Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.

OBJECTIVE: To investigate the involvement of the nuclear factor (NF)-kappaB in the interleukin (IL)-1 beta-mediated macrophage migration inhibitory factor (MIF) gene activation. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Nine women with endometriotic lesions. INTERVENTION(S): Endometriotic lesions were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): The MIF protein secretion was analyzed by ELISA, MIF mRNA expression by quantitative real-time polymerase chain reaction (PCR), NF-kappaB translocation into the nucleus by electrophoresis mobility shift assay, I kappaB phosphorylation and degradation by Western blot, and human MIF promoter activity by transient cell transfection. RESULT(S): This study showed a significant dose-dependent increase of MIF protein secretion and mRNA expression, the NF-kappaB translocation into the nucleus, I kappaB phosphorylation, I kappaB degradation, and human MIF promoter activity in endometriotic stromal cells in response to IL-1 beta. Curcumin (NF-kappaB inhibitor) significantly inhibited all these IL-1 beta-mediated effects. Analysis of the activity of deletion constructs of the human MIF promoter and a computer search localized two putative regulatory elements corresponding to NF-kappaB binding sites at positions -2538/-2528 bp and -1389/-1380 bp. CONCLUSION(S): This study suggests the involvement of the nuclear transcription factor NF-kappaB in MIF gene activation in ectopic endometrial cells in response to IL-1 beta and identifies a possible pathway of endometriosis-associated inflammation and ectopic cell growth.

Chlamydia: signes d'appel, diagnostic et traitement [Chlamydia: diagnostic and treatment].

Chlamydia are obligate intracellular bacteria. Three species are considered human pathogens. Chlamydophila pneumoniae is one of the most common agents of atypical community-acquired pneumonia. Chlamydophila psittaci causes psittacosis, a severe zoonotic pneumonia transmitted by birds. Finally, Chlamydia trachomatis is the etiologic agent of trachoma and urogenital infections. The latter are commonly asymptomatic or paucisymptomatic. Thus, they may remain undiagnosed for years, leading to serious late complications such as salpingitis, ectopic pregnancy and infertility. Currently, the diagnosis of chlamydial infections is essentially based on molecular methods. Treatment should use an antibiotic with good intracellular bioavailability such as tetracycline, macrolides and new generation fluoroquinolones.

Role of Chlamydia trachomatis and emerging Chlamydia-related bacteria in ectopic pregnancy in Vietnam.

In this case-control study, we investigated the seroprevalence and molecular evidence of Chlamydia trachomatis and Waddlia chondrophila in ectopic pregnancies (EP) and uneventful control pregnancies in 343 women from Vietnam. Whereas presence of C. trachomatis IgG was strongly associated with EP [adjusted odds ratio (aOR) 5·41, 95% confidence interval (CI) 2·58-11·32], its DNA remained undetected in all tubal lesions. We confirmed an independent association between antibodies against Waddlia and previous miscarriage (aOR 1·87, 95% CI 1·02-3·42). Further investigations are needed to understand the clinical significance of Waddlia's high seroprevalence (25·9% in control pregnancies) in this urban population.

Preliminary results of venlafaxine exposure in pregnancy, a multicenter prospective cohort ENTIS study

Introduction: Venlafaxine (Efexor®) is a serotonin and noradrenaline reuptake inhibitor (SNRI) used for the treatment of depression and anxiety disorders. The limited data on the use of venlafaxine in human pregnancy do not indicate an increased risk of congenital malformations. The main purpose of the study is to assess the rate of major malformations after first trimester exposure to venlafaxine. Methods: This multicenter, prospective cohort study was performed using data from nine centers who are member of the European Network of Teratology Information Services (ENTIS). Data on pregnancy and pregnancy outcome of women who used venlafaxine in pregnancy were collected during individual risk counseling. Standardized procedures for data collection and followup were used by each center. Results: Follow up data were collected on 744 pregnancies of womenwhoused venlafaxine during gestation. In 583 (78.4%) cases the exposure had occurred at least in the first trimester. In total, there were 600 live births (5 twins), 85 spontaneous abortions, 57 elective terminations of pregnancy, 5 fetal deaths, and 2 ectopic pregnancies. The overall rate of major malformations after first trimester exposure and excluding chromosomal and genetic disorders was 3.2% (16/500) in all pregnancies ending in delivery, pregnancy terminations or fetal deaths with fetal-pathological examination. Among live births the malformation rate was 2.7% (13/490). We observed no increased risk for organ specific malformations. Conclusions: The present study indicates that venlafaxine is not a major human teratogen.

Women's decision making and experience of subsequent pregnancy following stillbirth.

INTRODUCTION: This study sought to increase understanding of women's thoughts and feelings about decision making and the experience of subsequent pregnancy following stillbirth (intrauterine death after 24 weeks' gestation). METHODS: Eleven women were interviewed, 8 of whom were pregnant at the time of the interview. Modified grounded theory was used to guide the research methodology and to analyze the data. RESULTS: A model was developed to illustrate women's experiences of decision making in relation to subsequent pregnancy and of subsequent pregnancy itself. DISCUSSION: The results of the current study have significant implications for women who have experienced stillbirth and the health professionals who work with them. Based on the model, women may find it helpful to discuss their beliefs in relation to healing and health professionals to provide support with this in mind. Women and their partners may also benefit from explanations and support about the potentially conflicting emotions they may experience during this time.

Pregnancy Outcome Following Maternal Exposure To Statins: A Multicenter Prospective Study

Introduction: Statin use for the treatment of hypercholesterolemia in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of exposure to statins during pregnancy.Method: In a multi-center (n = 11) observational, prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fluvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). The data were collected by members of the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1990 and 2009. Standardized procedures for data collection were used in each center.Results: The difference in the rate of major birth defects between the statin-exposed group and the control group was not statistically significant (4.0% vs. 2.7% OR 1.5; 95% CI 0.5-4.5, P = 0.44). The crude rate of spontaneous abortions (12.8% vs. 7.1%, OR 1.9, 95% CI 1.0-3.6, P = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became statistically insignificant. The rate of elective pregnancy-termination (8.8% vs. 4.4%, P = 0.05) was higher and the rate of deliveries resulting in live births was significantly lower in the statin exposed group (77.9% vs. 88.4%, P = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% vs. 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 vs. 39 weeks, IQR 38-40, P = 0.27) and birth weight (median 3280 g, IQR 2835-3590 vs. 3250 g, IQR 2880-3600, P = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion: This study did not detect a clear teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy. At most, the results are reassuring in case of inadvertent exposure.

Pregnancy-related changes in activity energy expenditure and resting metabolic rate in Switzerland.

BACKGROUND/OBJECTIVES: To measure resting metabolic rate (RMR), activity energy expenditure (AEE), total energy expenditure (TEE) and physical activity pattern, that is, duration and intensity (in metabolic equivalents, METs) of activities performed in late pregnancy compared with postpartum in healthy, well-nourished women living in Switzerland. SUBJECTS/METHODS: Weight, height, RMR, AEE, TEE and physical activity patterns were measured longitudinally in 27 healthy women aged 23-40 years at 38.2+/-1.5 weeks of gestation and 40.0+/-7.2 weeks postpartum. RESULTS: The RMR during late pregnancy was 7480 kJ per day, that is, 1320+/-760 kJ per day (21.4%) higher than the postpartum RMR (P<0.001). Absolute changes in RMR were positively correlated with the corresponding changes in body weight (r=0.61, P<0.001). RMR per kg body weight was similar in late pregnancy vs postpartum (P=0.28). AEE per kg during pregnancy and postpartum was 40+/-13 and 50+/-20 kJ/kg, respectively (P=0.001). There were significant differences in daily time spent at METs<1.5 (1067 vs 998 min, P=0.045), at 2.5< or =METs <3.0 (58 vs 82 min, P=0.002) and METs> or =6 (1 vs 6 min, P=0.014) during pregnancy and postpartum, respectively. CONCLUSIONS: Energy expenditure in healthy women living in Switzerland increases in pregnancy compared with the postpartum state. Additional energy expenditure is primarily attributed to an increase in RMR, which is partly compensated by a decrease in AEE. The decrease in physical activity-related energy costs is achieved by selecting less demanding activities and should be taken into account when defining extra energy requirements for late pregnancy in Switzerland.

Médicaments et grossesse : modifications pharmacocinétiques et place du suivi thérapeutique pharmacologique [Pharmacokinetic Alterations in Pregnancy and Use of Therapeutic Drug Monitoring].

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Intracellular bacteria and adverse pregnancy outcomes.

Clin Microbiol Infect 2011; 17: 1312-1322 ABSTRACT: This review considers the role of intracellular bacteria in adverse pregnancy outcomes, such as miscarriage, stillbirths, and preterm labour. The cause of miscarriage, stillbirth and preterm labour often remains unexplained. Intracellular bacteria that grow either poorly or not at all on media used routinely to detect human pathogens could be the aetiological agents of these obstetric conditions. For example, Listeria monocytogenes and Coxiella burnetti are intracellular bacteria that have a predilection for the fetomaternal unit and may induce fatal disease in the mother and/or fetus. Both are important foodborne or zoonotic pathogens in pregnancy. Preventive measures, diagnostic tools and treatment will be reviewed. Moreover, we will also address the importance in adverse pregnancy outcomes of other intracellular bacteria, including Brucella abortus and various members of the order Chlamydiales. Indeed, there is growing evidence that Chlamydia trachomatis, Chlamydia abortus and Chlamydia pneumoniae infections may also result in adverse pregnancy outcomes in humans and/or animals. Moreover, newly discovered Chlamydia-like organisms have recently emerged as new pathogens of both animals and humans. For example, Waddlia chondrophila, a Chlamydia-related bacterium isolated from aborted bovine fetuses, has also been implicated in human miscarriages. Future research should help us to better understand the pathophysiology of adverse pregnancy outcomes caused by intracellular bacteria and to determine the precise mode of transmission of newly identified bacteria, such as Waddlia and Parachlamydia. These emerging pathogens may represent the tip of the iceberg of a large number of as yet unknown intracellular pathogenic agents.

Poumon et grossesse [Lung and pregnancy].

During pregnancy several adaptations develop in response to the enhanced maternal and fetal metabolic needs. This review summarizes the major cardiorespiratory modifications of pregnancy as well as their consequences in chronic respiratory diseases such as restrictive ventilatory defects (post-tuberculosis pneumonectomy, kyphoscoliosis, neuromuscular disorders), asthma, cystic fibrosis, and pulmonary hypertension. It is important to recognize early the cardiorespiratory situations for which pregnancy is contraindicated or associated with a high risk of respiratory complications. Clinical management by an expert and often pluridisciplinary team is recommended.

Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis.

Apoptosis is a highly controlled process, whose triggering is associated with the activation of caspases. Apoptosis can be induced via a subgroup of the tumor necrosis factor (TNF) receptor superfamily, which recruit and activate pro-caspase-8 and -10. Regulation of apoptosis is achieved by several inhibitors, including c-FLICE-inhibitory protein, which prevents apoptosis by inhibiting the pro-apoptotic activation of upstream caspases. Here we show that the human intracellular serine protease inhibitor (serpin), protease inhibitor 9 (PI9), inhibits TNF-, TNF-related apoptosis-inducing ligand- and Fas ligand-mediated apoptosis in certain TNF-sensitive cell lines. The reactive center P1 residue of PI9 was required for this inhibition since PI9 harboring a Glu --&gt; Ala mutation in its reactive center failed to impair death receptor-induced cell death. This suggests a classical serpin-protease interaction. Indeed, PI9 inhibited apoptotic death by directly interacting with the intermediate active forms of caspase-8 and -10. This indicates that PI9 can regulate pro-apoptotic apical caspases.

Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection.

To determine if gestational factors affect the severity of L. major infection, this study assessed the levels of IL-4 mRNA and IFN-gamma mRNA in popliteal lymph node cells of pregnant C57BL/6 mice mated at 5 hours, 16 hours and 15 days post L. major infection using PCR. Infected pregnant C57BL/6 mice developed larger cutaneous footpad lesions compared with non-pregnant infected C57BL/6 mice. The resolution of footpad lesions commenced after 8th week in C57BL/6 mice mated at 16 hrs post L. major infection but 12 weeks in C57BL/6 mice mated at 5 hrs and 15 days post L. major infection. C57BL/6 mice that were infected 20 days post partum resolved L. major infection effectively. But, the lesions in infected pregnant C57BL/6 mice and infected non-pregnant C57BL/6 mice were not as large as in susceptible BALB/c mice. The mean litter weights were similar in pregnant infected C57BL/6 mice mated at different stages of L. major infection but were slightly lower than weights of litters from pregnant uninfected C57BL/6 mice. In 5 days infected pregnant C57BL/6 mice, the levels of IFN-gamma were raised compared with the levels of IL-4 but those mated at 15 days post L. major infection had highest level of IFN-gamma mRNA. In 10 days pregnant infected C57BL/6 mice, levels of IL-4 were raised compared with IFN-gamma but mice mated at 16 hrs post L. major infection had highest level of IL-4. In 15 days pregnant infected mice, the levels of IL-4 were higher than IFN-gamma irrespective of the stage of L. major infection when the mice were mated. Mice infected with L. major 20 days post-partum produced more IFN-gamma than IL-4 from 16 hrs post L. major infection onwards. It may be concluded that increased IL-4 in pregnant infected C57BL/6 mice impairs the resistance of C57BL/6 mice to L. major infection especially in mice that were pregnant before effective immunity (5 hours post L. major infection) is mounted against L. major infection.

A dynamic assessment of medication-taking behavior during pregnancy and postpartum: should cART adherence be reinforced during postpartum?

This study compared adherence (persistence and execution) during pregnancy and postpartum in HIV-positive women having taken part in the adherence-enhancing program of the Community Pharmacy of the Department of Ambulatory Care and Community Medicine in Lausanne between 2004 and 2012. This interdisciplinary program combined electronic drug monitoring and semi-structured, repeated motivational interviews. This was a retrospective, observational study. Observation period spread over from first adherence visit after last menstruation until 6 months after childbirth. Medication-taking was recorded by electronic drug monitoring. Socio-demographic and delivery data were collected from Swiss HIV Cohort database. Adherence data, barriers and facilitators were collected from pharmacy database. Electronic data were reconciled with pill-count and interview notes in order to include reported pocket-doses. Execution was analyzed over 3-day periods by a mixed effect logistic model, separating time before and after childbirth. This model allowed us to estimate different time slopes for both periods and to show a sudden fall associated with childbirth. Twenty-five pregnant women were included. Median age was 29 (IQR: 26.5, 32.0), women were in majority black (n_17,68%) and took a cART combining protease and nucleoside reverse transcriptase inhibitors (n_24,96%). Eleven women (44%) were ART-naı¨ve at the beginning of pregnancy. Twenty women (80%) were included in the program because of pregnancy. Women were included at all stages of pregnancy. Six women (24%) stopped the program during pregnancy, 3 (12%) at delivery, 4 (16%) during postpartum and 12 (48%) stayed in program at the end of observation time. Median number of visits was 4 (3.0, 6.3) during pregnancy and 3 (0.8, 6.0) during postpartum. Execution was continuously high during pregnancy, low at beginning of postpartum and increased gradually during the 6 months of postpartum. Major barriers to adherence were medication adverse events and difficulties in daily routine. Facilitators were motivation for promoting child-health and social support. The dramatic drop and very slow increase in cART adherence during postpartum might result in viral rebound and drug resistance. Although much attention is devoted to pregnant women, interdisciplinary care should also be provided to women in the community during first trimester of postpartum to support them in sustaining cART adherence.

Pregnancy outcome following maternal exposure to Mirtazapine: Preliminary results of a collaborative ENTIS study.

Introduction: Mirtazapine is a noradrenergic and serotonergic antidepressant mainly acting through blockade of presynaptic alpha-2 receptors. Published data on pregnancy outcome after exposure to mirtazapine are scarce. This study addresses the risk associated with exposure to mirtazapine during pregnancy. Patients (or Materials) and Methods: Multicenter (n = 11), observational prospective cohort study comparing pregnancy outcomes after exposure to mirtazapine with 2 matched control groups: exposure to any selective serotonin reuptake inhibitor (SSRI) as a diseasematched control group, and general controls with no exposure to medication known to be teratogenic or to any antidepressant. Data were collected by members of the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1995 and 2011. Standardized procedures for data collection were used in each center. Results: A total of 357 pregnant women exposed to mirtazapine at any time during pregnancy were included in the study and compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; unadjusted odds ratio, 1.1; 95% confidence interval, 0.5-2.3, P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general controls did not reach statistical significance (4.2% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08). The crude rate of spontaneous abortions did not differ significantly between the mirtazapine, the SSRI, and the general control groups (9.5% vs 10.4% vs 8.4%; P = 0.67), neither did the rate of deliveries resulting in live births (79.6% vs 84.3% in both control groups; P = 0.15). However, a higher rate of elective pregnancy-termination was observed in the mirtazapine group compared with SSRI and general controls (7.8% vs 3.4% vs 5.6%; P = 0.03). Premature birth (< 37 weeks) (10.6% vs 10.1% vs 7.5%; P = 0.38), gestational age at birth (median, 39 weeks; interquartile range (IQR), 38-40 in all groups; P = 0.29), and birth weight (median, 3320 g; IQR, 2979-3636 vs 3230 g; IQR, 2910-3629 vs 3338 g; IQR, 2967-3650; P = 0.34) did not differ significantly between the groups. Conclusion: This study did not observe a statistically significant difference in the rate of major birth defects between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A slightly higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general controls. Overall, the pregnancy outcome after mirtazapine exposure in this study is very similar to that of the SSRI-exposed control group.