Ergebnisse gezeigt. Es wird deutlich, dass zahlreiche pathophysiologische Mechanismen im Rahmen der vorzeitigen Wehentätigkeit und Frühgeburtlichkeit zum Zeitpunkt des Infektionsnachweises bereits irreversibel induziert sind und somit eine antibiotische Therapie diese Kaskaden nicht mehr unterdrücken kann. Wird eine lokale Dysbiose bzw. beginnende genitale infektion frühzeitig erkannt, so belegt mittlerweile eine stetig steigende Zahl von prospektiv randomisierten Studien einen Benefit der Interventionsgruppen. Die Hypothese der infektiologischen Genese eines Großteils der spontanen vorzeitigen Wehentätigkeit und Frühgeburtlichkeit wird somit unterstützt. Darüber hinaus häufen sich Berichte, dass genetische Faktoren eine Überempfindlichkeit gegenüber antenatalen Infektionen mit inadäquater Inflammationsreaktion vermitteln und somit eine Risikosteigerung für eine Frühgeburtlichkeit darstellen [[3]]. Diese so genannten Gen-Umwelt-Interaktionen sind seit Jahren für das Verständnis komplexer Krankheitsbilder, wie Atherosklerose, Adipositas, Hypertonus, Depression etc. beschrieben. In der vorliegenden Übersichtsarbeit wird der Stellenwert antenataler Infektionen in der Pathogenese der Frühgeburtlichkeit unter besonderer Berücksichtigung prädisponierender genetischer Faktoren diskutiert.

Secondary predictors of preterm labour

In addition to primary predictors of preterm birth which are used to estimate the baseline risk of preterm birth, secondary predictors (based on examinations done during the current pregnancy) allow a more accurate assessment of the risk of preterm birth in individual women. Screening for early signs of spontaneous preterm labour has always been an important topic in obstetric care. During the last two decades, the detection of fetal fibronectin (FFN) from cervicovaginal secretions and cervical shortening diagnosed by transvaginal ultrasonography have emerged as the major secondary predictors of preterm birth. Both markers have been extensively studied and consistently shown to be strong short term predictors of preterm birth across a wide range of gestational ages. Other secondary predictors that confirm the role of intrauterine infection in the pathogenesis of preterm birth are bacterial vaginosis (BV) and elevated levels of interleukin (IL)-6, IL-8, ferritin and granulocyte colony-stimulating factor. Apart from BV, inflammatory markers are still not routinely used. The sensitivity of single markers in predicting preterm birth is only moderate and serial examinations of markers, combinations of different markers and multiple marker tests have been studied, with limited results. Studies of interventions in order to prevent preterm birth have also yielded mixed benefits, as a consequence of which the use of these markers to screen low risk pregnancies is generally not recommended. Currently, secondary predictors of preterm birth are used mainly to design new intervention studies tailored to specific high risk populations and to avoid unnecessary interventions in the management of high risk women.

Maternal and perinatal long-chain fatty acids: Possible roles in preterm birth

OBJECTIVE: We conducted a case-control study to evaluate whether maternal and fetal ω-3 and ω-6 essential fatty acid status play possible roles in the pathogenesis of preterm birth. STUDY DESIGN: Essential fatty acid status in blood and trophoblast tissues was measured in (1) women and their newborns with spontaneous preterm birth and (2) control women and newborns at 34 weeks' gestation (maternal blood) and at term delivery. RESULTS: Thirty-seven preterm (mean gestational age 34 weeks) and 34 control mother-baby dyads (gestational age 40 weeks) were evaluated. The maternal percent of total arachidonic acid in red blood cells and plasma was increased in preterm cases versus controls at delivery (3.8- and 1.6-fold, respectively, p < 0.05). Maternal red blood cell eicosapentaenoic acid (1.98 ± 0.15, p < 0.0001) and ω-3/ω-6 ratios (0.58 ± 0.22, p < 0.009) were lower in preterm cases than in controls at delivery (4.64 ± 0.32 and 1.27 ± 0.12, respectively). Docosapentaenoic acid, a marker of ω-3 essential fatty acid deficiency, was higher in preterm maternal red blood cells (1.26 ± 0.18, p < 0.0001) and amnion (1.27 ± 0.19, p < 0.001) compared with term controls (0.12 ± 0.07 and 0.58 ± 0.13, respectively). CONCLUSION: Women delivered preterm demonstrated higher arachidonic acid and docosapentaneoic acid levels in maternal blood and trophoblast tissue than did women delivered at term. This suggests (1) altered essential fatty acid intake or metabolism in a portion of women delivered preterm and (2) increased maternal red blood cell arachidonic acid is associated with an increased risk of preterm birth. (Am J Obstet Gynecol 1997;176:907-14.)

Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: Results of a controlled trial of topical clindamycin cream

OBJECTIVE: The pathogenesis of preterm birth and other adverse pregnancy outcomes linked with reproductive tract infection remains poorly understood. Mucolytic enzymes, including mucinases and sialidases (neuraminidase), are recognized virulence factors among enteropathogens and bacteria that cause periodontal infection. Perturbation of maternal cervicovaginal mucosal membrane host defenses by such enzyme-producing microorganisms may increase the risk of subclinical intrauterine infection during pregnancy and thus increase risks of preterm birth. STUDY DESIGN: We prospectively evaluated vaginal fluid mucinase and sialidase and selected cervicovaginal bacteria along with pregnancy outcomes in 271 women. Within this study, women with bacterial vaginosis (16 to 27 weeks' gestation) were treated with 2% clinadmycin vaginal cream or placebo. Enzyme, microbial findings, treatment effects, and pregnancy outcomes were compared among drug- and placebo-treated women and control women without bacterial vaginosis. RESULTS: Presence of bacterial vaginosis at intake was associated with increased risk of preterm birth (relative risk 3.3, 95% confidence interval 1.2 to 9.1, p = 0.02), premature rupture of membranes (relative risk 3.8, 95% confidence interval 1.6 to 9.0, p = 0.002), and preterm premature rupture of membranes. Mucinase and sialidase activities were more commonly identified, and they occurred in higher concentrations, if present, in women with bacterial vaginosis (mucinase: 44.3% with bacterial vaginosis vs 27.4% without, p = 0.007; sialidase: 45% with bacterial vaginosis vs 12% without, p < 0.001). Sialidase activity was associated with bacterial vaginosis - linked organisms (Gardnerella vaginalis, Mobiluncus spp, and Mycoplasma hominis) and Chlamydia trachomatis and yeast species; mucinase activity was associated only with bacterial vaginosis - linked microorganisms. Clindamycin, 2% cream, was effective treatment for bacterial vaginosis and temporarily reduced mucinase and sialidase activities. Topical treatment of bacterial vaginosis did not reduce risks of perinatal morbidity. Women with persistent or recurrent sialidase 8 weeks after treatment were at increased risk of preterm birth (15.6% vs 7.4%) premature rupture of membranes (30% vs 15%), and low birth weight (20% vs 3%, relative risk 6.8, 95% confidence interval 1.6 to 28.1). CONCLUSIONS: Persistence of sialidase-producing vaginal microorganisms in numbers sufficient to increase vaginal fluid sialidase activity may be a risk factor for possibly preventable subclinical intrauterine infection and preterm birth. This study confirms and further informs our understanding of the association of bacterial vaginosis and preterm birth; studies to evaluate whether systemic treatment for bacterial vaginosis can effectively reduce vaginal mucolytic enzymes and risks of prematurity and other morbid outcomes are continuing. (AM J OBSTET GYNECOL 1994; 170:1048-60.)

Facts and Artifacts About Anemia and Preterm Delivery

The effect of anemia (hematocrit less than or equal to 0.34) on subsequent preterm birth was prospectively studied in 35,423 pregnancies. The incidence of preterm birth among women with and without anemia at each week during the third trimester was compared. Early in the third trimester, there was a weak association between anemia and preterm delivery. However, anemia early in the third trimester did not account for the substantial increase in preterm birth seen among black women. Anemia after 30 weeks' gestation was not associated with preterm birth. Among women delivering term infants weighing 2500 g or more, the mean hematocrit rose 0.029 among black women and 0.021 among white women from 25 weeks to term. Compared with hematocrits at 40 weeks' gestation, the odds ratios for anemia reached a maximum at 28 weeks and fell sharply as term approached. When the hematocrits of women in term labor were compared with those of women in preterm labor, a spurious dose-response effect for anemia was created. We conclude that anemia is not a strong factor in the pathogenesis of preterm birth and that comparison of hematocrits from women who are in preterm and term labor produces biased results.