Progesterone for Prevention of Preterm Birth

Preterm birth is a major cause of perinatal mortality and morbidity. It is also the main directed cause of neonatal death globally(1). Preterm birth is responsible for more than 80% of neonatal deaths and 50% of long term morbidity in the surviving infants(1-3). Preterm birth rates have been rising over the past 3 decades. The worldwide incidence of preterm birth is 9.6 % with the highest rate occurs in the least developed regions(4). The increase in assisted reproductive technologies, labor induction or elective cesarean section during preterm period may be responsible for these high rates(2). Various risk factors are associated with preterm birth but only half of them can be identified(5). Although there are many interventions to prevent or treat preterm births, none of them appears to be efficacious(6). Recent evidences showed that progesterone supplementations are helpful to prevent preterm birth. This article pays attention to the role of progesterone for the prevention of preterm birth

Does low-dose aspirin initiated before 11 weeks' gestation reduce the rate of preeclampsia?

OBJECTIVE: DATA: Pre-conception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization and organogenesis. Most studies have evaluated the potential benefit of pre-conception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery and fetal growth restriction. STUDY: We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. STUDY APPRAISAL AND SYNTHESIS METHODS: We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.Gov and the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at 85% of the study population. Relative risks (RR) with 95% confidence intervals (CI) were calculated for each study and pooled for global analysis as the effect measure. We assessed statistical heterogeneity in each meta-analysis using the Chi2 statistics, I2 and Tau2. Heterogeneity was considered substantial if an I2 was greater than 50% and either the Tau2 was greater than zero, or there was a low P-value (<0.10) in the Chi2 test for heterogeneity. Random-effects meta-analysis, weighted by the size of the studies, was performed to produce an overall summary on aspirin effect for each outcome. Sensitivity analysis by sequential omission of each individual study and by fixed-effects model was performed. Publication bias was not assessed due to the small number of included studies. Statistical analysis was performed using Stata release 14.0 (StataCorp, College Station, TX). RESULTS: The entry criteria were fulfilled by eight randomized controlled trials on a combined total of 1,426 participants. Low-dose aspirin initiated at <11 weeks' gestation was associated with a non-significant reduction in the risk of preeclampsia (RR 0.52; 95% CI: 0.23-1.17, P=0.115), gestational hypertension (RR 0.49; 95% CI: 0.20-1.21; P=0.121) and any hypertensive disorder of pregnancy (RR 0.59; 95% CI 0.33-1.04, P=0.067). Early low-dose aspirin reduced the risk of preterm delivery (RR 0.52; 95% CI: 0.27-0.97, p=0.040) but had no impact on the risk of fetal growth restriction (RR 1.10; 95% CI 0.58-2.07, P=0.775). Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations; therefore confirming the robustness of the analysis. CONCLUSION: The administration of low-dose aspirin at <11 weeks' gestation in high risk women does not decrease the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy and fetal growth restriction. However, it might reduce the risk of preterm delivery. Larger randomized controlled trials will be required to substantiate the findings.pre-print408 K

Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest—fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

BACKGROUND: Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. OBJECTIVE: We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. STUDY DESIGN: A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025). RESULTS: We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker (P < .001). A significant correlation (R2 = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were intercellular adhesion molecule-1-positive, in none of the 14 placentas with failure of physiologic transformation that were intercellular adhesion molecule-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure (P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation. CONCLUSION: Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies

Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals upâ regulation of leukotriene B4

Bioactive lipids derived from the metabolism of polyunsaturated fatty acids are important mediators of the inflammatory response. Labor per se is considered a sterile inflammatory process. Intraâ amniotic inflammation (IAI) due to microorganisms (i.e., intraâ amniotic infection) or danger signals (i.e., sterile IAI) has been implicated in the pathogenesis of preterm labor and clinical chorioamnionitis at term. Early and accurate diagnosis of microbial invasion of the amniotic cavity (MIAC) requires analysis of amniotic fluid (AF). It is possible that IAI caused by microorganisms is associated with a stereotypic lipidomic profile, and that analysis of AF may help in the identification of patients with this condition. To test this hypothesis, we analyzed the fatty acyl lipidome of AF by liquid chromatographyâ mass spectrometry from patients in spontaneous labor at term and preterm gestations. We report that the AF concentrations of proinflammatory lipid mediators of the 5â lipoxygenase pathway are significantly higher in MIAC than in cases of sterile IAI. These results suggest that the concentrations of 5â lipoxygenase metabolites of arachidonic acid, 5â hydroxyeicosatetraenoic acid, and leukotriene B4 in particular could serve as potential biomarkers of MIAC. This finding could have important implications for the rapid identification of patients who may benefit from antimicrobial treatment.â Maddipati, K. R., Romero, R., Chaiworapongsa, T., Chaemsaithong, P., Zhou, S.â L., Xu, Z., Tarca, A. L., Kusanovic, J. P., Gomez, R., Chaiyasit, N., Honn, K. V. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals upâ regulation of leukotriene B4. FASEBJ. 30, 3296â 3307 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154488/1/fsb2fasebj30100583.pd

The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138402/1/aji12686_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138402/2/aji12686.pd

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

BackgroundTwin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM.MethodsWe carried out whole exome sequencing (WES) of genomic DNA from neonates born of Africanâ American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies (N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes. Targeted genotyping of mutations in the candidates discovered by WES was conducted on an additional 188 PPROM cases and 175 controls.ResultsWe identified rare heterozygous nonsense and frameshift mutations in several of the candidate genes, including CARD6, CARD8, DEFB1, FUT2, MBL2, NLP10, NLRP12, and NOD2. We discovered that some mutations (CARD6, DEFB1, FUT2, MBL2, NLRP10, NOD2) were present only in PPROM cases.ConclusionsWe conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in Africanâ Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.Rare damaging mutations in fetal innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by preterm premature rupture of membranes. An increased risk of preterm birth may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140041/1/mgg3330.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140041/2/mgg3330_am.pd

Prevalence and Clinical Significance of Sterile Intra‐amniotic Inflammation in Patients with Preterm Labor and Intact Membranes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109340/1/aji12296.pd

A Novel Molecular Microbiologic Technique for the Rapid Diagnosis of Microbial Invasion of the Amniotic Cavity and Intra‐Amniotic Infection in Preterm Labor with Intact Membranes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106726/1/aji12189.pd

A Role for the Inflammasome in Spontaneous Labor at Term

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143689/1/aji12440.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143689/2/aji12440_am.pd