Group B streptococcus induces cellular senescence in human amnion epithelial cells through a partial interleukin-1-mediated mechanism.

Group B streptococcus (GBS) infection is a significant public health concern associated with adverse pregnancy complications and increased neonatal mortality and morbidity. However, the mechanisms underlying the impact of GBS on the fetal membrane, the first line of defense against pathogens, are not fully understood. Here, we propose that GBS induces senescence and inflammatory factors (IL-6 and IL-8) in the fetal membrane through interleukin-1 (IL-1). Utilizing the existing transcriptomic data on GBS-exposed human fetal membrane, we showed that GBS affects senescence-related pathways and genes. Next, we treated primary amnion epithelial cells with conditioned medium from the choriodecidual layer of human fetal membrane exposed to GBS (GBS collected choriodecidual [CD] conditioned medium) in the absence or presence of an IL-1 receptor antagonist (IL-1Ra). GBS CD conditioned medium significantly increased ß-galactosidase activity, IL-6 and IL-8 release from the amnion epithelial cells. Cotreatment with IL1Ra reduced GBS-induced ß-galactosidase activity and IL-6 and IL-8 secretion. Direct treatment with IL-1α or IL-1ß confirmed the role of IL-1 signaling in the regulation of senescence in the fetal membrane. We further showed that GBS CD conditioned medium and IL-1 decreased cell proliferation in amnion epithelial cells. In summary, for the first time, we demonstrate GBS-induced senescence in the fetal membrane and present evidence of IL-1 pathway signaling between the choriodecidua and amnion layer of fetal membrane in a paracrine manner. Further studies will be warranted to understand the pathogenesis of adverse pregnancy outcomes associated with GBS infection and develop therapeutic interventions to mitigate these complications.

Restless Legs Syndrome and Sleep-Wake Disturbances in Pregnancy.

STUDY OBJECTIVES: To estimate the association of restless legs syndrome (RLS) and its frequency with sleep-wake disturbances in pregnancy. METHODS: A cohort of 1,563 women in their third trimester of pregnancy were recruited from prenatal clinics between March 2007 and December 2010. Demographic, pregnancy, and delivery data were extracted from medical records and sleep information was collected with questionnaires. To diagnose RLS, we used standardized criteria of RLS symptoms and frequency that were developed by the International Restless Legs Study Group. Logistic regression models were constructed to investigate the association of RLS and its frequency with sleep-wake disturbances (poor sleep quality, daytime sleepiness, poor daytime function) and delivery outcomes. RESULTS: Overall 36% of the pregnant women had RLS, and half had moderate to severe symptoms. Compared to women without RLS, those with RLS were more likely to have poor sleep quality (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.7-2.9), poor daytime function (OR 1.9, 95% CI 1.4-2.4), and excessive daytime sleepiness (OR 1.6, 95% CI 1.3-2.0). A dose-response relationship also was evident between RLS frequency and each of the sleep-wake disturbances. There was no evidence for any association between RLS and delivery outcomes. CONCLUSIONS: RLS is a significant contributor to poor sleep quality, daytime sleepiness, and poor daytime function, all common and often debilitating conditions in pregnancy. Obstetric health care providers should be aware of these associations and screen women for RLS. COMMENTARY: A commentary on this article appears in this issue on page 857.

The trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine but not trichloroacetate inhibits pathogen-stimulated TNF-α in human extraplacental membranes in vitro.

Extraplacental membranes define the gestational compartment and provide a barrier to infectious microorganisms ascending the gravid female reproductive tract. We tested the hypothesis that bioactive metabolites of trichloroethylene (TCE) decrease pathogen-stimulated innate immune response of extraplacental membranes. Extraplacental membranes were cultured for 4, 8, and 24h with the TCE metabolites trichloroacetate (TCA) or S-(1,2-dichlorovinyl)-l-cysteine (DCVC) in the absence or presence of lipoteichoic acid (LTA) or lipopolysaccharide (LPS) to simulate infection. In addition, membranes were cocultured with DCVC and Group B Streptococcus (GBS). DCVC (5-50µM) significantly inhibited LTA-, LPS-, and GBS-stimulated cytokine release from tissue cultures as early as 4h (P≤0.05). In contrast, TCA (up to 500µM) did not inhibit LTA-stimulated cytokine release from tissue punches. Because cytokines are important mediators for host response to infectious microorganisms these findings suggest that TCE exposure could potentially modify susceptibility to infection during pregnancy.

Role of cytokine signaling in group B Streptococcus-stimulated expression of human beta defensin-2 in human extraplacental membranes.

PROBLEM: Group B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality. We tested the hypothesis that the choriodecidua plays a role in GBS-stimulated human beta defensin(HBD)-2 increases in amnion cells through a secreted factor of choriodecidual origin. METHOD OF STUDY: Human amnion epithelial cells were treated with choriodecidual GBS-conditioned medium, live GBS, lipoteichoic acid (LTA), or lipopolysaccharide (LPS), with and without IL-1 inhibitors. RESULTS: Choriodecidual tissue punches released IL-1α and IL-1ß in response to GBS and this medium significantly stimulated release of HBD-2 by amnion cell cultures. Inhibitors of IL-1 significantly impaired the release of HBD-2 from amnion cells treated with GBS choriodecidual conditioned medium. Direct stimulation of amnion cells with GBS, LTA, or LPS did not increase HBD-2 release. CONCLUSION: Paracrine signaling involving IL-1 of choriodecidual origin is likely a critical driver for amnion HBD-2 increases in response to GBS infection of extraplacental membranes.

Snoring during pregnancy and delivery outcomes: a cohort study.

STUDY OBJECTIVE: This cohort study examined the impact of maternal snoring on key delivery outcomes such as mode of delivery, infant birth centile, and small-for-gestational age. DESIGN: Cohort study. SETTING: A large tertiary medical center. PATIENTS OR PARTICIPANTS: Pregnant women in their third trimester were recruited between March 2007 and December 2010. MEASUREMENTS AND RESULTS: Women were screened for habitual snoring, as a known marker for sleep disordered breathing. Outcome data were obtained from medical records following delivery and birth centiles were calculated. Of 1,673 women, a total of 35% reported habitual snoring (26% with pregnancy-onset snoring and 9% with chronic snoring). After adjusting for confounders, chronic snoring was associated with small-forgestational age (OR 1.65, 95%CI 1.02-2.66, P = 0.041) and elective cesarean delivery (OR 2.25, 95%CI 1.22-4.18, P = 0.008). Pregnancy-onset snoring was associated with emergency cesarean delivery (OR 1.68, 95%CI 1.22-2.30, P = 0.001). CONCLUSION: Maternal snoring during pregnancy is a risk factor for adverse delivery outcomes including cesarean delivery and small-for-gestational age. Screening pregnant women for symptoms of SDB may provide an early opportunity to identify women at risk of poor delivery outcomes. CLINICAL TRIALS REGISTRATION: IDENTIFIER: NCT01030003.

Myomectomy during cesarean delivery.

BACKGROUND: The optimal management of leiomyomas during cesarean delivery is unclear. OBJECTIVES: To assess the safety of myomectomy performed during cesarean delivery. SEARCH STRATEGY: PubMed, MEDLINE, EMBASE, and Cochrane Library were searched to identify potentially relevant studies published prior to June 30, 2012. SELECTION CRITERIA: Case-control study comparing myomectomy with no myomectomy in patients undergoing cesarean delivery. DATA COLLECTION AND ANALYSIS: The quality of the studies was assessed and data were extracted independently by 2 authors. MAIN RESULTS: Nine studies, including 1 082 women with leiomyomas, met the inclusion criteria; 443 (41.0%) women underwent cesarean myomectomy and 639 (59.1%) underwent cesarean delivery alone. The drop in hemoglobin after surgery was 0.30 g/dL greater in the cesarean myomectomy group than in the control group, but the difference was not significant. The operative time was 4.94 minutes longer in the cesarean myomectomy group, but again the difference was not significant. The overall incidence of fever was comparable in the 2 groups. No hysterectomies were performed in any of the included studies. CONCLUSIONS: Cesarean myomectomy may be a reasonable option for some women with leiomyoma. However, no definite conclusion can be drawn because the data included in the meta-analysis were of low quality.

Pregnancy-onset habitual snoring, gestational hypertension, and preeclampsia: prospective cohort study.

OBJECTIVE: This study aimed to prospectively examine the impact of chronic vs pregnancy-onset habitual snoring on gestational hypertension, preeclampsia, and gestational diabetes. STUDY DESIGN: Third-trimester pregnant women were recruited from a large, tertiary medical center from March 2007 through December 2010 and screened for the presence and duration of habitual snoring, as a known marker for sleep-disordered breathing. Clinical diagnoses of gestational hypertension, preeclampsia, and gestational diabetes were obtained. RESULTS: Of 1719 pregnant women, 34% reported snoring, with 25% reporting pregnancy-onset snoring. After adjusting for confounders, pregnancy-onset, but not chronic, snoring was independently associated with gestational hypertension (odds ratio, 2.36; 95% confidence interval, 1.48-3.77; P < .001) and preeclampsia (odds ratio, 1.59; 95% confidence interval, 1.06-2.37; P = .024) but not gestational diabetes. CONCLUSION: New-onset snoring during pregnancy is a strong risk factor for gestational hypertension and preeclampsia. In view of the significant morbidity and health care costs associated with hypertensive diseases of pregnancy, simple screening of pregnant women may have clinical utility.

Validation of Watch-PAT-200 against polysomnography during pregnancy.

STUDY OBJECTIVES: To determine the relationships between key variables obtained from ambulatory polysomnography (PSG) and the wrist-worn Watch-PAT 200 device in pregnant women. METHODS: In this prospective cohort study, women in their third trimester of pregnancy underwent full overnight home PSG using the 22-channel MediPalm system and the Watch-PAT 200 device. PSGs were scored by a blinded, experienced technologist using AASM 2007 criteria; the Watch-PAT was scored automatically by the manufacturer's proprietary software. RESULTS: A total of 31 pregnant women were studied. Mean age was 30.2 ± 7.1 years; mean gestational age was 33.4 ± 3.0 weeks; mean BMI was 31.9 ± 8.1 kg/m(2); 39% of women were nulliparous. Key variables generated by PSG and Watch-PAT correlated well over a wide range, including the apnea-hypopnea index (AHI, r = 0.76, p < 0.001); respiratory disturbance index (RDI, r = 0.68, p < 0.001), mean oxygen saturation (r = 0.94, p < 0.001), and minimum oxygen saturation (r = 0.88, p < 0.001). The area under the curve for AHI ≥ 5 and RDI ≥ 10 were 0.96 and 0.94, respectively. Association between stage 3 sleep on PSG and deep sleep on Watch-PAT was poor. Watch-PAT tended to overscore RDI, particularly as severity increased. CONCLUSIONS: Among pregnant women, Watch-PAT demonstrates excellent sensitivity and specificity for identification of obstructive sleep apnea, defined as AHI ≥ 5 on full PSG. Watch-PAT may overestimate RDI somewhat, especially at high RDI values.

Tissue-specific induction of COX-2 and prostaglandins in lipopolysaccharide-stimulated extraplacental human gestational membranes in a 2-chamber transwell culture system.

The current study investigates tissue-specific prostaglandin secretion and cyclooxygenase 2 (COX-2) induction in full-thickness human gestational membranes. Gestational membranes were collected from healthy, nonlaboring cesarean deliveries at 37 to 39 weeks gestation and cultured in 2-chamber Transwell devices. Lipopolysaccharide exposure (100 ng/mL for 8 hours) elevated prostaglandin E(2) and F(2α) concentrations in the amniotic chamber medium regardless of whether exposure was to the amniotic, decidual, or both sides of the membranes. However, prostaglandin E(2) and F(2 α) concentrations in the decidual chamber medium were elevated compared with controls only if the decidual side was exposed directly to lipopolysaccharide. Whereas prostaglandin F(2α) concentrations increased to similar extents in the amniotic and decidual chambers regardless of lipopolysaccharide exposure modality, prostaglandin E(2) concentrations were 22-fold higher on the amniotic side than the decidual side after lipopolysaccharide stimulation of the amnion. These findings demonstrate the propagation of prostaglandins, prostaglandin precursors, or other factors in the direction of the decidua to the amnion, but the reverse situation was not evident. Immunostaining for COX-2 was related to the side of lipopolysaccharide exposure, that is, exposure to the amnion caused immunostaining in cells of the collagen layers of the amnion and chorion, whereas exposure to the decidual side caused staining in decidual cells. These findings suggest that the inflammatory effect of lipopolysaccharide on COX-2 induction occurs within a localized area of exposure and that prostaglandins or their precursors move across the tissues of the gestational membranes by currently undefined transport mechanisms.

National survey of obstetrician attitudes about timing the subsequent pregnancy after perinatal death.

OBJECTIVE: After stillbirth or early infant death, parents often query when they can try for another pregnancy. We conducted a national survey of US obstetricians to assess attitudes about optimal timing of next pregnancy and advice given to parents. STUDY DESIGN: The study was an anonymous mail survey of 1500 randomly selected US obstetricians asking about physician experiences with perinatal death. RESULTS: In all, 804 of 1500 obstetricians completed the survey for a 54% usable response rate. Two-thirds of respondents endorsed a waiting time <6 months for parents bereaved by stillbirth who desired another pregnancy. CONCLUSION: Physicians in this national survey supported very short interpregnancy intervals for parents bereaved by perinatal death. Responses may reflect efforts to support parents emotionally while recognizing individuals vary in coping and clinical circumstances. However, this is a provocative finding since short intervals may confer greater fetal risks for poor outcome.

Tissue-specific cytokine release from human extra-placental membranes stimulated by lipopolysaccharide in a two-compartment tissue culture system.

BACKGROUND: The extra-placental gestational membranes secrete cytokines in response to bacteria and other infectious agents, with potentially adverse consequences for pregnancy. The present study used lipopolysaccharide (LPS) as a prototype endotoxin to investigate the pattern of stimulated cytokine release from the amniotic and choriodecidual sides of full-thickness human gestational membranes in a two-compartment tissue culture system. METHODS: Gestational membranes were collected from healthy non-laboring caesarean deliveries at term. Full-thickness membranes from each placenta were cut into pieces, mounted on Transwell frames, and placed in culture wells to create a two-compartment culture with the gestational membranes serving as the barrier between compartments. The LPS (100 ng/ml) was added to the amniotic, choriodecidual or both chambers of the culture, and cytokines were assayed in the medium of the amniotic and choriodecidual chambers after 8 h of LPS exposure. Cytokine concentrations were analyzed by two-way analysis of variance for effects of treatment and side specificity of cytokine release from the membranes. RESULTS: LPS exposure on the choriodecidual side of the membranes significantly increased TNF-alpha, IL-6, IL-10 and IL-8 in the choriodecidual compartment, whereas TNF-alpha was the only cytokine observed to increase in the amniotic compartment. When LPS treatment was to the amniotic side of the membranes, there were significant increases in TNF-alpha and IL-6 in the amniotic compartment as well as increased concentrations of TNF-alpha, IL-6 and IL-8 in the choriodecidual compartment; however, there were no statistically significant differences for IL-10 in either compartment. No statistically significant differences were observed for IL-1beta, TGF-beta or IL-4 concentrations in response to LPS, regardless of the exposure modality. CONCLUSION: The amnion and choriodecidua exhibited distinct patterns of response to LPS with evidence of inflammatory signaling across the layers of the gestational membranes. These results suggest a complicated network of signaling within the gestational membranes, in which cytokine- and tissue-specific responses to inflammatory stimulation may have important implications for maintaining pregnancy in the challenge of microbial invasion of the uterine compartment.

Trauma during pregnancy: outcomes and clinical management.

Trauma affects up to 6% to 7% of all pregnancies, and accounts for up to 46% of maternal death. Adverse consequences such as preterm labor and delivery, abruptio, fetomaternal hemorrhage, and fetal demise may be seen with even apparently minor degrees of injury. Maternal physiologic considerations are reviewed and a protocol for evaluation and management of the injured gravida is presented.

Preventive counseling among women with histories of gestational diabetes mellitus.

OBJECTIVE: The purpose of this study was to examine the association between recall of recommendations for diabetes prevention and both health behaviors and screening among women with histories of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We surveyed 228 women with histories of GDM within the past 5 years who were enrolled in a university-affiliated managed care plan. In a cross-sectional analysis, we assessed the association between recall of health care provider advice and both postpartum lifestyle behaviors and reported performance of postpartum diabetes screening. Multivariate models were constructed that adjusted for correlates of counseling including postpartum diabetes, dyslipidemia, insulin use during pregnancy, and provider type. RESULTS: Participants were predominantly non-Hispanic white, college educated and affluent, and overweight or obese. The majority reported that they received counseling on lifestyle modification and postpartum diabetes screening. Postpartum physical activity levels, fruit and vegetable intake, and screening were suboptimal. No significant association existed between recall of advice and physical activity or between recall of advice and diet. Recall of advice along with distribution of laboratory slips for glucose testing was associated with performance of postpartum diabetes screening using self-report (adjusted odds ratio 2.07 [95% CI 1.51-2.84]) or claims data (1.64 [1.16-2.32]). CONCLUSIONS: Women with histories of GDM who recalled advice regarding postpartum glucose testing and received laboratory slips were significantly more likely to report having had postpartum diabetes screening. Although women's recall of services may not reflect the actual services received, simple counseling may not be sufficient to optimize postpartum behaviors to reduce future risk of diabetes.

Risk factors for the breakdown of perineal laceration repair after vaginal delivery.

OBJECTIVE: The purpose of this study was to identify risk factors that are associated with the breakdown of perineal laceration repair in the postpartum period. STUDY DESIGN: We conducted a retrospective, case-control study to review perineal laceration repair breakdown in patients who were delivered between September 1995 and February 2005 at the University of Michigan. Bivariate analysis with chi-square test and t-test and stepwise logistic regression analysis were performed. RESULTS: Fifty-nine cases and 118 control deliveries were identified from a total of 14,124 vaginal deliveries. Risk factors were longer second stage of labor (142 vs 87 minutes; P = .001), operative vaginal delivery (odds ratio, 3.6; 95% CI, 1.8-7.3), mediolateral episiotomy (odds ratio, 6.9; 95% CI, 2.6-18.7), third- or fourth-degree laceration (odds ratio, 3.1; 95% CI, 1.5-6.4), and meconium-stained amniotic fluid (odds ratio, 3.0; 95% CI, 1.1-7.9). Previous vaginal delivery was protective (odds ratio, 0.38; 95% CI, 0.18-0.84). Logistic regression showed the most significant factor to be an interaction between operative vaginal delivery and mediolateral episiotomy (odd ratio, 6.36; 95% CI, 2.18-18.57). CONCLUSION: The most significant events were mediolateral episiotomy, especially in conjunction with operative vaginal delivery, third- and fourth-degree lacerations, and meconium.

Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes.

Studying liver microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced or vehicle-treated (noninduced) mice, we evaluated the in vitro effects of added chemicals on the production of reactive oxygen due to substrate/P450-mediated uncoupling. The catalase-inhibited NADPH-dependent H(2)O(2) production (luminol assay) was lower in induced than noninduced microsomes. The effects of adding chemicals (2.5 microM) in vitro could be divided into three categories: Group 1, highly halogenated and coplanar compounds that increased H(2)O(2) production at least 5-fold in induced, but not in noninduced, microsomes; Group 2, non-coplanar halogenated biphenyls that did not affect H(2)O(2) production; Group 3, minimally halogenated biphenyls and benzo[a]pyrene that decreased H(2)O(2) production. Molar consumption of NADPH and O(2) and molar H(2)O(2) production (o-dianisidine oxidation) revealed that Group 1 compounds mostly increased, Group 2 had no effect, and Group 3 decreased the H(2)O(2)/O(2) and H(2)O(2)/NADPH ratios. Microsomal lipid peroxidation (thiobarbituric acid-reactive substances) was proportional to H(2)O(2) production. Although TCDD induction decreased microsomal production of H(2)O(2), addition of Group 1 compounds to TCDD-induced microsomes in vitro stimulated the second-electron reduction of cytochrome P450 and subsequent release of H(2)O(2) production. This pathway is likely to contribute to the oxidative stress response and associated toxicity produced by many of these environmental chemicals.

Subsequent pregnancy outcome in women with a history of HELLP syndrome at < or = 28 weeks of gestation.

OBJECTIVE: The purpose of this study was to describe subsequent pregnancy outcome in women with a history of hemolysis, elevated liver enzymes, and low platelet count syndrome for which delivery occurred at < or = 28 weeks of gestation during the index pregnancy. STUDY DESIGN: A descriptive report of women with previous hemolysis, elevated liver enzymes, and low platelet count syndrome who were delivered between August 1984 and July 1998 at the E.H. Crump Women's Hospital (Memphis, Tenn) and between March 1994 and July 1998 at the Central Baptist Hospital (Lexington, Ky). To have adequate time to study subsequent pregnancy outcome, only patients who were delivered >2 years before the analysis were included. Medical records of the index pregnancy and subsequent outcomes were available for review. RESULTS: Adequate follow-up data were available in 69 patients; the median duration of follow-up was 5 years (range: 2-14 years). There were 76 subsequent pregnancies among 48 women, of which 62 pregnancies (82%) progressed beyond 20 weeks of gestation. Preeclampsia developed in 34 of 62 subsequent pregnancies (55%). Recurrent hemolysis, elevated liver enzymes, and low platelet count syndrome developed in 4 of these pregnancies (6%), and abruptio placentae developed in 3 of these pregnancies (5%). There were no cases of eclampsia in our population. Delivery before 37 weeks of gestation occurred in 33 of the cases (53%), and 17 of the newborn infants (27%) were small for gestational age (<10th percentile). The perinatal mortality rate was 11%. CONCLUSION: Patients with a history of hemolysis, elevated liver enzymes, and low platelet count syndrome at < or = 28 weeks of gestation during the index pregnancy are at increased risk for obstetric complications in subsequent pregnancies. Overall, however, the rate of recurrent hemolysis, elevated liver enzymes, and low platelet count syndrome is only 6%.

Late postpartum eclampsia: a preventable disease?

OBJECTIVE: The purpose of this study was to determine whether there is a shift in the timing of eclampsia in relation to delivery and whether traditional symptoms precede impending postpartum eclampsia. STUDY DESIGN: A multicenter analysis of data from patients with eclampsia from March 1996 through February 2001 at the University of Cincinnati, the University of Tennessee, Memphis, and Central Baptist Hospital, Lexington. Data were collected regarding the relationship of the patient's first seizure to delivery, prodromal symptoms, neuroimaging studies, use of magnesium sulfate, antihypertensive therapy, and follow-up medical care. The analysis focused on women who had late postpartum eclampsia. RESULTS: During the study period, 89 patients were diagnosed with eclampsia. Twenty-nine women (33%) had postpartum eclampsia, of whom 23 women (79%) had late onset (>48 hours). Interestingly, only 5 of these 23 women (22%) had been previously diagnosed with preeclampsia. Twenty-one patients (91%) with late postpartum eclampsia had at least 1 prodromal symptom, and 12 patients (52%) had >1 symptom that heralded the seizure: 20 women (87%) had headache; 10 women (44%) had visual changes; 5 women (22%) had nausea or vomiting; and 2 women (9%) experienced epigastric pain. Only 7 of these 21 women (33%) sought care for their symptoms, of whom 6 women (86%) had clinical evidence of preeclampsia that was not considered by the treating physician. Among all patients with eclampsia, there were 7 cases of aspiration pneumonia, 3 cases of pulmonary edema, 3 cases of pleural effusion, 2 cases of disseminated intravascular coagulation, and no cases of maternal death. CONCLUSION: Current obstetric treatment in the United States has resulted in a shift of eclampsia toward the postpartum period, with most cases being seen as late post partum. To reduce the rate of late postpartum eclampsia, efforts should be directed to the education of the health care providers and patients regarding the importance of prompt reporting and evaluation of symptoms of preeclampsia during the postpartum period.