Cell-free DNA, inflammation, and the initiation of spontaneous term labor.

BACKGROUND: Hypomethylated cell-free DNA from senescent placental trophoblasts may be involved in the activation of the inflammatory cascade to initiate labor. OBJECTIVE: To determine the changes in cell-free DNA concentrations, the methylation ratio, and inflammatory markers between women in labor at term vs women without labor. STUDY DESIGN: In this prospective cohort study, eligible participants carried a nonanomalous singleton fetus. Women with major medical comorbidity, preterm labor, progesterone use, aneuploidy, infectious disease, vaginal bleeding, abdominal trauma, or invasive procedures during the pregnancy were excluded. Maternal blood samples were collected at 28 weeks, 36 weeks, and at admission for delivery. Total cell-free DNA concentration, methylation ratio, and interleukin-6 were analyzed. The primary outcome was the difference in methylation ratio in women with labor vs without labor. Secondary outcomes included the longitudinal changes in these biomarkers corresponding to labor status. RESULTS: A total of 55 women were included; 20 presented in labor on admission and 35 presented without labor. Women in labor had significantly greater methylation ratio (P = .001) and interleukin-6 (P < .001) on admission for delivery than women without labor. After we controlled for body mass index and maternal age, methylation ratio (adjusted relative risk, 1.38; 95% confidence interval, 1.13 to 1.68) and interleukin-6 (adjusted relative risk, 1.12, 95% confidence interval, 1.07 to 1.17) remained greater in women presenting in labor. Total cell-free DNA was not significantly different in women with labor compared with women without. Longitudinally, total cell-free DNA (P < .001 in labor, P = .002 without labor) and interleukin-6 (P < .001 in labor, P = .01 without labor) increased significantly across gestation in both groups. The methylation ratio increased significantly in women with labor from 36 weeks to delivery (P = .02). CONCLUSION: Spontaneous labor at term is associated with a greater cell-free DNA methylation ratio and interleukin-6 compared with nonlabored controls. As gestation advances, total cell-free DNA concentrations and interleukin-6 levels increase. A greater methylation ratio reflects a greater maternal contribution (vs placental) in women with labor, likely resulting from greater levels of neutrophils, lymphocytes, and uterine activation proteins at the time of labor. Although not significant, women in labor had a greater total cell-free DNA concentration and thus could theoretically have more hypomethylated DNA available for interaction with the inflammatory cascade. Larger studies are needed to investigate this theory.

What Is New in Cervical Insufficiency? Best Articles From The Past Year.

This month we focus on current research in cervical insufficiency. Dr. Jackson discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts.

Pregnancy After Bariatric Surgery.

Bariatric surgery is the most effective weight loss treatment available for morbidly obese patients. The majority of bariatric surgery cases are now performed on reproductive-aged women. The pregnant bariatric surgery patient is unique, with specific care needs that often require a multidisciplinary approach. Here, we will review the rationale for bariatric surgery and contemporary surgical modalities. We will then consider the obstetric and neonatal implications following these procedures and discuss the tenets of pregnancy care in the patient after bariatric surgery.

Selective Reduction Using Intravascular Potassium Chloride Injection after Laser Surgery for Twin-Twin Transfusion Syndrome.

Selective reduction (SR) via intravascular potassium chloride (KCl) injection is contraindicated in monochorionic twins due to the presence of placental vascular communications, which may serve as a conduit for inter-twin passage of KCl or allow exsanguination of the living twin into the demised twin. After successful selective laser photocoagulation of communicating vessels (SLPCV) for twin-twin transfusion syndrome (TTTS), the twins' circulatory systems are rendered independent. Theoretically, intravascular KCl injection into one twin after successful SLPCV should not result in passage of the feticidal agent nor cause hemodynamic alterations in the co-twin. We describe 3 cases of 1,069 patients (0.3%) that underwent SLPCV for TTTS between 2003 and 2013 and subsequent SR. SLPCV was successfully completed at 180, 226, and 230 weeks' gestational age for Quintero stages III, IV, and III TTTS, respectively. SR via intravascular KCl injection was later performed at maternal request due to the risk of neurological compromise in one twin at 226, 254, and 236 weeks' gestational age. All co-twins survived after SR, and no neurological sequelae were suspected after birth. Further study is necessary before SR can be routinely considered after laser surgery for TTTS.

Tocolysis for Women With Early Spontaneous Preterm Labor and Advanced Cervical Dilation.

OBJECTIVE: To characterize tocolytic use and examine perinatal outcomes among women presenting very preterm with spontaneous labor and cervical dilation 4 cm or greater. METHODS: This was a retrospective cohort study. Data from January 2000 to June 2011 in a single health care system were reviewed. Women with singleton, nonanomalous fetuses and preterm labor with intact membranes between 23 and 32 weeks of gestation who had cervical dilation 4 cm or greater and less than 8 cm at admission were included. Women receiving one or more tocolytics (magnesium sulfate, indomethacin, or nifedipine) were compared with those who did not receive tocolysis. The primary outcome was composite major neonatal morbidity. RESULTS: Two hundred ninety-seven women were included; 233 (78.5%) received at least one tocolytic. Women receiving tocolysis were slightly less dilated (median 5 compared with 6 cm, P<.001) at presentation and were more likely to receive at least a partial course of corticosteroids (88.4% compared with 56.3%, P<.001). Initial composite severe neonatal morbidity rates were similar (41.6% compared with 43.8%, P=.761) regardless of tocolytic administration. Those receiving tocolysis were significantly more likely to be pregnant at least 48 hours after admission (23.6% compared with 7.8%, P=.005), but a similar proportion delivered within 7 days of admission (94.8% compared with 95.3%, P>.99), and delivery gestational ages were similar (28.9 compared with 29.2 weeks, P=.408). The incidence of chorioamnionitis and postpartum endometritis was similar between groups. CONCLUSION: The majority of women presenting very preterm with advanced cervical dilation received tocolysis. Although tocolysis administration increased the likelihood of achieving at least 48 hours of latency, initial neonatal outcomes were similar. LEVEL OF EVIDENCE: II.

What is new in multiple gestations? Best articles from the past year.

This month, we focus on current research on multiple gestations. Dr. Jackson discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts.

Biobanking informatics infrastructure to support clinical and translational research.

The University of Utah Health Sciences (UUHSC) and Intermountain Healthcare (IH) support high value clinical and translational research programs. The Utah Biohealth Initiative will facilitate next generation research by leveraging the combined resources of both institutions through an infrastructure which links biospecimens and electronic health records (EHR). During phase I of the Utah BioHealth Initiative (UBI) the participating institutions developed a legal, regulatory and information technology infrastructure that supports clinical and translational research, and advances our understanding of health and disease, improves healthcare value and health for current and future generations of Utahns. We used the Federated Utah Research and Translational Health electronic Repository (FURTHeR) 1 to combine EHR and biospecimen data from an actual study populated by both institutions to demonstrate the robustness of the infrastructure.

Simple, validated vaginal birth after cesarean delivery prediction model for use at the time of admission.

OBJECTIVE: To create a simple tool for predicting the likelihood of successful trial of labor after cesarean delivery (TOLAC) during the pregnancy after a primary cesarean delivery using variables available at the time of admission. METHODS: Data for all deliveries at 14 regional hospitals over an 8-year period were reviewed. Women with one cesarean delivery and one subsequent delivery were included. Variables associated with successful VBAC were identified using multivariable logistic regression. Points were assigned to these characteristics, with weighting based on the coefficients in the regression model to calculate an integer VBAC score. The VBAC score was correlated with TOLAC success rate and was externally validated in an independent cohort using a logistic regression model. RESULTS: A total of 5,445 women met inclusion criteria. Of those women, 1,170 (21.5%) underwent TOLAC. Of the women who underwent trial of labor, 938 (80%) had a successful VBAC. A VBAC score was generated based on the Bishop score (cervical examination) at the time of admission, with points added for history of vaginal birth, age younger than 35 years, absence of recurrent indication, and body mass index less than 30. Women with a VBAC score less than 10 had a likelihood of TOLAC success less than 50%. Women with a VBAC score more than 16 had a TOLAC success rate more than 85%. The model performed well in an independent cohort with an area under the curve of 0.80 (95% confidence interval 0.76-0.84). CONCLUSIONS: Prediction of TOLAC success at the time of admission is highly dependent on the initial cervical examination. This simple VBAC score can be utilized when counseling women considering TOLAC. LEVEL OF EVIDENCE: II.

How do good candidates for trial of labor after cesarean (TOLAC) who undergo elective repeat cesarean differ from those who choose TOLAC?

OBJECTIVE: Our aim was to compare good candidates for trial of labor after cesarean (TOLAC) who underwent repeat cesarean to those who chose TOLAC. STUDY DESIGN: Data for all deliveries at 14 regional hospitals over an 8-year period were reviewed. Women with a primary cesarean and 1 subsequent delivery in the dataset were included. The choice of elective repeat cesarean vs TOLAC was assessed in the first delivery following the primary cesarean. Women with ≥70% chance of successful vaginal birth after cesarean as calculated by a published nomogram were considered good candidates for TOLAC. Good candidates who chose an elective repeat cesarean were compared to those who chose TOLAC. Women who were delivered at 2 preselected tertiary centers by a general obstetrician-gynecologist practice were subanalyzed to determine whether there was an effect of physician group. RESULTS: In all, 5445 women had a primary cesarean and a subsequent delivery. A total of 3120 women were calculated to be good TOLAC candidates. Of this group, 925 (29.7%) chose TOLAC. Women managed by a family practitioner or who were obese were less likely to choose TOLAC while women who were managed by a midwife or had a prior vaginal delivery were more likely to choose TOLAC. At the 2 tertiary centers, 1 general obstetrician-gynecologist group had significantly more patients who chose TOLAC compared to the other obstetrician-gynecologist physician groups (P < .001), with 63% of their patients choosing TOLAC. CONCLUSION: Less than one-third of the good candidates for TOLAC chose TOLAC. Managing provider influences this decision.

The impact of utilization of early aneuploidy screening on amniocenteses available for training in obstetrics and fetal medicine.

OBJECTIVE: First-trimester aneuploidy screening has high detection rates and low false-positive rates. Their use as well as the implementation of non-invasive prenatal testing may affect specialty training in prenatal diagnosis procedures. STUDY DESIGN: Descriptive study of first-trimester aneuploidy screening and amniocentesis in an obstetric training program. Screening methods were tracked from their introduction in 2004 through 2011. The volume of amniocentesis procedures from 2000 to 2011 was evaluated. RESULTS: First-trimester screening tests increased from 283 to 1225 between 2005 and 2011, whereas genetic amniocenteses declined from 460 to 168 during the same period. The percent of older women who chose a first-trimester screen test rose from 12.7% to 44.2% CONCLUSION: First-trimester screening options reduce genetic amniocenteses available for training. Fetal medicine and general obstetrics training programs need to evaluate their clinical experience and determine whether simulation training methods are needed for education.

Frequency of fetal heart rate categories and short-term neonatal outcome.

OBJECTIVE: To estimate the time spent in each fetal heart rate category during labor and during the last 2 hours before delivery in term singleton pregnancy and to estimate the relationship between the time spent in each category and short-term neonatal outcomes. METHODS: This study reviewed fetal heart rate data and newborn outcomes of women in term labor in 10 hospitals over 28 months. Fetal heart rate characteristics were assessed by labor and delivery nurses, and categories were assigned by computer using definitions from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The duration of time in each category was calculated and correlated with newborn outcome. RESULTS: Forty-eight thousand four hundred forty-four patients were identified. Considering all of labor, category I was present 77.9% of the time, category II was present 22.1% of the time, and category III was present 0.004% of the time. In the last 2 hours before delivery, category I decreased to 60.9% of the duration, category II increased to 39.1%, and category III increased to 0.006%. Newborns of women whose last 2 hours were exclusively category I did well; only 0.6% had 5-minute Apgar scores less than 7, and 0.2% had low Apgar scores with neonatal intensive care unit (NICU) admission. When more than 75% of the last 2 hours was category II, low 5-minute Apgar score increased to 1.3% of patients, and low 5-minute Apgar score with NICU admission increased to 0.7% (both P<.001). CONCLUSION: Category I and category II fetal heart rate patterns are common in labor, and category III patterns are rare. Increasing time in category II in the last 2 hours of labor is associated with increased short-term newborn morbidity. LEVEL OF EVIDENCE: III.

Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches.

While scientific knowledge of the potential health significance of chemical exposures has grown, experimental methods for predicting the carcinogenicity of environmental agents have not been substantially updated in the last two decades. Current methodologies focus first on identifying genotoxicants under the premise that agents capable of directly damaging DNA are most likely to be carcinogenic to humans. Emphasis on the distinction between genotoxic and non-genotoxic carcinogens is also motivated by assumed implications for the dose-response curve; it is purported that genotoxicants would lack a threshold in the low dose region, in contrast to non-genotoxic agents. However, for the vast majority of carcinogens, little if any empirical data exist to clarify the nature of the cancer dose-response relationship at low doses in the exposed human population. Recent advances in scientific understanding of cancer biology-and increased appreciation of the multiple impacts of carcinogens on this disease process-support the view that environmental chemicals can act through multiple toxicity pathways, modes and/or mechanisms of action to induce cancer and other adverse health outcomes. Moreover, the relationship between dose and a particular outcome in an individual could take multiple forms depending on genetic background, target tissue, internal dose and other factors besides mechanisms or modes of action; inter-individual variability and susceptibility in response are, in turn, key determinants of the population dose-response curve. New bioanalytical approaches (e.g., transcriptomics, proteomics, and metabolomics) applied in human, animal and in vitro studies could better characterize a wider array of hazard traits and improve the ability to predict the potential carcinogenicity of chemicals.

Antimicrobial susceptibility of Salmonella isolated from various products, from 1999 to 2003.

Foodborne salmonellosis continues to be a major health concern worldwide; thus, detection and tracking of antimicrobial resistance in Salmonella isolates is of interest. The U.S. Food and Drug Administration initiated antimicrobial sensitivity screening of Salmonella isolates from food and related samples in 1999. This paper summarizes the antimicrobial resistance data for Salmonella isolates obtained from 1999 to 2003. A total of 22,231 imported and domestic samples were analyzed for Salmonella, of which 1,319 (5.9%) yielded the pathogen. Since more than one culture was isolated from some samples, the total number of isolates obtained and tested for antimicrobial sensitivity was 1,382. Antimicrobial sensitivity screening was performed with the disc diffusion assay on 11 antimicrobial agents. Of the 1,108 food isolates screened, 42.1% (n = 467) were serotypes Weltevreden, Newport, Lexington, Senftenberg, Typhimurium, Saint Paul, Paratyphi, Enteritidis, Thompson, and Bareilly. A total of 249 (18.0%) isolates from all sources were resistant to two or more antimicrobials. Resistance to sulfisoxazole, streptomycin, and tetracycline was most common, whereas resistance to ciprofloxacin was least common. Weltevreden (n = 148) was the most common serotype isolated from food, but only nine (6.1%) of these isolates were resistant to two or more antimicrobials. In contrast, although Derby was recovered only 19 times, 11 (57.9 %) of these isolates were resistant to two or more antimicrobials. Of the 274 isolates from animal feed, dog treats and environmental swabs, 49.6% (n = 136) belonged to serotypes Infantis, Mbandaka, Anatum, Senftenberg, Typhimurium, Montevideo, Cerro, Enteritidis, and Bredeney, with 76 (27.7%) of these isolates resistant to two or more antimicrobials. Only limited trends in antimicrobial resistance were observed over time, with resistance to sulfisoxazole increasing, resistance to tetracycline decreasing, and resistance to streptomycin fluctuating.

The management of acardiac twins: a conservative approach.

OBJECTIVE: Optimal management of acardiac twin pregnancies is controversial. Data suggest a 50% mortality rate in the "pump" twin when the pregnancy is managed expectantly. Because of increased antenatal diagnosis, outcomes in expectantly managed cases may be better than reported. Our objective was to determine the outcome of expectantly managed acardiac twin pregnancies. STUDY DESIGN: All cases of antenatally diagnosed acardiac twins delivered in our community between 1994 and 2001 were ascertained. All were managed expectantly. Perinatal outcome of pump twins was the primary outcome variable. RESULTS: Ten cases were identified. Nine women were delivered of healthy pump twins. There was one neonatal death. The mean gestational age at delivery was 34.2 weeks. The mean weights of the pump and acardiac twins were 2279 g and 1372 g, respectively. CONCLUSION: Neonatal mortality of pump twins in antenatally diagnosed acardiac twin pregnancies may be considerably less than reported. Expectant management with close antepartum surveillance deserves consideration.