An examination of the relationship between maternal and neighborhood-level characteristics and intrauterine growth retardation in Harris County, Texas, 1999--2001

The persistence of low birth weight and intrauterine growth retardation (IUGR) in the United States has puzzled researchers for decades. Much of the work that has been conducted on adverse birth outcomes has focused on low birth weight in general and not on IUGR. Studies that have examined IUGR specifically thus far have focused primarily on individual-level maternal risk factors. These risk factors have only been able to explain a small portion of the variance in IUGR. Therefore, recent work has begun to focus on community-level risk factors in addition to the individual-level maternal characteristics. This study uses Social Ecology to examine the relationship of individual and community-level risk factors and IUGR. Logistic regression was used to establish an individual-level model based on 155, 856 births recorded in Harris County, TX during 1999-2001. IUGR was characterized using a fetal growth ratio method with race/ethnic and sex specific mean birth weights calculated from national vital records. The spatial distributions of 114,460 birth records spatially located within the City of Houston were examined using choropleth, probability and density maps. Census tracts with higher than expected rates of IUGR and high levels of neighborhood disadvantage were highlighted. Neighborhood disadvantage was constructed using socioeconomic variables from the 2000 U.S. Census. Factor analysis was used to create a unified single measure. Lastly, a random coefficients model was used to examine the relationship between varying levels of community disadvantage, given the set of individual-level risk factors for 152,997 birth records spatially located within Harris County, TX. Neighborhood disadvantage was measured using three different indices adapted from previous work. The findings show that pregnancy-induced hypertension, previous preterm infant, tobacco use and insufficient weight gain have the highest association with IUGR. Neighborhood disadvantage only slightly further increases the risk of IUGR (OR 1.12 to 1.23). Although community level disadvantage only helped to explain a small proportion of the variance of IUGR, it did have a significant impact. This finding suggests that community level risk factors should be included in future work with IUGR and that more work needs to be conducted. ^

Retrospective assesment of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and early endometrioid endometrial cancer

Objective: The primary objective of this project was to describe the efficacy of the Levonorgestrel Intrauterine Device (LIUD) for treatment of Complex Endometrial Cancer (CAH) and Grade 1 Endometrial Cancer (G1EEC) in terms of rate of Complete Response (CR) and Partial Response (PR) after 6 months of therapy. Finally, we assessed if any clinical or pathologic features were associated with response to the LIUD. ^ Methods: This study was a retrospective case series designed to report the response rate of patients with CAH or G1EEC treated with LIUD therapy. In addition, this study has a laboratory component to assess molecular predictors of response to LIUD therapy. Retrospective data already collected from patients diagnosed with CAH or EEC grade 1 and treated with LIUD therapy at MD Anderson Cancer Center (MDACC) were used for this study. Patients from all ethnic and race groups were included. A Complete Response (CR) was defined in patients diagnosed with CAH if pathologic report at 6 months demonstrated either no evidence of hyperplasia or no atypia in the setting of simple or complex hyperplasia. Partial Response (PR) was recorded if disease downgraded to only CAH from G1EEC. No Response (NR) was recorded if pathologic report demonstrates no change (Stable Disease, SD) or progression to cancer (Progressive Disease, PD). We calculated the proportion of patients with complete response to LIUD therapy with 95% confidence interval. We compared the response rates (CR/PR vs NR) by obesity status (Obese if BMI > 40 kg/m2 vs non-obese if BMI <= 40 kg/m2) as well as other clinical and pathologic factors, such as age, uterine size (median size), and presence of exogenous progesterone effect. ^ Results: There were 39 patients diagnosed with either CAH or G1EEC treated with the LIUD. Of 39 patients, 12 did not have pathological results of biopsy at 6months time period. Of 27 evaluable patients, 17 were diagnosed with CAH and 10 with G1EEC. Overall response rate (RR) was 78% (95% CI = 62-94%) at 6 months, 18 patients had CR (4 in G1EEC; 14 in CAH), 3 patients had PR (3 in G1EEC), 3 had SD (1 in CAH; 2 in G1EEC), 3 had PD (2 in CAH; 1 in G1EEC). After histology stratification, RR at 6 months was 82.35% (14/17; 95%CI = 67.4-97.3%) in CAH and 70% (7/10; 95% CI = 41-98.4%) in G1EEC. ^ There was no difference in response (R) and no response (NR) based on BMI (p=0.56). He observed a trend showing association between age with response (p=0.1). There was no association between uterine size and response to therapy (p=0.17). We recorded strong association between exogenous progesterone effect and response. ^ Conclusion: LIUD therapy for the treatment of CAH and G1EEC may be effective and safe. Presence of exogenous progesterone effect may predict the response to LIUD therapy at earlier time points. There is need of further studies with larger sample size to explore the relationship of response with other clinical and pathologic factors^

Sildenafil citrate modifies fetoplacental development in a rabbit model of intrauterine growth restriction

The failure of fetuses to achieve the ir full growth potential is known as intrauterine growth restriction (IUGR). Silde nafil citrate (SC) is a phosphodiesterase 5 (PDE 5) inhibitor, which enhances nitric oxide (NO) dependent vasodilatation, adn it may have a potential therapeutic role in the treatment of IUGR.

Hepatic IGF1 DNA methylation is influenced by gender but not by intrauterine growth restriction in the young lamb

Acknowledgements: The authors would like to thank Chaz Mein and Eva Wozniak at the Genome Centre, Queen Mary University of London, who were integral to the development of the DNA methylation assays and processing of samples. Financial Support: This work was supported by Wellbeing of Women (D.J.C., grant number RTF318) and the Scottish Government’s Rural and Environment Science and Analytical Services Division including the Strategic Partnership for Animal Science Excellence (J.M.W., R.P.A., J.S.M. and C.L.A.).

Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy

Objectives: To assess whether the levonorgestrel intrauterine system could provide a conservative alternative to hysterectomy in the treatment of excessive uterine bleeding.

Effects of exercise training on intrauterine growth restriction in an animal model

Résumé Selon l'OMS, la retard de croissance intra-utérine (RCIU; 10% en dessous du poids normal pendant la grossesse) affecte 5-10% des grossesses et est une cause principale de la morbidité et de la mortalité périnatales. Dans notre étude précédente sur un modèle de souris transgénique de prééclampsie (R+A+), nous avons constaté que l’entraînement physique (ExT) avant et pendant la grossesse réduisait la pression artérielle maternelle et empêchait la RCIU en améliorant le développement placentaire. Dans le cadre de mon projet, nous avons confirmé les bénifices de l’ExT dans un modèle de RCIU (souris déficiente en p57Kip2 (p57-/+). Ainsi, nous avons observé la présence de RCIU, d’une masse placentaire réduite, d’une augmentation de la pathologie placentaire ainsi qu’une plus petite taille des portées chez les souris p57-/+ sédentaire. L’ExT prévient la RCIU ainsi que tous les paramètres mentionnés ci-haut. Nous avons observé que l'expression du facteur de croissance de l’endothélium vasculaire, un régulateur clé de l'angiogenèse lors de la croissance placentaire, était réduite dans le placenta des souris p57-/+ et normalisée par l’ExT. Nous avons également trouvé que l'expression en ARN dans le placenta de 2 facteurs inflammatoires (interleukine-1β et MCP-1) était augmenté chez les souris sédentaires p57-/+ alors que ceci n’était pas présent chez les souris entraînées, ce qui suggère que l'inflammation placentaire peut contribuer à la pathologie placentaire. Toutefois, contrairement aux souris R+A+, le système rénine-angiotensine placentaire chez les souris p57-/+ était normale et aucun effet de l’ExT a été observé. Ces résultats suggèrent que l’ExT prévient la RCIU en normalisant la pathologie placentaire, l’angiogenèse et l’inflammation placentaire.

Ueber intrauterine Behandlung des chronischen Uteruskatarrhs.

Mode of access: Internet.

Pontosubicular apoptosis ("necrosis") in human neonates with intrauterine growth retardation and placental infarction

In a previous study of 37 autopsied stillbirths with non-dysmorphic intrauterine growth retardation ( IUGR), 26 cases were associated with placental infarction, a morphologic marker of uteroplacental insufficiency. Nine of the 26 cases with both IUGR and placental infarction, where archival tissue was available, had grey matter ischaemic lesions that were subsequently identified as pontosubicular necrosis. This lesion is now regarded as a localized form of apoptosis. A further eight third trimester stillbirth cases with both IUGR and placental infarction were ascertained prospectively. Sixteen of these 17 cases showed pontosubicular apoptosis, identified morphologically and verified using activated caspase-3 and TUNEL. Five of the 17 cases showed apoptosis in the frontal or temporal cortex as well. In this current study, pontosubicular apoptosis was strongly associated with IUGR and placental infarction in third trimester stillborns, suggesting that uteroplacental insufficiency leading to chronic fetal hypoxaemia may cause cerebral apoptosis.

Intrauterine growth restriction due to uteroplacental vascular insufficiency leads to increased hypoxia-induced cerebral apoptosis in newborn piglets

Uteroplacental vascular insufficiency in humans is a common cause of intrauterine growth restriction (IUGR) and is associated with an increased incidence of perinatal asphyxia and neurodevelopmental disorders compared to normal weight newborns. Experimental models that provide an opportunity to analyze the pathogenesis of these relationships are limited. Here, we used neonatal pigs from large litters in which there were piglets of normal birth weight (for controls) and of low birth weight (for uteroplacental vascular insufficiency). Hypoxia was induced in paired littermates by reducing the fraction of inspired oxygen to 4% for 25 min. Brain tissue was collected 4 h post-hypoxia. Cerebral levels of apoptosis were quantified morphologically and verified with caspase-3 activity and TUNEL. Expression of Bcl-2, BcI-XL and Bax proteins was investigated using immunohistochemistry. Cellular positivity for Bcl-2 was consistently higher in the non-apoptotic white matter of the hypoxic IUGR animals compared with their littermates and reached significance at P < 0.05 in several pairs of littermates. Alterations in Bax showed a trend towards higher expression in the hypoxic IUGR littermates but rarely reached significance. The IUGR piglets showed a significantly greater amount of apoptosis in response to the hypoxia than the normal weight piglets, suggesting an increased vulnerability to apoptosis in the IUGR piglets. (c) 2006 Elsevier B.V. All rights reserved.

Levonorgestrel intrauterine system versus medical therapy for menorrhagia

Background - Menorrhagia is a common problem, yet evidence to inform decisions about therapy is limited. In a pragmatic, multicenter, randomized trial, we compared the levonorgestrel-releasing intrauterine system (levonorgestrel-IUS) with usual medical treatment in women with menorrhagia who presented to their primary care providers. Methods - We randomly assigned 571 women with menorrhagia to treatment with levonorgestrel-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined estrogen–progestogen, or progesterone alone). The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) (ranging from 0 to 100, with lower scores indicating greater severity), assessed over a 2-year period. Secondary outcomes included general quality-of-life and sexual-activity scores and surgical intervention. Results - MMAS scores improved from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group (mean increase, 32.7 and 21.4 points, respectively; P<0.001 for both comparisons). The improvements were maintained over a 2-year period but were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9 to 16.9; P<0.001). Improvements in all MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health) were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group, and this was also true for seven of the eight quality-of-life domains. At 2 years, more of the women were still using the levonorgestrel-IUS than were undergoing the usual medical treatment (64% vs. 38%, P<0.001). There were no significant between-group differences in the rates of surgical intervention or sexual-activity scores. There were no significant differences in serious adverse events between groups. Conclusions - In women with menorrhagia who presented to primary care providers, the levonorgestrel-IUS was more effective than usual medical treatment in reducing the effect of heavy menstrual bleeding on quality of life. (Funded by the National Institute of Health Research Health Technology Assessment Programme; ECLIPSE Controlled-Trials.com number, ISRCTN86566246.)

Levonorgestrel intrauterine system versus medical therapy for menorrhagia

ABSTRACT: Menorrhagia is a common problem that interferes with a woman’s physical, emotional, and social life. Evidence to guide physicians for decision about therapy for heavy menstrual bleeding is lacking. One treatment option, the levonorgestrel-releasing intrauterine system (levonorgestrel-IUS), has been available in the United States since 2009. Updated meta-analyses comparing the levonorgestrel-IUS with nonhormonal and hormonal treatments showed that the levonorgestrel-IUS produced a greater reduction in menstrual blood loss at 3 to 12 months of follow-up. It is not clear whether these short-term benefits persist. Moreover, the rates of discontinuation of the levonorgestrel-IUS at 2 years are as high as 28%, and effects on bleeding-related quality of life are not known. This pragmatic, multicenter, randomized trial compared the effectiveness of the levonorgestrel-IUS with that of usual medical treatment among women with menorrhagia in a primary care setting. A total of 571 women with menorrhagia were randomized to treatment with levonorgestrel-IUS (n = 285) or usual medical treatment (n = 286). Usual treatment was tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progesterone alone. The primary study outcome measure was the patient-reported score on the condition-specific Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period. The MMAS scores range from 0 to 100, with lower scores indicating greater severity. Summary MMAS scores were assessed at 6, 12, and 24 months. Secondary outcome measures included general health-related quality of life, sexual-activity scores, and surgical intervention. There was a significant improvement in total MMAS scores from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group; the mean increase was 32.7 and 21.4 points, respectively; P < 0.001 for both comparisons. Over the 2-year follow-up, improvements were maintained in both groups but were significantly greater in the levonorgestrel-IUS group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9–16.9; P < 0.001). Significantly greater improvements in all MMAS domains (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships) occurred with the levonorgestrel-IUS than with the usual treatment (P < 0.001 with the use of a test for trend). This was also found for 7 of the 8 quality-of-life domains. At the 2-year end point, almost twice as many women were still using the levonorgestrel-IUS than were those receiving the usual medical treatment (64% vs 38%, P < 0.001). No significant between-group differences were noted in the rates of surgical intervention or sexual-activity scores as well as in the frequency of serious adverse events. These data show that levonorgestrel-IUS is more effective than usual medical treatment in improving the quality of life of women with menorrhagia in a primary care setting.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia:the ECLIPSE trial

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

Randomised trial of levonorgestrel intrauterine system compared to usual medical treatment for heavy menstrual bleeding:the ECLIPSE Trial

Objective: Heavy menstrual bleeding (menorrhagia) is a common problem, yet evidence is limited to inform therapeutic decisions.We compared the levonorgestrel-releasing intrauterine system(LNG-IUS) to usual medical treatment in a pragmatic randomised trial in primary care. Methods: We randomly assigned 571 women consulting their primary care providers with menorrhagia to LNG-IUS or to usual medical treatment as clinically appropriate (tranexamic acid, mefenamic acid, combined estrogen/progestogen or progestogen only). The primary outcome was a patient-reported measure ofimpact of menorrhagia, the validated Menorrhagia Multi-Attribute Scale (MMAS), assessed over 2 years. Secondary measures included generic quality of life (SF-36), sexual activity and surgical intervention.Results MMAS scores improved from baseline in both the LNG-IUS and usual medical treatment groups by 6 months (mean increases 32.7 points versus 21.4 points, respectively; P < 0.001for both) and were maintained over 2 years, but improvements were significantly greater with LNG-IUS (mean between-group difference 13.4 points, 95%CI, 9.9–16.9; P < 0.001).All domains of MMAS (practical difficulties, social life, family life,work/daily routine, psychological well being and physical health)improved significantly more with LNG-IUS, as were seven of the eight domains of SF-36. More women were still using LNG-IUSthan usual medical treatment at 2 years (64% versus 38%,P < 0.001). There were no significant between-group differences in surgical intervention rates or sexual activity scores. There were no serious adverse events in either group.Conclusions Among women presenting to primary care providers with menorrhagia, LNG-IUS was more effective than usual medical treatment at reducing the impact of this problem on their quality of life. In practice therefore, conventional treatments, such as tranexamic and mefenamic acid, remain helpful choices in women for whom LNG-IUS is considered unsuitable, or due to individual preference. For other women, LNG-IUS can be confidently recommended as an effective initial medical therapy for menorrhagia. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 02/06/02)

Effects of exercise training on intrauterine growth restriction in an animal model

Résumé Selon l'OMS, la retard de croissance intra-utérine (RCIU; 10% en dessous du poids normal pendant la grossesse) affecte 5-10% des grossesses et est une cause principale de la morbidité et de la mortalité périnatales. Dans notre étude précédente sur un modèle de souris transgénique de prééclampsie (R+A+), nous avons constaté que l’entraînement physique (ExT) avant et pendant la grossesse réduisait la pression artérielle maternelle et empêchait la RCIU en améliorant le développement placentaire. Dans le cadre de mon projet, nous avons confirmé les bénifices de l’ExT dans un modèle de RCIU (souris déficiente en p57Kip2 (p57-/+). Ainsi, nous avons observé la présence de RCIU, d’une masse placentaire réduite, d’une augmentation de la pathologie placentaire ainsi qu’une plus petite taille des portées chez les souris p57-/+ sédentaire. L’ExT prévient la RCIU ainsi que tous les paramètres mentionnés ci-haut. Nous avons observé que l'expression du facteur de croissance de l’endothélium vasculaire, un régulateur clé de l'angiogenèse lors de la croissance placentaire, était réduite dans le placenta des souris p57-/+ et normalisée par l’ExT. Nous avons également trouvé que l'expression en ARN dans le placenta de 2 facteurs inflammatoires (interleukine-1β et MCP-1) était augmenté chez les souris sédentaires p57-/+ alors que ceci n’était pas présent chez les souris entraînées, ce qui suggère que l'inflammation placentaire peut contribuer à la pathologie placentaire. Toutefois, contrairement aux souris R+A+, le système rénine-angiotensine placentaire chez les souris p57-/+ était normale et aucun effet de l’ExT a été observé. Ces résultats suggèrent que l’ExT prévient la RCIU en normalisant la pathologie placentaire, l’angiogenèse et l’inflammation placentaire.

Ureaplasma colonization of amniotic fluid and efficacy of antenatal corticosteroids for preterm lung maturation in sheep

Objective: To assess the efficacy of maternal betamethasone for improving preterm lung function, in the presence of inflammation induced by amniotic fluid ureaplasma colonization. ----- ----- Study design: Ewes bearing single fetuses were randomized to receive an intra-amniotic injection of Ureaplasma parvum (serovar 6; 2×107 colony forming units) or vehicle at 86±2 days of pregnancy (mean±SD: term is 150d), followed by maternal intramuscular betamethasone (0.5mg/kg) or saline, either 2 or 7 days before delivery of lambs at 123±1d. ----- ----- Results: Amniotic fluid IL-8 was elevated by ureaplasmas (p=0.049) but unaffected by betamethasone. Lung inflammation induced by ureaplasmas was not affected by betamethasone. Lung compliance was increased by ureaplasma colonization (p=0.009) and betamethasone (p=0.042), and effects were additive. Lung surfactant was increased by ureaplasma colonization (p<0.001) and betamethasone 7 days (p=0.001), but not 2 days, before delivery. ----- ----- Conclusion: Inflammation improves preterm lung function due to increases in surfactant. Antenatal corticosteroids further augment lung function, through an apparently independent mechanism.