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Preterm birth affects approximately 1 out of every 10 births in the United States, leading to high rates of mortality and long-term negative health consequences. To investigate the mechanisms leading to preterm birth so as to develop prevention strategies, researchers have developed numerous mouse models of preterm birth. However, the lack of standard definitions for preterm birth in mice limits our field's ability to compare models and make inferences about preterm birth in humans. In this review, we discuss numerous mouse preterm birth models, propose guidelines for experiments and reporting, and suggest markers that can be used to assess whether pups are premature or mature. We argue that adoption of these recommendations will enhance the utility of mice as models for preterm birth.
Globally, an estimated 13 million preterm babies are born each year. These babies are at increased risk of infant mortality and life-long health complications. Interventions to prevent preterm birth (PTB) require an understanding of processes driving parturition. Prostaglandins (PGs) have diverse functions in parturition, including regulation of uterine contractility and tissue remodeling. Our studies on cervical remodeling in mice suggest that although local synthesis of PGs are not increased in term ripening, transcripts encoding PG-endoperoxide synthase 2 (Ptgs2) are induced in lipopolysaccharide (LPS)-mediated premature ripening. This study provides evidence for two distinct pathways of cervical ripening: one dependent on PGs derived from paracrine or endocrine sources and the other independent of PG actions. Cervical PG levels are increased in LPS-treated mice, a model of infection-mediated PTB, consistent with increases in PG synthesizing enzymes and reduction in PG-metabolizing enzymes. Administration of SC-236, a PTGS2 inhibitor, along with LPS attenuated cervical softening, consistent with the essential role of PGs in LPS-induced ripening. In contrast, during term and preterm ripening mediated by the antiprogestin, mifepristone, cervical PG levels, and expression of PG synthetic and catabolic enzymes did not change in a manner that supports a role for PGs. These findings in mice, supported by correlative studies in women, suggest PGs do not regulate all aspects of the parturition process. Additionally, it suggests a need to refocus current strategies toward developing therapies for the prevention of PTB that target early, pathway-specific processes rather than focusing on common late end point mediators of PTB.
OBJECTIVE - The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes.
STUDY DESIGN - We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007.
RESULTS - Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6-9.5) for filling 1, 2, and ≥3 prescriptions, respectively.
CONCLUSION - Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.
Copyright © 2012 Mosby, Inc. All rights reserved.
The goal of this research is to determine whether Raman spectroscopy (RS), an optical method that probes the vibrational modes of tissue components, can be used in vivo to study changes in the mouse cervix during pregnancy. If successful, such a tool could be used to detect cervical changes due to pregnancy, both normal and abnormal, in animal models and humans. For this study, Raman spectra were acquired before, during and after a 19-day mouse gestational period. In some cases, after Raman data was obtained, cervices were excised for structural testing and histological staining for collagen and smooth muscle. Various peaks of the Raman spectra, such as the areas corresponding to fatty acid content and collagen organization, changed as the cervix became softer in preparation for labor and delivery. These findings correspond to the increase in compliance of the tissue and the collagen disorganization visualized with the histological staining. The results of this study suggest that non-invasive RS can be used to study cervical changes during pregnancy, labor and delivery and can possibly predict preterm delivery before overt clinical manifestations, potentially lead to more effective preventive and therapeutic interventions.
OBJECTIVE - To evaluate amniotic fluid arachidonic acid metabolites using enzymatic and nonenzymatic (lipid peroxidation) pathways in spontaneous preterm birth and term births, and to estimate whether prostanoid concentrations correlate with risk factors (race, cigarette smoking, and microbial invasion of amniotic cavity) associated with preterm birth.
METHODS - In a case-control study, amniotic fluid was collected at the time of labor or during cesarean delivery. Amniotic fluid samples were subjected to gas chromatography, negative ion chemical ionization, and mass spectrometry for prostaglandin (PG) E2, PGF2α, and PGD2 and for 6-keto-PGF1α (thromboxane 2 and F2-isoprostane). Primary analysis examined differences between prostanoid concentrations in preterm birth (n=133) compared with term births (n=189). Secondary stratified analyses (by race, cigarette smoking, and microbial invasion of amniotic cavity) compared eicosanoid concentrations in three epidemiological risk factors.
RESULTS - Amniotic fluid F2-isoprostane, PGE2, and PGD2 were significantly higher at term than in preterm birth, whereas PGF2α was higher in preterm birth 6-keto-PGF1α and thromboxane 2 concentrations were not different. Data stratified by race (African American or white) showed no significant disparity among prostanoid concentrations. Regardless of gestational age status, F2-isoprostane was threefold higher in smokers, and other eicosanoids were also higher in smokers compared with nonsmokers. Preterm birth with microbial invasion of amniotic cavity had significantly higher F2-isoprostane compared with preterm birth without microbial invasion of amniotic cavity.
CONCLUSION - Most amniotic fluid eicosanoid concentrations (F2-isoprostane, PGE2, and PGD2), are higher at term than in preterm births. The only amniotic fluid eicosanoid that is not higher at term is PGF2α.
BACKGROUND - Localized inflammation and increased expression of TLR4 receptors within the uterus has been implicated in the pathogenesis of preterm labor. It remains unclear whether intrauterine inflammatory responses activate the maternal peripheral circulatory system. Therefore we determined whether increased TLR4 expression is present in the peripheral maternal white blood cells of women with spontaneous preterm labor.
METHODS - This is a cross-sectional study of 41 preterm labor cases and 41 non-preterm controls. For each case and control sample, RNA was purified from white blood cells and TLR4 mRNA pool size was evaluated by quantitative PCR. Protein expression levels were determined by flow cytometry. Statistical evaluation using multiple linear regressions was used to determine any significant differences between the cases and controls. The purpose was to determine association prevalence of TLR4 levels and preterm labor.
RESULTS - Adjusted mean TLR4 mRNA levels of 0.788 ± 0.037 (standard error) for preterm labor and 0.348 ± 0.038 for the corresponding pregnant control women were statistically significantly different (P = 0.002). Using the lower 95% confidence interval of the mean expression level in PTL subjects (0.7) as a cutoff value for elevated TLR4 mRNA levels, 25/41 (60.9%) of PTL patients expressed elevated TLR4 mRNA as compared to 0/41 (0%) in control subjects. The TLR4 receptor levels in the granulocyte fraction of white blood cells from preterm labor and pregnant controls were similar. However, TLR4+/CD14+monocytes were 2.3 times more frequent (70% vs. 30%) and TLR4 also had a 2.6-fold higher density (750 vs. 280 molecules per cell) in preterm labor women compared with pregnant controls. There was no difference in the levels of TLR4 in patients at term.
CONCLUSIONS - Patients with preterm labor exhibited elevated levels of CD14+ maternal blood monocytes each bearing enhanced expression of TLR4, indicating that the peripheral circulatory system is activated in patients with preterm labor. Elevated leukocyte TLR4 levels may be a useful biomarker associated with preterm labor.
OBJECTIVE - To assess the prescription patterns of progesterone for the prevention of preterm birth in a tertiary center.
STUDY DESIGN - We examined electronic medical records for all women receiving care in the high risk obstetric clinics at a tertiary care center from July 2003 to June 2004. Demographic information, progesterone offers, progesterone therapy accepted and received, and barriers to receiving progesterone were collected. Women were placed into 1 of 4 categories: appropriate offer, appropriate nonoffer, inappropriate offer and inappropriate nonoffer.
RESULTS - Five hundred two patients sought prenatal care in the clinics during the study period. Of 143 women with a prior preterm birth, 60 (42%) were considered to be candidates for progesterone. Of these, 34 of 60 (57%) were offered progesterone therapy (appropriate offer). Of the 442 women who were not appropriate progesterone candidates, 9 (2%) were offered progesterone (inappropriate offer).
CONCLUSION - Our data suggest that a substantial proportion of eligible women are not being offered progesterone for the prevention of preterm birth. More data are needed regarding barriers to progesterone use and what programs may best influence physicians to use progesterone appropriately.
OBJECTIVE - The objective of this study was to design a method to identify patients at risk for preterm premature rupture of the membranes using a simple assay of salivary proteinase activity.
STUDY DESIGN - Saliva samples were collected from women in the following groups using Salivette: (1) nonpregnant control; (2) during the second trimester of pregnancy; (3) during active labor at term; (4) women with premature rupture of the membranes before preterm delivery; and (5) postpartum (within 3 hours after delivery at term). Total proteolytic activity in saliva samples was measured by fluorometry using the generic substrate DQ-gelatin in the presence of specific inhibitors to selectively detect matrix metalloproteinase activities. The concentrations of various matrix metalloproteinases in saliva samples were also measured by multiplex bead assay using the Luminex platform.
RESULTS - All saliva samples exhibited detectable matrix metalloproteinase activity. Salivary matrix metalloproteinase activity is low in nonpregnant females (0.27 +/- 0.15) and increases in samples taken in the second trimester (0.5 +/- 0.5) and at term during active labor (1.03 +/- 1.2). Samples collected from women with premature rupture of the membranes before preterm delivery had the highest activity (2.5 +/- 3.7) followed by postpartum after normal term delivery (2.1 +/- 1.6). The matrix metalloproteinase activity was higher in premature rupture of the membranes before preterm delivery samples, compared with all other stages of pregnancy. Multiplex matrix metalloproteinase assay documented a significant increase in total matrix metalloproteinase-9 concentration in saliva from premature rupture of the membranes before preterm delivery, compared with any of the other groups. Similarly matrix metalloproteinase-9 activity was also significantly increased in premature rupture of the membranes before preterm delivery group, compared with all others.
CONCLUSION - Herein we report a simple test to monitor proteolytic enzyme activity in saliva during pregnancy. The highest matrix metalloproteinase activity is seen in premature rupture of the membranes before preterm delivery and postpartum samples. Ongoing studies aim to further define salivary proteinase activity in patients at high risk for premature rupture of the membranes before preterm delivery and to evaluate its potential as a predictive test for premature rupture of the membranes before preterm delivery.
Biochemical changes of cervical connective tissue, including progressive disorganization of the collagen network and increased water content, occur during gestation to allow for cervical dilatation during labor, but the mechanisms that regulate cervical fluid balance are not fully understood. We examined whether aquaporins (AQPs), a family of membrane channel proteins that facilitate water transport, help mediate fluid balance in the mouse cervix during parturition. Of the 13 known murine AQPs, AQP0-2, 6, 7, 9, 11, and 12 were absent or at the limits of detection. By Northern blot and real-time PCR, AQP3 expression was low in nongravid and mid-pregnancy cervices with peak expression on d 19 and postpartum d 1 (PP1). AQP4 expression was generally low throughout pregnancy but showed a small upward trend at the time of parturition. AQP5 and AQP8 expression were significantly increased on d 12-15 but fell to nongravid/baseline by d 19 and PP1. By in situ hybridization and immunohistochemistry, AQP3 was preferentially expressed in basal cell layers of the cervical epithelium, whereas AQP4, 5, and 8 were primarily expressed in apical cell layers. Females with LPS-induced preterm labor had similar trends in AQP4, 5, and 8 expression to mice with natural labor at term gestation. Mice with delayed cervical remodeling due to deletion of the steroid 5alpha-reductase type 1 gene showed significant reduction in the levels of AQP3, 4, and 8 on d 19 or PP1. Together, these studies suggest that AQPs 3, 4, 5, and 8 regulate distinct aspects of cervical water balance during pregnancy and parturition.
This study evaluates maternal age, race, cigarette smoking, prior spontaneous abortion, prior induced abortion, and prior preterm birth in relation to vaginal bleeding during the first two trimesters of pregnancy. Information on vaginal bleeding and predictors came from the Pregnancy, Infection, and Nutrition Study, which enrolled 2806 pregnant women at 24-29 weeks' gestation during 1995-2000 in central North Carolina, USA. Generalised estimating equations were applied to take into account repeated episodes of vaginal bleeding during pregnancy. Women with advanced maternal age and passive smoking exposure were more likely to experience more intense vaginal bleeding during pregnancy, as were women with prior preterm birth. More intense bleeding was also more likely to be reported among women with multiple prior spontaneous abortions or multiple prior induced abortions, but not among women with a single prior spontaneous or induced abortion. The combination of prior spontaneous and induced abortion showed a dose-response association with the occurrence of vaginal bleeding during pregnancy.