Length of the Second Stage of Labor and the Risk of Preterm Delivery in a Subsequent Pregnancy

Abstract OBJECTIVE: To evaluate whether an increased duration of the second stage of labor in a primiparous singleton term delivery increases the risk of preterm birth in the subsequent singleton pregnancy. METHODS: Cohort study of retrospectively collected obstetric data at Lehigh Valley Health Network between April 2007 and November 2013. The characteristics of a woman’s first pregnancy delivered ≥ 37 weeks gestation were obtained and the length of the second stage of labor was used as the exposure of interest. Characteristics of the woman’s subsequent delivered pregnancy were analyzed and the gestational age at delivery was the primary outcome of interest. Other outcomes of interest included the diagnosis of spontaneous preterm labor and/ or the diagnosis of cervical shortening in the second pregnancy. RESULTS: Twenty-six out of thirty-three patients were identified as eligible for inclusion in the study, for a total of 52 pregnancies included in analysis. Out of the pregnancies analyzed, 3 patients delivered preterm in their second pregnancy. Our primary outcome of interest, gestational age in a subsequent pregnancy, was similar between the groups (38.8 weeks + 1.5 weeks in those with a normal second stage of labor (n=17, 73.9%) vs. 39.6 + 1.0 weeks in those with a prolonged second stage of labor (n=6, 26.1%), p=0.26). CONCLUSION: Our data thus far does not demonstrate a difference in gestational age among women by the length of the second stage of labor, although results are limited by the small sample size. Through this study possible risk factors for cervical shortening and spontaneous preterm birth in women who have previously delivered at term will be evaluated. The observations made from this study may influence health care providers to make recommendations for preterm delivery screening and labor management in women who do not have obvious risk factors for preterm birth. Introduction Preterm birth (PTB) is defined as a delivery that occurs prior to 37 weeks of gestation. Within the United States, twelve percent of births occur before 37 weeks (Norwitz, 2014). Around 70 to 80 percent of preterm births occur spontaneously, which is often due to preterm labor or preterm premature rupture of membranes (PPROM). Preterm labor comprises 40 to 50 percent of preterm births and preterm premature rupture of membranes (PPROM) is responsible for 20 to 30 percent of preterm births. The other 20 to 30 percent of preterm births are medically indicated due to maternal or fetal complications such as preeclampsia, placenta previa, abruptio placenta, fetal growth restriction and multiple gestations (Lockwood, 2014). Preterm birth is the main cause of neonatal death, defined as death in the first 28 days of life. Twenty seven percent of neonatal deaths worldwide are due to preterm birth, making up over one million deaths annually. Preterm birth is associated with neonatal morbidity and long-term after effects such as neurodevelopmental deficits, which include cerebral palsy, impaired learning or visual disorders. Preterm birth is also correlated with having an increased risk of an array of diseases in adulthood (Lockwood, 14). The increasing rate of preterm birth in some countries may be due to an increase in multiple gestations that occurred through assisted reproductive technology. Ultrasound identification of a short cervix (mm) in symptomatic and asymptomatic preterm patients, often relates to an increased risk of preterm labor and birth (Lockwood, 14). The greatest risk factor for preterm birth is a prior preterm birth (PTB) with recurrence risks in the range of 25-55%. A prior term birth seems to reduce the PTB risk to 5-8%. This observation suggests that women with PTB after a prior term birth may have a different etiologic distribution than other women with PTB. Cervical insufficiency is the inability of the uterine cervix to retain a pregnancy in the absence of contractions or labor, most often due to a structural weakness of the cervix. Cervical insufficiency may stem from diethylstilbestrol exposure, over-dilation of the cervix during pregnancy termination, cervical trauma from conization, loop electrosurgical excision procedure, congenital Müllerian anomalies, and deficiencies in cervical collagen and elastin. A precipitous delivery and a prolonged second stage of labor have shown to have a correlation with cervical insufficiency. Women who have had a first trimester curettage procedure have shown to be five times more susceptible to cervical insufficiency than other multiparous women who have never had the procedure done (Vyas, 2006). There is a chance that cervical insufficiency increases the likelihood of having a second trimester abortion or premature labor (Johnstone, 1976). The etiology for cervical shortening/insufficiency and preterm delivery in women without otherwise obvious risk factors may be structural damage to the cervix during a previous term birth, due to a precipitous or prolonged second stage, cervical laceration, or an operative vaginal delivery. The objective of our study is to determine if an increased duration of the second stage of labor or prolonged labor dystocia in a primiparous term delivery increases the likelihood in the subsequent pregnancy of delivery before 37 weeks gestation, second trimester loss and/or cervical shortening. We propose that the length of the second stage of labor may cause cervical trauma that will possibly increase the chance of preterm labor, cervical malfunction and thus preterm delivery in a subsequent pregnancy. Material and Methods To determine whether the duration of the second stage of labor in a first term pregnancy impacts the risk of early delivery (weeks) gestation in a subsequent pregnancy, a cohort study of retrospectively collected obstetric data from April 2007 to November 2013 at Lehigh Valley Health Network was performed. Characteristics of the first pregnancy delivered at a gestational age of ≥37 weeks, including the exposure of interest: the length of the second stage of labor (normal vs. prolonged; \u3e3 hours), were obtained. Information regarding the women’s second pregnancy was collected and the gestational age at delivery was the primary outcome of interest. Other outcomes evaluated included the diagnosis of spontaneous preterm labor and/or the diagnosis of cervical shortening in the subsequent pregnancy. Data analyzed was obtained from the Lehigh Valley Health Network (LVHN) Department of Obstetrics and Gynecology Division of Quality Assurance. A total of 1000 patients were identified in the database to have had both a first term delivery at LVHN and a subsequent birth also at LVHN. Medical records were reviewed for 33 patients. Data gathered from both the first and subsequent pregnancies included maternal demographic information such as age, race and pre-pregnancy body mass index. Data regarding medical co-morbidities, gestational age at delivery, duration of the first stage of labor, duration of the second stage of labor regardless of mode of delivery, mode of delivery (spontaneous vaginal, operative vaginal or cesarean), indication for cesarean delivery, intrapartum complications (chorioamnionitis, abruption placentae, preeclampsia), postpartum complications (postpartum hemorrhage) and neonatal birthweight were also obtained from the database. Data abstracted from the first and subsequent pregnancy included antepartum course, cervical dilation on admission, oxytocin use in spontaneous labor, whether labor was spontaneous or induced, presence of cervical lacerations and use of regional analgesia. Data abstracted from the subsequent pregnancy included antenatal complications including the diagnosis of cervical shortening, advanced cervical dilation or preterm labor, use of cerclage or progesterone, as well as fetal and/or neonatal outcome including birth weight and other complications such as fetal demise. Pregnancies excluded from the study include women that had a previous cervical conization or excision procedure, pregnancies in which there were fetal anomalies, the presence of aneuploidy or a subsequent pregnancy with a delivery at less than 16 weeks gestation. The network’s Institutional Review Board approved the study. The primary outcome of this study was the rate of early delivery (gestation) in subsequent pregnancies as related to a normal vs. prolonged second stage of labor in the first delivery. Statistical analyses included descriptive statistics such as chi- square or Fisher’s exact test for categorical variables and the Student’s t or Mann Whitney U tests for continuous variables. Statistical significance was defined by a p value \u3c 0.05. Once the entire patient database is reviewed, risk ratios will be calculated in order to determine the risk of preterm birth/ and or cervical shortening in a subsequent pregnancy by the length of the second stage of labor of the first pregnancy. Multivariate regression models will be created in order to assess adjusted risk ratios for cervical shortening and/or preterm delivery in a subsequent pregnancy determined by the length of the second stage of labor in a first pregnancy, adjusted for potential confounders. Results Record reviews were performed for 33 patients in the database, 26 of which met criteria for study analysis for a total of 52 births analyzed. Seven women were excluded from analysis since their deliveries were either scheduled as cesareans due to macrosomia or were not eligible for vaginal birth due to malpresentation. A multiparous woman was misclassified as primiparous in the database and was thus excluded from the study analysis. Patient demographics and labor characteristics were similar between patients in their first and subsequent deliveries (Table 1), except for maternal age as expected. Six patients had a prolonged second stage (\u3e3 hours) in their first delivery whereas 17 patients had a normal second stage of labor in their first delivery. Our primary outcome of interest, gestational age in a subsequent pregnancy, was similar between the groups (Figure, p=0.26). The lengths of the first and second stages of labor in the first delivery were similar between women who delivered either at term or preterm in the subsequent pregnancy (Table 2). Although gestational ages in the subsequent pregnancy were similar regardless of the second stage of labor length in the first delivery, we reviewed the etiology of PTB in the 3 women who delivered preterm in the subsequent pregnancy. One of the women who delivered preterm was admitted for preterm contractions/labor. Upon record review, it was determined that she had complete placenta previa and this was the indication for preterm delivery via cesarean at 36+1 weeks gestation. One of the other women was also admitted for preterm contractions/labor. This woman was admitted three times before she delivered. On her first admission she was 28 weeks pregnant and two centimeters dilated. She received tocolysis to prevent a preterm birth and also received corticosteroids for fetal benefit. She was eventually discharged home in stable condition. On her second admission she was at 33 weeks gestation and six centimeters dilated. She eventually delivered preterm, at a gestational age of 36+4 weeks gestation. A woman with suspected chorioamnionitis in her second pregnancy delivered preterm at a gestational age of 36+6 weeks gestation. Discussion Our data thus far does not demonstrate a difference in gestational age in a subsequent pregnancy exposed to a normal vs. prolonged second stage of labor in a first delivery. Limitations of our study include the small sample of patients analyzed when compared to the total number of patients whose pregnancies are to be included in the study. While at the Division of Maternal Fetal Medicine there was time to only review 52 pregnancies. Our sample size calculation estimates that we need to evaluate at least 1000 patients to find an increased risk of preterm birth from 8% in those with a normal second stage of labor to 24% in those with a prolonged second stage of labor. Once the entire database is analyzed we hope to identify whether the length of the second stage of labor in a first pregnancy impacts the gestational age at delivery of a subsequent pregnancy. Results at this time are thus limited to reach definitive conclusions. Loss of confidentiality of the patients being reviewed is a factor that is to be taken into consideration in this study. To decrease such risk, the data was only monitored by the primary investigators and the data was de-identified and maintained safely using password protection. Once completed, the information gathered from this study could give support to the literature in terms of risk factors for cervical shortening and spontaneous preterm birth in women who have previously delivered at term, women who otherwise are not identified to be at risk of preterm birth after experiencing a term birth. Labor may be handled in a different manner if certain clinical outcomes such as the length of labor, length of pushing, cervical lacerations and neonatal birthweight are found to potentially impact future pregnancies. There may be an emphasis on preterm delivery screening and different labor management in women who otherwise do not have traditional risk factors for preterm birth. Understanding the cause of a potential risk for preterm birth in a subsequent pregnancy would allow physicians to focus their attention on preventing these specific events from occurring. The significant impact of preterm birth on neonatal morbidity, neonatal mortality, and resource utilization makes our research question an important topic to further investigate. Table 1. Patient demographics and labor characteristics by first and subsequent delivery Demographics and labor characteristics First delivery n = 26 Subsequent delivery n = 26 Maternal age (years)a 27.4 ± 5.0 29.6 ± 5.0 Resident service (vs. private), n (%) 4 (15.4) 5 (19.2) Cesarean delivery, n (%) 3 (11.5) 4 (15.4) First stage labor length (hours)a 9.9 ± 4.6 8.0 ± 4.5 Second stage labor length (hours)a 2.0 + 1.6 0.5 + 0.7 Gestational age at delivery (weeks) a 39.2 ± 1.2 39.0 ± 1.4 Neonatal birthweight (grams) 3249.2 + 507.8 3447.8 + 595.7 Data analyzed with Student t and chi square tests, as indicated. aData expressed in mean + SD Table 2. Labor characteristics by gestational age in subsequent pregnancy Labor characteristics Term delivery in subsequent pregnancy n = 23 PTB in subsequent pregnancy n = 3 p value Gestational age in subsequent pregnancy (weeks) a 39.4 ± 1.1 36.4 ± 0.3 0.0001 First stage labor length in the first term delivery (hours)a n = 18 9.9 ± 4.7 n = 3 9.8 ± 4.7 0.98 Second stage labor length in the first term delivery (hours)a n = 20 2.0 + 1.7 n = 3 1.0 + 0.7 0.27 Data analyzed with Student t tests, as indicated. aData expressed in mean + SD Figure. Study flow diagram with primary outcome of interest References Johnstone, F. D., Beard, R. J., Boyd, I. E., & Mccarthy, T. G. (1976). Cervical diameter after suction termination of pregnancy.BMJ, 1(6001), 68-69. Lockwood, C.J. (2014). Overview of preterm labor and birth. In S.M. Ramin (Ed.), UpToDate. Retrieved from http://www.uptodate.com/contents/prevention-of-spontaneous-preterm-birth Norwitz, E.R. (2014). Prevention of spontaneous preterm birth. In C.J. Lockwood (Ed.), UpToDate. Retrieved from http://www.uptodate.com/contents/overview-of-preterm-labor-and-birth Vyas, N. A., Vink, J. S., Ghidini, A., Pezzullo, J. C., Korker, V., Landy, H. J., et al. (2006). Risk factors for cervical insufficiency after term delivery. American Journal of Obstetrics and Gynecology, 195(3), 787-791

Nicotinic acetylcholine receptor subunit variants are associated with blood pressure; findings in the Old Order Amish and replication in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Systemic blood pressure, influenced by both genetic and environmental factors, is regulated via sympathetic nerve activity. We assessed the role of genetic variation in three subunits of the neuromuscular nicotinic acetylcholine receptor positioned on chromosome 2q, a region showing replicated evidence of linkage to blood pressure.</p> <p>Methods</p> <p>We sequenced <it>CHRNA1</it>, <it>CHRND </it>and <it>CHRNG </it>in 24 Amish subjects from the Amish Family Diabetes Study (AFDS) and identified 20 variants. We then performed association analysis of non-redundant variants (n = 12) in the complete AFDS cohort of 1,189 individuals, and followed by genotyping blood pressure-associated variants (n = 5) in a replication sample of 1,759 individuals from the Framingham Heart Study (FHS).</p> <p>Results</p> <p>The minor allele of a synonymous coding SNP, rs2099489 in <it>CHRNG</it>, was associated with higher systolic blood pressure in both the Amish (p = 0.0009) and FHS populations (p = 0.009) (minor allele frequency = 0.20 in both populations).</p> <p>Conclusion</p> <p><it>CHRNG </it>is currently thought to be expressed only during fetal development. These findings support the Barker hypothesis, that fetal genotype and intra-uterine environment influence susceptibility to chronic diseases later in life. Additional studies of this variant in other populations, as well as the effect of this variant on acetylcholine receptor expression and function, are needed to further elucidate its potential role in the regulation of blood pressure. This study suggests for the first time in humans, a possible role for genetic variation in the neuromuscular nicotinic acetylcholine receptor, particularly the gamma subunit, in systolic blood pressure regulation.</p

Genome-wide binding of the orphan nuclear receptor TR4 suggests its general role in fundamental biological processes

<p>Abstract</p> <p>Background</p> <p>The orphan nuclear receptor TR4 (human testicular receptor 4 or NR2C2) plays a pivotal role in a variety of biological and metabolic processes. With no known ligand and few known target genes, the mode of TR4 function was unclear.</p> <p>Results</p> <p>We report the first genome-wide identification and characterization of TR4 <it>in vivo </it>binding. Using chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we identified TR4 binding sites in 4 different human cell types and found that the majority of target genes were shared among different cells. TR4 target genes are involved in fundamental biological processes such as RNA metabolism and protein translation. In addition, we found that a subset of TR4 target genes exerts cell-type specific functions. Analysis of the TR4 binding sites revealed that less than 30% of the peaks from any of the cell types contained the DR1 motif previously derived from <it>in vitro </it>studies, suggesting that TR4 may be recruited to the genome via interaction with other proteins. A bioinformatics analysis of the TR4 binding sites predicted a <it>cis </it>regulatory module involving TR4 and ETS transcription factors. To test this prediction, we performed ChIP-seq for the ETS factor ELK4 and found that 30% of TR4 binding sites were also bound by ELK4. Motif analysis of the sites bound by both factors revealed a lack of the DR1 element, suggesting that TR4 binding at a subset of sites is facilitated through the ETS transcription factor ELK4. Further studies will be required to investigate the functional interdependence of these two factors.</p> <p>Conclusions</p> <p>Our data suggest that TR4 plays a pivotal role in fundamental biological processes across different cell types. In addition, the identification of cell type specific TR4 binding sites enables future studies of the pathways underlying TR4 action and its possible role in metabolic diseases.</p

ATL9, a RING Zinc Finger Protein with E3 Ubiquitin Ligase Activity Implicated in Chitin- and NADPH Oxidase-Mediated Defense Responses

Pathogen associated molecular patterns (PAMPs) are signals detected by plants that activate basal defenses. One of these PAMPs is chitin, a carbohydrate present in the cell walls of fungi and in insect exoskeletons. Previous work has shown that chitin treatment of Arabidopsis thaliana induced defense-related genes in the absence of a pathogen and that the response was independent of the salicylic acid (SA), jasmonic acid (JA) and ethylene (ET) signaling pathways. One of these genes is ATL9 ( = ATL2G), which encodes a RING zinc-finger like protein. In the current work we demonstrate that ATL9 has E3 ubiquitin ligase activity and is localized to the endoplasmic reticulum. The expression pattern of ATL9 is positively correlated with basal defense responses against Golovinomyces cichoracearum, a biotrophic fungal pathogen. The basal levels of expression and the induction of ATL9 by chitin, in wild type plants, depends on the activity of NADPH oxidases suggesting that chitin-mediated defense response is NADPH oxidase dependent. Although ATL9 expression is not induced by treatment with known defense hormones (SA, JA or ET), full expression in response to chitin is compromised slightly in mutants where ET- or SA-dependent signaling is suppressed. Microarray analysis of the atl9 mutant revealed candidate genes that appear to act downstream of ATL9 in chitin-mediated defenses. These results hint at the complexity of chitin-mediated signaling and the potential interplay between elicitor-mediated signaling, signaling via known defense pathways and the oxidative burst

A Novel Role for MAPKAPK2 in Morphogenesis during Zebrafish Development

One of the earliest morphogenetic processes in the development of many animals is epiboly. In the zebrafish, epiboly ensues when the animally localized blastoderm cells spread, thin over, and enclose the vegetally localized yolk. Only a few factors are known to function in this fundamental process. We identified a maternal-effect mutant, betty boop (bbp), which displays a novel defect in epiboly, wherein the blastoderm margin constricts dramatically, precisely when half of the yolk cell is covered by the blastoderm, causing the yolk cell to burst. Whole-blastoderm transplants and mRNA microinjection rescue demonstrate that Bbp functions in the yolk cell to regulate epiboly. We positionally cloned the maternal-effect bbp mutant gene and identified it as the zebrafish homolog of the serine-threonine kinase Mitogen Activated Protein Kinase Activated Protein Kinase 2, or MAPKAPK2, which was not previously known to function in embryonic development. We show that the regulation of MAPKAPK2 is conserved and p38 MAP kinase functions upstream of MAPKAPK2 in regulating epiboly in the zebrafish embryo. Dramatic alterations in calcium dynamics, together with the massive marginal constrictive force observed in bbp mutants, indicate precocious constriction of an F-actin network within the yolk cell, which first forms at 50% epiboly and regulates epiboly progression. We show that MAPKAPK2 activity and its regulator p38 MAPK function in the yolk cell to regulate the process of epiboly, identifying a new pathway regulating this cell movement process. We postulate that a p38 MAPKAPK2 kinase cascade modulates the activity of F-actin at the yolk cell margin circumference allowing the gradual closure of the blastopore as epiboly progresses

Single nucleotide polymorphisms unravel hierarchical divergence and signatures of selection among Alaskan sockeye salmon (Oncorhynchus nerka) populations

<p>Abstract</p> <p>Background</p> <p>Disentangling the roles of geography and ecology driving population divergence and distinguishing adaptive from neutral evolution at the molecular level have been common goals among evolutionary and conservation biologists. Using single nucleotide polymorphism (SNP) multilocus genotypes for 31 sockeye salmon (<it>Oncorhynchus nerka</it>) populations from the Kvichak River, Alaska, we assessed the relative roles of geography (discrete boundaries or continuous distance) and ecology (spawning habitat and timing) driving genetic divergence in this species at varying spatial scales within the drainage. We also evaluated two outlier detection methods to characterize candidate SNPs responding to environmental selection, emphasizing which mechanism(s) may maintain the genetic variation of outlier loci.</p> <p>Results</p> <p>For the entire drainage, Mantel tests suggested a greater role of geographic distance on population divergence than differences in spawn timing when each variable was correlated with pairwise genetic distances. Clustering and hierarchical analyses of molecular variance indicated that the largest genetic differentiation occurred between populations from distinct lakes or subdrainages. Within one population-rich lake, however, Mantel tests suggested a greater role of spawn timing than geographic distance on population divergence when each variable was correlated with pairwise genetic distances. Variable spawn timing among populations was linked to specific spawning habitats as revealed by principal coordinate analyses. We additionally identified two outlier SNPs located in the major histocompatibility complex (MHC) class II that appeared robust to violations of demographic assumptions from an initial pool of eight candidates for selection.</p> <p>Conclusions</p> <p>First, our results suggest that geography and ecology have influenced genetic divergence between Alaskan sockeye salmon populations in a hierarchical manner depending on the spatial scale. Second, we found consistent evidence for diversifying selection in two loci located in the MHC class II by means of outlier detection methods; yet, alternative scenarios for the evolution of these loci were also evaluated. Both conclusions argue that historical contingency and contemporary adaptation have likely driven differentiation between Kvichak River sockeye salmon populations, as revealed by a suite of SNPs. Our findings highlight the need for conservation of complex population structure, because it provides resilience in the face of environmental change, both natural and anthropogenic.</p

Inflammation and breast cancer. Metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer

Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease and uncover novel therapeutic strategies. The metalloproteinase class of enzymes is well studied in mammary gland development and physiology, but mostly in the context of extracellular matrix modification. Aberrant metalloproteinase expression has also been implicated in breast cancer progression, where these genes act as tumor modifiers. Here, we review how the metalloproteinase axis impacts mammary physiology and tumorigenesis and is associated with inflammatory cell influx in human breast cancer, and evaluate its potential as a regulator of inflammation in the mammary gland