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.