Vitamins E and C FAIL to prevent prostate and other cancer

Vitamins E and C FAIL to prevent prostate and other cancers in men: the Physicians’ Health Study II randomized controlled trial.

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JAMA. 2009 Jan 7;301(1):52-62. Epub 2008 Dec 9.

Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial.

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    J Matern Fetal Neonatal Med. 2010 Sep;23(9):1004-8.

    Diabetes mellitus and the risk of preterm birth with regard to the risk of spontaneous preterm birth.

    Köck K, Köck F, Klein K, Bancher-Todesca D, Helmer H.

    Department of Obstetrics and Feto-Maternal Medicine, University of Vienna General Hospital, Austria.


    INTRODUCTION: It is internationally agreed that diabetes mellitus (DM) is associated with increased maternal and fetal morbidity and long-term complications. To avoid these complications, it is often necessary to induce birth before term. The impact of DM on spontaneous preterm birth (spontaneous labor, preterm premature rupture of membranes and/or cervical incompetence resulting in delivery before the completion of 37 gestation weeks) is still unexplained. Preterm birth accounts for the most neonatal deaths and infant morbidities, and therefore it still remains one of the biggest challenges in obstetrics.

    OBJECTIVE: Our study determined if there is an increasing tendency towards spontaneous preterm birth in mothers with gestational and preexisting DM.

    METHODS: In this retrospective cohort study, 187 pregnant women with gestational DM and preexisting DM were compared to a randomized control group consisting of 192 normoglycemic women concerning gestational age and perinatal outcome. Data were collected by the Medical University of Vienna. Multiple pregnancies and women with severe maternal diseases, such as preeclampsia, were excluded.

    RESULTS: Women with DM tended significantly more often to preterm births (P = 0.002). A significant difference in the incidence of spontaneous preterm birth was found (P = 0.047).

    CONCLUSION: DM affects the length of gestation and incidence of spontaneous preterm birth.

    PMID: 20059440 [PubMed – in process]

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    Obstet Gynecol. 2010 Sep;116(3):653-8.

    Vitamin C and e supplementation to prevent spontaneous preterm birth: a randomized controlled trial.

    Hauth JC, Clifton RG, Roberts JM, Spong CY, Myatt L, Leveno KJ, Pearson GD, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y, Anderson GB; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU).

    Departments of Obstetrics and Gynecology at the University of Alabama at Birmingham, Birmingham, Alabama, USA.


    OBJECTIVE: To estimate whether maternally administered vitamins C and E lower the risk of spontaneous preterm birth.

    METHODS: This is a secondary analysis of a randomized, double-masked, placebo-controlled trial in nulliparous women at low-risk administered 1,000 mg vitamin C and 400 international units vitamin E or placebo daily from 9 to 16 weeks of gestation until delivery. Outcomes include preterm birth attributable to premature rupture of membranes (PROM) and total spontaneous preterm births (spontaneous preterm birth attributable to PROM or spontaneous labor).

    RESULTS: Of the 10,154 women randomized, outcome data were available for 9,968 (4,992 vitamin group and 4,976 placebo group). A total of 1,038 women (10.4%) delivered preterm, of whom 698 (7.0%) had spontaneous preterm birth. A spontaneous preterm birth occurred in 356 women (7.1%) assigned to daily vitamin C and E supplementation and in 342 (6.9%) assigned to placebo. There were 253 women (2.5%) who delivered after preterm PROM and 445 (4.5%) after a spontaneous preterm labor. In women supplemented with vitamins C and E, births attributed to preterm PROM were similar at less than 37 and 35 weeks of gestation, but births were less frequent before 32 weeks of gestation (0.3% compared with 0.6%, adjusted odds ratio 0.3-0.9). However, total spontaneous preterm births across gestation in women supplemented with vitamins C and E or a placebo were similar.

    CONCLUSION: Maternal supplementation with vitamins C and E beginning at 9 to 16 weeks of gestation in nulliparous women at low risk did not reduce spontaneous preterm births.



    PMID: 20733448 [PubMed – in process]

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    Lancet. 2010 Jul 24;376(9737):259-66. Epub 2010 Jun 26.

    Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial.

    McCance DR, Holmes VA, Maresh MJ, Patterson CC, Walker JD, Pearson DW, Young IS; Diabetes and Pre-eclampsia Intervention Trial (DAPIT) Study Group.

    Collaborators (85)

    McErlean L, Pearson DW, Cameron EA, Crombie MH, Leese G, Hamilton BA, MacLeod A, Walker JD, Alexander C, Patrick AW, Love C, Strachan MW, Lindsay R, Lunan CB, Mackenzie F, Paterson K, Cameron AD, Small M, Gallagher AP, Gibson J, Pringle S, McLellan D, McKenna K, MacPherson HD, Holmes P, Buchanan L, Kelly C, Allcoat P, Urquhart R, Hooper S, Dunne F, Gee H, Basu A, Milles J, Balachandar C, Longworth H, Walkinshaw S, Casson I, Marshall J, Maresh MJ, Young R, Corry C, Donnelly UG, King OM, Langan AT, Loughridge S, Moles K, Kennedy A, Ritchie K, McCance DR, Tharma S, Traub AI, Harper R, Clark M, Szczepura A, Patterson CC, Hill A, Halliday H, McFarland M, Holmes VA, King OM, Loughridge S, McCance DR, Young IS, Krueger H, Mercer C, McGonigle L, McKeeman GC, McMaster C, Woodside JV, Young IS, McGinty A, Pogue K, Johnston P, Gilchrist SE, Allen I, Holmes VA, Maresh MJ, McCance DR, Pearson DW, Walker JD, Young IS, Elbourne D, Fraser RB, Hey E.

    Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK.

    Comment in:


    BACKGROUND: Results of several trials of antioxidant use during pregnancy have not shown a reduction in pre-eclampsia, but the effect in women with diabetes is unknown. We aimed to assess whether supplementation with vitamins C and E reduced incidence of pre-eclampsia in women with type 1 diabetes.

    METHODS: We enrolled women from 25 UK antenatal metabolic clinics in a multicentre randomised placebo-controlled trial. Eligibility criteria were type 1 diabetes preceding pregnancy, presentation between 8 weeks’ and 22 weeks’ gestation, singleton pregnancy, and age 16 years or older. Women were randomly allocated in a 1:1 ratio to receive 1000 mg vitamin C and 400 IU vitamin E (alpha-tocopherol) or matched placebo daily until delivery. The randomisation sequence was stratified by centre with balanced blocks of eight patients. All trial personnel and participants were masked to treatment allocation. The primary endpoint was pre-eclampsia, which we defined as gestational hypertension with proteinuria. Analysis was by modified intention to treat. This study is registered, ISRCTN27214045.

    FINDINGS: Between April, 2003, and June, 2008, 762 women were randomly allocated to treatment groups (379 vitamin supplementation, 383 placebo). The primary endpoint was assessed for 375 women allocated to receive vitamins, and 374 allocated to placebo. Rates of pre-eclampsia did not differ between vitamin (15%, n=57) and placebo (19%, 70) groups (risk ratio 0.81, 95% CI 0.59-1.12). No adverse maternal or neonatal outcomes were reported.

    INTERPRETATION: Supplementation with vitamins C and E did not reduce risk of pre-eclampsia in women with type 1 diabetes. However, the possibility that vitamin supplementation might be beneficial in women with a low antioxidant status at baseline needs further testing.

    FUNDING: The Wellcome Trust.

    PMID: 20580423 [PubMed – indexed for MEDLINE]PMCID: PMC2911677Free PMC Article

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    Reprod Sci. 2010 Jul;17(7):685-95.

    The impact of vitamin C supplementation in pregnancy and in vitro upon fetal membrane strength and remodeling.

    Mercer BM, Abdelrahim A, Moore RM, Novak J, Kumar D, Mansour JM, Perez-Fournier M, Milluzzi CJ, Moore JJ.

    From the Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44109, USA.


    Generation of reactive oxygen species (ROS) has been suggested as a mechanism of fetal membrane (FM) weakening leading to rupture, particularly with preterm premature rupture of the fetal membranes (PROM). In vitro, FM incubation with tumor necrosis factor (TNF) mimics physiological FM weakening, concomitant with generation of ROS and collagen remodeling. Proinflammatory cytokines are also postulated to have a role in the development of the FM physiological weak zone where rupture normally initiates in-term gestations. We hypothesized that antioxidant treatment may block ROS development and resultant FM weakening. Two studies examining antioxidant effects upon FM strength were conducted, one in vivo and the other in vitro. Fetal membrane of patients enrolled in a multicenter placebo-controlled trial to determine the effect of vitamin C (1 g/day) and vitamin E (400 IU/day) upon complications of pre-eclampsia were examined for FM biomechanical properties and biochemical remodeling at birth. Separately, biomechanics and biochemical markers of remodeling were determined in FM fragments incubated with TNF with or without vitamin C preincubation. Supplemental dietary vitamin C in combination with vitamin E did not modify rupture strength, work to rupture, or matrix metalloproteinase-9 (MMP9; protein or activity) either within or outside the term FM physiological weak zone. In vitro, TNF decreased FM rupture strength by 50% while increasing MMP9 protein. Vitamin C did not inhibit these TNF-induced effects. Vitamin C alone had a weakening effect on FM in vitro. We speculate that vitamin C supplementation during pregnancy will not be useful in the prevention of preterm PROM.

    PMID: 20581351 [PubMed – in process]PMCID: PMC2930608 [Available on 2011/1/1]

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    Obstet Gynecol. 2010 Jun;115(6):1125-33.

    Inherited predisposition to spontaneous preterm delivery.

    Bhattacharya S, Raja EA, Mirazo ER, Campbell DM, Lee AJ, Norman JE, Bhattacharya S.

    Section of Population Health, University of Aberdeen, Dugald Baird Centre for Research on Women’s Health, Aberdeen Maternity Hospital, Aberdeen, United Kingdom AB25 2ZL.

    Comment in:


    OBJECTIVE: To assess inherited predisposition to spontaneous preterm delivery.

    METHODS: In this retrospective cohort study, intergenerational data on deliveries in mother-daughter pairs were analyzed from the Aberdeen Maternity Neonatal Databank using multilevel logistic regression. The study included an exposed cohort of all women born spontaneously preterm or whose mothers had experienced at least one spontaneous preterm delivery (at 24-37 weeks of gestation). The unexposed cohort included women who were born at term (after 37 weeks of gestation) or those whose mothers had never experienced any spontaneous preterm deliveries (24-37 weeks of gestation). The primary outcome was spontaneous preterm delivery in the daughters’ pregnancies. Results are shown as adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

    RESULTS: We identified 22,343 pregnancies occurring in 13,845 daughters born to 11,576 mothers. Women who were born spontaneously preterm had significantly higher odds of delivering preterm babies (OR 1.49, 95% CI 1.12-1.99). A stronger association was seen when the analysis was restricted to nulliparous women who had been born spontaneously preterm (OR 1.60, 95% CI 1.16-2.21). Other predictors of a woman having a spontaneous preterm delivery were age at delivery younger than 20 years (OR 1.67, 95% CI 1.43-1.94), lower socioeconomic status (OR 1.22, 95% CI 1.04-1.44), smoking more than 10 cigarettes per day (OR 1.47, 95% CI 1.27-1.71), body mass index 19 kg/m or less (OR 1.48, 95% CI 1.24-1.77), previous preterm delivery (OR 2.51, 95% CI 1.71-3.66). The risk of a woman delivering spontaneously preterm was increased even if her mother had a history of spontaneous preterm delivery in any other pregnancy (OR 1.35, 95% CI 1.12-1.63). The absolute risk of spontaneously delivering preterm in women who were born preterm was 9% as opposed to 6.2% in those who were born full-term. This gives an increase in risk of spontaneous preterm birth of 2.8% in women who were born spontaneously preterm.

    CONCLUSION: Women born spontaneously preterm or with siblings delivered in a similar manner have an increased risk of spontaneous preterm delivery in their own pregnancies.


    PMID: 20502281 [PubMed – indexed for MEDLINE]

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    Lancet. 2010 May 8;375(9726):1640-9.

    Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial.

    Kirkwood BR, Hurt L, Amenga-Etego S, Tawiah C, Zandoh C, Danso S, Hurt C, Edmond K, Hill Z, Ten Asbroek G, Fenty J, Owusu-Agyei S, Campbell O, Arthur P; ObaapaVitA Trial Team.

    Collaborators (24)

    Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    Comment in:


    BACKGROUND: A previous trial in Nepal showed that supplementation with vitamin A or its precursor (betacarotene) in women of reproductive age reduced pregnancy-related mortality by 44% (95% CI 16-63). We assessed the effect of vitamin A supplementation in women in Ghana.

    METHODS: ObaapaVitA was a cluster-randomised, double-blind, placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana. The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters. All women of reproductive age (15-45 years) who gave informed consent and who planned to remain in the area for at least 3 months were recruited. Participants were randomly assigned by cluster of residence to receive a vitamin A supplement (25 000 IU retinol equivalents) or placebo capsule orally once every week. Randomisation was blocked and based on an independent, computer-generated list of numbers, with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo. Capsules were distributed during home visits undertaken every 4 weeks, when data were gathered on pregnancies, births, and deaths. Primary outcomes were pregnancy-related mortality and all-cause female mortality. Cause of death was established by verbal post mortems. Analysis was by intention to treat (ITT) with random-effects regression to account for the cluster-randomised design. Adverse events were synonymous with the trial outcomes. This trial is registered with, number NCT00211341.

    FINDINGS: 544 clusters (104 484 women) were randomly assigned to vitamin A supplementation and 542 clusters (103 297 women) were assigned to placebo. The main reason for participant drop out was migration out of the study area. In the ITT analysis, there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group (348 deaths per 100 000 pregnancies) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group (377 per 100 000 pregnancies); adjusted odds ratio 0.92, 95% CI 0.73-1.17; p=0.51. 1326 women died in 292 560 woman-years in the vitamin A supplementation group (453 deaths per 100 000 years) compared with 1298 deaths in 289 310 woman-years in the placebo group (449 per 100 000 years); adjusted rate ratio 1.01, 0.93-1.09; p=0.85.

    INTERPRETATION: The body of evidence, although limited, does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies.

    FUNDING: UK Department for International Development, and USAID.

    PMID: 20435345 [PubMed – indexed for MEDLINE]

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    N Engl J Med. 2010 Apr 8;362(14):1282-91.

    Vitamins C and E to prevent complications of pregnancy-associated hypertension.

    Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, Pearson GD, Wapner RJ, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Smith WJ, Saade G, Sorokin Y, Anderson GB; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

    Collaborators (87)

    Caritis S, Kamon T, Cotroneo M, Fischer D, Reed P, Quinn S, Morby V, Porter F, Silver R, Miller J, Hill K, Rouse DJ, Northen A, Files P, Grant J, Wallace M, Bailey K, Bousleiman S, Alcon R, Saravia K, Loffredo F, Bayless A, Perez C, Lake M, Talucci M, Boggess K, Dorman K, Mitchell J, Clark K, Timlin S, Bailit J, Milluzzi C, Dalton W, Brezine C, Bazzo D, Sheffield J, Moseley L, Santillan M, Buentipo K, Price J, Sherman L, Melton C, Gloria-McCutchen Y, Espino B, Dinsmoor M, Matson-Manning T, Mallett G, Blackwell S, Cannon K, Lege-Humbert S, Spears Z, Tillinghast J, Seebeck M, Johnson F, Fyffe S, Latimer C, Frantz S, Wylie S, Talucci M, Hoffman M, Benson J, Reid Z, Tocci C, Meis P, Swain M, Davis L, Lairson E, Butcher S, Maxwell S, Fisher D, Moss J, Stratton B, Hankins G, Brandon J, Nelson-Becker C, Norman G, Blackwell S, Lockhart P, Driscoll D, Dombrowski M, Clifton R, Boekhoudt T, Leuchtenburg L, Pemberton V, Cutler J, Barouch W, Tolivaisa S.

    Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, USA.


    BACKGROUND: Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of preeclampsia with the clinical manifestations of the disorder. We assessed the effects of antioxidant supplementation with vitamins C and E, initiated early in pregnancy, on the risk of serious adverse maternal, fetal, and neonatal outcomes related to pregnancy-associated hypertension.

    METHODS: We conducted a multicenter, randomized, double-blind trial involving nulliparous women who were at low risk for preeclampsia. Women were randomly assigned to begin daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy. The primary outcome was severe pregnancy-associated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or perinatal death.

    RESULTS: A total of 10,154 women underwent randomization. The two groups were similar with respect to baseline characteristics and adherence to the study drug. Outcome data were available for 9969 women. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk in the vitamin group, 1.07; 95% confidence interval [CI], 0.91 to 1.25) or in the rates of preeclampsia (7.2% and 6.7%, respectively; relative risk, 1.07; 95% CI, 0.93 to 1.24). Rates of adverse perinatal outcomes did not differ significantly between the groups.

    CONCLUSIONS: Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk, nulliparous women did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-associated hypertension ( number, NCT00135707).

    PMID: 20375405 [PubMed – indexed for MEDLINE]

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    Am J Clin Nutr. 2010 Feb;91(2):391-7. Epub 2009 Nov 25.

    A randomized trial to determine the optimal dosage of multivitamin supplements to reduce adverse pregnancy outcomes among HIV-infected women in Tanzania.

    Kawai K, Kupka R, Mugusi F, Aboud S, Okuma J, Villamor E, Spiegelman D, Fawzi WW.

    Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.


    BACKGROUND: We previously reported that supplementation with multivitamins (vitamin B complex, vitamin C, and vitamin E) at multiples of the Recommended Dietary Allowance (RDA) significantly decreased the risk of adverse pregnancy outcomes among HIV-infected women. The minimum dosage of multivitamins necessary for optimal benefits is unknown.

    OBJECTIVE: We investigated the efficacy of multivitamin supplements at single compared with multiple RDAs on decreasing the risk of adverse pregnancy outcomes among HIV-infected women.

    DESIGN: We conducted a double-blind, randomized controlled trial among 1129 HIV-infected pregnant women in Tanzania. Eligible women between 12 and 27 gestational weeks were randomly assigned to receive daily oral supplements of either single or multiple RDA multivitamins from enrollment until 6 wk after delivery.

    RESULTS: Multivitamins at multiple and single doses of the RDA had similar effects on the risk of low birth weight (11.6% and 10.2%, respectively; P = 0.75). We found no difference between the 2 groups in the risk of preterm birth (19.3% and 18.4%, respectively; P = 0.73) or small-for-gestational-age (14.8% and 12.0%, respectively; P = 0.18). The mean birth weights were similar in the multiple RDA (3045 + or – 549 g) and single RDA multivitamins group (3052 + or – 534 g; P = 0.83). There were no significant differences between the 2 groups in the risk of fetal death (P = 0.99) or early infant death (P = 0.19).

    CONCLUSION: Multivitamin supplements at a single dose of the RDA may be as efficacious as multiple doses of the RDA in decreasing the risk of adverse pregnancy outcomes among HIV-infected women. This trial was registered at as NCT00197678.

    PMID: 19939985 [PubMed – indexed for MEDLINE]PMCID: PMC2806894 [Available on 2011/2/1]

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    Obstet Gynecol. 2010 Feb;115(2 Pt 1):234-42.

    Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial.

    Harper M, Thom E, Klebanoff MA, Thorp J Jr, Sorokin Y, Varner MW, Wapner RJ, Caritis SN, Iams JD, Carpenter MW, Peaceman AM, Mercer BM, Sciscione A, Rouse DJ, Ramin SM, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

    Department of Obstetrics and Gynecology, Wake Forest University Health Sciences, Winston-Salem, North Carolina27157, USA.


    OBJECTIVE: To assess whether the addition of an omega-3 long-chain polyunsaturated fatty acid supplement would reduce preterm birth in women with at least one prior spontaneous preterm birth receiving 17alpha-hydroxyprogesterone caproate.

    METHODS: We conducted a randomized, double-masked, placebo-controlled trial in 13 centers. Women with a history of prior spontaneous singleton preterm birth and a current singleton gestation were assigned to either a daily omega-3 supplement (1,200 mg eicosapentaenoic acid and 800 mg docosahexaenoic acid) or matching placebo from 16-22 through 36 weeks of gestation. All participants received weekly intramuscular 17alpha-hydroxyprogesterone caproate (250 mg). The primary study outcome was delivery before 37 weeks of gestation. A sample size of 800 was necessary to have 80% power to detect a 30% reduction in the primary outcome from 30%, assuming a type I error two-sided of 5%.

    RESULTS: A total of 852 women were included, and none was lost to follow up. Delivery before 37 weeks of gestation occurred in 37.8% (164/434) of women in the omega-3 group and 41.6% (174/418) in the placebo group (relative risk 0.91, 95% confidence interval 0.77-1.07).

    CONCLUSION: Omega-3 long-chain polyunsaturated fatty acid supplementation offered no benefit in reducing preterm birth among women receiving 17alpha-hydroxyprogesterone caproate who have a history of preterm delivery.



    PMID: 20093894 [PubMed – indexed for MEDLINE]

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    Arch Gynecol Obstet. 2010 Jan 22. [Epub ahead of print]

    Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.

    Cetingoz E, Cam C, Sakallı M, Karateke A, Celik C, Sancak A.

    Department of Obstetrics and Gynecology, Zeynep Kamil Women and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey,


    PURPOSE: The purpose of this study was to evaluate whether the prophylactic administration of vaginal progesterone would reduce the preterm birth rate in high-risk population including singleton and twin pregnancies.

    METHODS: This was a randomized, double blind, placebo-controlled study that included 150 high-risk pregnancies. Risk groups included prior spontaneous preterm birth, twin pregnancy, and uterine malformation. Micronized progesterone or placebo (100 mg) was administered daily by vaginal suppository between 24 and 34 weeks of gestation. We compared progesterone and placebo groups for incidence of preterm labor and preterm delivery. Data were compared by chi(2) analysis and Fisher exact test.

    RESULTS: There was a statistically significant difference in the rate of preterm labor between placebo and progesterone groups (45.7 vs. 25%, respectively; p < 0.05). More women delivered before 37 weeks in placebo group (57.2%) than in progesterone group (40%; p < 0.05). Administering progesterone also reduced the preterm birth before 34 weeks of gestation. The difference between placebo and progesterone group was statistically significant (24.3 vs. 8.8%; p < 0.05). However, there was no significant difference in neonatal death between placebo and progesterone groups.

    CONCLUSION: Prophylactic vaginal progesterone reduced the rate of preterm labor and preterm delivery in high-risk pregnancies.

    PMID: 20091317 [PubMed – as supplied by publisher]

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    Obstet Gynecol. 2010 Jan;115(1):134-40.

    High vaginal concentrations of Atopobium vaginae and Gardnerella vaginalis in women undergoing preterm labor.

    Menard JP, Mazouni C, Salem-Cherif I, Fenollar F, Raoult D, Boubli L, Gamerre M, Bretelle F.

    Department of Obstetrics and Gynecology, Marseille Public Hospital System (APHM), Marseille, France.


    OBJECTIVE: To estimate the relationship between vaginal quantification of the main microorganisms related with bacterial vaginosis and the risk of preterm delivery among women with preterm labor.

    METHODS: Molecular methods were used to prospectively quantify Lactobacillus species, Gardnerella vaginalis, Atopobium vaginae, and Mycoplasma hominis in vaginal fluid samples from women admitted for spontaneous preterm labor with intact membranes from July 2007 through July 2008. The primary outcome measure was the relationship between bacterial concentration at admission and preterm delivery, before 37 weeks of gestation. Sensitivity and specificity of molecular cutoff values and 95% confidence intervals (CIs) were calculated using the University of British Columbia Bayesian Calculator type 2.

    RESULTS: Of the 90 women included, 36 delivered before 37 weeks of gestation (40%). Preterm delivery was not associated with the presence of Lactobacillus species, G vaginalis, A vaginae, or M hominis. In contrast, molecular quantification detected high concentrations of A vaginae (10(6)/mL or more: 25.0% in the preterm group and 9.3% in the term group, P=.04) and G vaginalis (10(7)/mL or more: 16.7% and 3.7%, P=.03) more often in women with preterm deliveries compared with term deliveries. Moreover, high vaginal concentrations of these two microorganisms together were associated with a significantly (P=.03) shorter interval between preterm labor and delivery (46 days, 95% CI 30-61) than were lower concentrations (85 days, 95% CI 75-95). The hazard ratio for a short preterm labor-to-delivery interval was three times higher for high vaginal fluid concentrations of A vaginae and G vaginalis than for lower concentrations (hazard ratio 3.3, 95% CI 1.1-9.5, P=.03).

    CONCLUSION: The risk of preterm delivery is significantly associated with high vaginal concentrations of A vaginae and G vaginalis in women with preterm labor.



    PMID: 20027045 [PubMed – indexed for MEDLINE]

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    Rep Carcinog Backgr Doc. 2010 Jan;(10-5981):i-512.

    Final Report on Carcinogens Background Document for Formaldehyde.

    National Toxicology Program.


    Executive Summary: Introduction: Formaldehyde is a high-production-volume chemical with a wide array of uses. The predominant use of formaldehyde in the United States is in the production of industrial resins (mainly urea-formaldehyde, phenol-formaldehyde, polyacetal, and melamine-formaldehyde resins) that are used to manufacture products such as adhesives and binders for wood products, pulp and paper products, plastics, and synthetic fibers, and in textile finishing. Formaldehyde is also used as a chemical intermediate. Resin production and use as a chemical intermediate together account for over 80% of its use. Other, smaller uses of formaldehyde that may be important for potential human exposure include use in agriculture, medical use as a disinfectant and preservative (for pathology, histology, and embalming), and use in numerous consumer products as a biocide and preservative. Formaldehyde (gas) is listed in the Eleventh Report on Carcinogens (RoC) as reasonably anticipated to be a human carcinogen based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in laboratory animals (NTP 2005a); it was first listed in the 2nd RoC (NTP 1981). Formaldehyde (all physical forms) was nominated by NIEHS for possible reclassification in the 12th RoC based on the 2004 review by the International Agency for Research on Cancer (IARC 2006), which concluded that there was sufficient evidence for the carcinogenicity of formaldehyde in humans. Human Exposure: Formaldehyde has numerous industrial and commercial uses and is produced in very large amounts (billions of pounds per year in the United States) by catalytic oxidation of methanol. Its predominant use, accounting for roughly 55% of consumption, is in the production of industrial resins, which are used in the production of numerous commercial products. Formaldehyde is used in industrial processes primarily as a solution (formalin) or solid (paraformaldehyde or trioxane), but exposure is frequently to formaldehyde gas, which is released during many of the processes. Formaldehyde gas is also created from the combustion of organic material and can be produced secondarily in air from photochemical reactions involving virtually all classes of hydrocarbon pollutants. In some instances, secondary production may exceed direct air emissions. Formaldehyde is also produced endogenously in humans and animals. Formaldehyde is a simple, one-carbon molecule that is rapidly metabolized, is endogenously produced, and is also formed through the metabolism of many xenobiotic agents. Because of these issues, typical biological indices of exposure, such as levels of formaldehyde or its metabolites in blood or urine, have proven to be ineffective measures of exposure. Formaldehyde can bind covalently to single-stranded DNA and protein to form crosslinks, or with human serum albumin or the N-terminal valine of hemoglobin to form molecular adducts, and these reaction products of formaldehyde might serve as biomarkers for exposure to formaldehyde. Occupational exposure to formaldehyde is highly variable and can occur in numerous industries, including the manufacture of formaldehyde and formaldehyde-based resins, wood-composite and furniture production, plastics production, histology and pathology, embalming and biology laboratories, foundries, fiberglass production, construction, agriculture, and firefighting, among others. In fact, because formaldehyde is ubiquitous, it has been suggested that occupational exposure to formaldehyde occurs in all work places. Formaldehyde is also ubiquitous in the environment and has been detected in indoor and outdoor air; in treated drinking water, bottled drinking water, surface water, and groundwater; on land and in the soil; and in numerous types of food. The primary source of exposure is from inhalation of formaldehyde gas in indoor settings (both residential and occupational); however, formaldehyde also may adsorb to respirable particles, providing a source of additional exposure. Major sources of formaldehyde exposure for the general public have included combustion sources (both indoor and outdoor sources including industrial and automobile emissions, home cooking and heating, and cigarette smoke), off-gassing from numerous construction and home furnishing products, and off-gassing from numerous consumer goods. Ingestion of food and water can also be a significant source of exposure to formaldehyde. Numerous agencies, including the Department of Homeland Security, CPSC, DOT, EPA, FDA, HUD, the Mine Safety and Health Administration, OSHA, ACGIH, and NIOSH, have developed regulations and guidelines to reduce exposure to formaldehyde. Human Cancer Studies: A large number of epidemiological studies have evaluated the relationship between formaldehyde exposure and carcinogenicity in humans. The studies fall into the following main groups: (1) historical cohort studies and nested case-control studies of workers in a variety of industries that manufacture or use formaldehyde, including the chemical, plastics, fiberglass, resins, and woodworking industries, as well as construction, garment, iron foundry, and tannery workers; (2) historical cohort studies and nested case-control studies of health professionals, including physicians, pathologists, anatomists, embalmers, and funeral directors; (3) population-based cohort or cancer registry studies; and (4) population-based or occupationally based case-control incidence or mortality studies of specific cancer endpoints. In addition, several studies have re-analyzed data from specific cohort or case-control studies or have conducted pooled analyses or meta-analyses for specific cancer endpoints. The largest study available to date is the cohort mortality study of combined mixed industries conducted by the National Cancer Institute (NCI). This cohort includes 25,691 male and female workers, enrolled from 10 different formaldehyde-producing or -using plants, employed before 1966 and followed most recently to 1994 and 2004, most of whom were exposed to formaldehyde (Hauptmann et al. 2003, 2004 and Beane Freeman et al. 2009). Quantitative exposure data were used to construct job-exposure matrices for individual workers, some of whom experienced peak exposures to formaldehyde >/= 4 ppm. This cohort is the only study in which exposure-response relationships between peak, average, cumulative, and duration of exposure and mortality for multiple cancer sites were investigated. Two other large cohort studies are available: (1) a large multi-plant cohort study (N = 14,014) of workers in six chemical manufacturing plants in the United Kingdom (Coggon et al. 2003), which calculated SMRs among ever-exposed and highly exposed workers for formaldehyde, and (2) a NIOSH cohort of garment workers (N = 11,039) (Pinkerton et al. 2004) which evaluated mortality for duration of exposure, time since first exposure, and year of first exposure to formaldehyde for selected cancer sites. The other cohort studies (for both industrial and health professional workers) were smaller, and in general only reported mortality or incidence for ever-exposed workers in external (SMR or PMR) analyses, although some of the studies of health professional workers attempted indirect measures of exposure (such as length in a professional membership) as a proxy for exposure duration. Several of the nested case-control studies attempted to evaluate exposure-response relationships, but were limited by small numbers of exposed cases, and many of the population-based case-control studies lacked quantitative data or sufficient numbers of cases to evaluate exposure-response relationships. However, the nested case-control study of lymphohematopoietic, nasopharyngeal, and brain cancers among U.S. embalmers and funeral directors by Hauptmann et al. (2009) had large numbers of exposed cases of lymphohematopoietic cancer and used both questionnaire- and experimental model-based exposure metrics of exposure, including average, cumulative, peak, and duration of exposure, and number of embalmings. [Since most of the cohorts have relatively low statistical power to evaluate rare cancers such as sinonasal and nasopharyngeal cancers, case-control studies are generally more informative for these outcomes.] Findings across studies for cancer sites that have been the principal focus of investigation are summarized below. Sinonasal cancers: In cohort studies, increased risks of sinonasal cancers were observed among male (SPIR = 2.3, 95% CI = 1.3 to 4.0, 13 exposed cases) and female (SPIR = 2.4, 95% CI = 0.6 to 6.0, 4 exposed cases) Danish workers exposed to formaldehyde (Hansen and Olsen 1995, 1996) and among formaldehyde-exposed workers in the NCI cohort (SMR = 1.19, 95% CI = 0.38 to 3.68, 3 deaths) (Hauptmann et al. 2004). One death from squamous-cell sinonasal cancer was reported in the study of tannery workers among formaldehyde-exposed workers by Stern et al. (1987). No increase in risk was found among formaldehyde-exposed workers in the other large cohort studies (Coggon et al. 2003, Pinkerton et al. 2004). The smaller cohort studies did not report findings or did not observe any deaths for this specific endpoint. [Sinonasal cancers are rare, and even the larger cohort studies have insufficient numbers of exposed workers and expected deaths (e.g., approximately three in the NCI cohort) to be very informative.] Of the six case-control studies reviewed, four (Olsen et al. 1984 and Olsen and Asnaes 1986; Hayes et al. 1986; Roush et al. 1987; and Luce et al. 1993) reported an association between sinonasal cancers and formaldehyde exposure; statistically significant risks were found in three studies among individuals ever exposed to formaldehyde or with higher probabilities or levels of exposure (Olsen et al. 1994 and Olsen and Asnaes 1986; Hayes et al. 1986; and Luce et al. 1993). All of these studies found elevated risks among individuals with low or no exposure to wood dust or after adjusting for exposure to wood dust. Stronger associations were found for adenocarcinoma, with higher risks for this endpoint observed among individuals with higher average and cumulative exposure, duration of exposure, and earlier dates of first exposure (Luce et al. 1993). A pooled analysis of 12 case-control studies of sinonasal cancer from seven countries (Luce et al. 2002) found statistically significant increases in adenocarcinoma among subjects in the highest exposure groups (OR = 3.0, 95% CI = 1.5 to 5.7, 91 exposed cases for men, adjusted for wood dust exposure; and OR = 6.2, 95% CI = 2.0 to 19.7, 5 exposed cases for women, unadjusted for wood dust exposure). For squamous-cell carcinoma, the corresponding ORs were 1.2 (95% CI = 0.8 to 1.8, 30 exposed cases) for men and 1.5 (95% CI = 0.6 to 3.8, 6 exposed cases) for women; neither OR was adjusted for wood dust exposure. A statistically significant increase in risk for sinonasal cancers (mRR = 1.8, 95% CI = 1.4 to 2.3, 933 deaths) was found in a meta-analysis of 11 case-control studies by Collins et al. (1997); however, no increase in risks was found in meta-analyses of three cohort studies by Collins et al. (1987) or in eight industrial cohort studies by Bosetti et al. (2008). Nasopharyngeal cancers: Similar to sinonasal cancers, nasopharyngeal cancers are rare [and most of the risk estimates reported in the cohort studies are based on small numbers of expected cases or deaths]. Among cohort studies, a statistically significant increase in mortality from nasopharyngeal cancer was observed in the large NCI cohort (SMR = 2.10, 95% CI = 1.05 to 4.21, 8 deaths) (Hauptmann et al. 2004), and statistically nonsignificant elevated risks were observed among white embalmers from the United States (PMR = 1.89, 95% CI = 0.39 to 5.48, 3 deaths) (Hayes et al. 1990) and among male Danish workers exposed to formaldehyde (SPIR = 1.3, 95% CI = 0.3 to 3.2, 4 cases) (Hansen and Olsen 1995, 1996). One incident case of nasopharyngeal cancer was reported among Swedish workers in the abrasive materials industry (expected deaths not reported, but only 506 workers were potentially exposed) (Edling et al. 1987b). No associations between formaldehyde exposure and nasopharyngeal cancer were found in the other two large cohorts: one death was observed (vs. 2 expected) in the British chemical workers cohort (Coggon et al. 2003) and no deaths were observed (vs. 0.96 expected) in the NIOSH cohort (Pinkerton et al. 2004). The other, smaller, cohort studies did not report findings or did not observe any deaths for nasopharyngeal cancer. Exposure-response relationships between formaldehyde exposure and nasopharyngeal cancer were evaluated in the large NCI cohort study. Among seven exposed and two unexposed deaths, relative risks of nasopharyngeal cancers increased with cumulative exposure (Ptrend = 0.025 among exposed groups) and with peak and average exposure (Ptrend = 0.044 and 0.126, respectively, across exposed and unexposed groups, using unexposed as the referent as no deaths were observed in the lowest exposed group). Adjustment for duration of exposure to a number of potentially confounding substances and plant type did not substantively alter the findings. Most of the deaths occurred at one factory (Plant 1), which appears to have had the largest numbers of highly exposed workers. In a nested case-control analysis of nasopharyngeal deaths in this plant, Marsh et al. (2007b) reported that several of the nasopharyngeal cancers occurred among workers with previous employment in metal-working occupations. Six of the nine available case-control studies reported increases in nasopharyngeal cancers in association with probable exposure to formaldehyde or at higher levels or duration of estimated exposure (Olsen et al. 1984 [women only], Vaughan et al. 1986a, Roush et al. 1987, West et al. 1993, Vaughan et al. 2000, and Hildesheim et al. 2001). Risks of nasopharyngeal cancers increased with exposure duration and cumulative exposure in two population-based case-control studies (Vaughan et al. 2000, Hildesheim et al. 2001). In some studies, higher risks were found among individuals in the high-exposure groups (Vaughan et al. 1986a, Roush et al 1987), or with more years since first exposure (West et al. 1993), and some studies reported that risks were still elevated after taking into account smoking (Vaughan et al. 2000, Vaughan et al. 1986a, West et al. 1993) or exposure to wood dust (Hildesheim et al. 2001, Vaughan et al. 2000, West et al. 1993). No associations between nasopharyngeal cancer and formaldehyde exposure were found in population-based case-control studies in Denmark (Olsen et al. 1984 [men only]), and Malaysia (Armstrong et al. 2000), a case-cohort study among Chinese textile workers (Li et al. 2006), or in a nested case-control study among embalmers (Hauptmann et al. 2009). Several meta-analyses were available. A statistically significant increase in risk (mRR = 1.3, 95% CI = 1.2 to 1.5, 455 deaths) was reported in a large meta-analysis of 12 case-control and cohort studies (Collins et al. 1997), and a nonsignificant increase in risk in a small meta-analysis of three other cohort mortality studies (SMR = 1.33, 95% CI = 0.69 to 2.56, 9 deaths) (Bosetti et al. 2008). Bachand et al. (2010) reported a borderline statistically significant risk in a meta-analysis of seven case-control studies (mRR = 1.22, 95% CI = 1.00 to 1.50) but did not find an increase in risk (mRR = 0.72, 95% CI = 0.4 to 1.29) in an analysis of data from six cohort studies, which excluded Plant 1 of the NCI cohort and used the re-analysis data from Marsh et al. (2005) for the other plants. [The Bachand meta-analysis used data for all pharyngeal cancer or buccal cavity cancer from some cohort studies and one case-control study, however.] Other head and neck cancers, and respiratory cancer Most of the cohort studies reported risk estimates for cancers of the buccal cavity, pharynx, larynx, and lung, or combinations of these cancers. Most of these studies, including two of the large cohorts (Pinkerton et al. 2004 and Coggon et al. 2003), three of the professional health worker studies (Hayes et al. 1990, Walrath and Fraumeni 1983 and 1984), and two of the smaller industrial cohorts (Andjelkovich et al. 1995 and Hansen and Olsen 1995, 1996) found elevated (between approximately 10% and 30%) but statistically nonsignificant risks for cancers of the buccal cavity or buccal cavity and pharynx combined; risk estimates were usually based on small numbers of deaths or cases. In the NCI cohort, increased risks for all upper respiratory cancers or buccal cavity cancer combined were generally found among workers in the highest categories of exposure (compared with the lowest category), but trends were not statistically significant (Hauptmann et al. 2004). Most of the population-based or nested case-control studies that reported on head and neck cancers found small increases (usually statistically nonsignificant) in risks for formaldehyde exposure and cancers of the buccal cavity and pharynx (or parts of the pharynx) (Vaughan et al. 1986a, Merletti et al. 1991, Gustavsson et al. 1998, Laforest et al. 2000, Marsh et al. 2002, Wilson et al. 2004, Berrino et al. 2003) or of the upper respiratory tract (Partanen et al. 1990). Exposure-response relationships were not clear in most of the available studies; however, positive exposure-response relationships between probability and duration of exposure and cancers of the hypopharynx and larynx combined were reported by Laforest et al. (2000) and between combined probability and intensity of exposure and salivary cancer by Wilson et al. (2004). No associations between formaldehyde exposure and pharyngeal cancers (subtypes or combinations) were observed in case-control studies by Shangina et al. (2006) and Tarvainen et al. (2008). Most of the cohort studies and two of the four available case-control studies found no association between formaldehyde exposure and laryngeal cancer. Two case-control studies (Wortley et al. 1992, Shangina et al. 2006) reported increased risk among subjects with the highest exposure to formaldehyde. Small excesses of mortality or incidence of cancers of the lung or respiratory system among formaldehyde-exposed workers were observed in four cohort studies (Andjelkovich et al. 1995, Dell and Teta 1995, Hansen and Olsen 1996 [women only], and Coggon et al. 2003). A statistically significant increase in risk of lung cancer was observed in the large study of British chemical workers (SMR = 1.22, 95% CI = 1.12 to 1.32, 594 deaths, among all workers) (Coggon et al. 2003). In this study, risks increased with increasing exposure level (Ptrend < 0.001) but not with duration of exposure. No association between formaldehyde exposure and lung cancer was observed in the other two large cohorts (Pinkerton et al. 2004, Hauptmann et al. 2004), in several of the smaller cohorts (Bertazzi et al. 1989, Hansen and Olsen 1995 [in men], Edling et al. 1987b, Stellman et al. 1998, Stern 2003), or in the six studies of health professional workers. Findings from the population-based or nested case-control studies were also mixed. Increases in risk were reported in several studies (De Stefani et al. 2005, Gérin et al. 1989, Andjelkovich et al. 1994, Chiazze et al. 1997), and were statistically significant in two studies (Marsh et al. 2001, Coggon et al. 1984). Risks did not increase with increasing exposure in most of the studies. An exception is the study by De Stefani et al. (2005), in which a statistically significant trend with duration of employment was observed. No association between lung cancer and formaldehyde exposure was reported in three other occupational case-control studies (Bond et al. 1986, Jensen and Andersen 1982, Partanen et al. 1990) and one population-based study (Brownson et al. 1993). Lymphohematopoietic cancers: Among workers in the NCI cohort study, peak exposure to formaldehyde was associated with increased mortality for several types of lymphohematopoietic cancers (Beane Freeman et al. 2009). For all lymphohematopoietic cancers combined, for leukemias combined, and for myeloid leukemia, relative risks increased with increasing peak exposure: statistically significant increased risks were found among workers with the highest peak exposure (>/= 4 ppm) vs. the lowest exposed category for all lymphohematopoietic cancers (RR = 1.37, 95% CI = 1.03 to 1.81, 108 deaths, Ptrend = 0.02), and statistically nonsignificant increases for all leukemias combined and peak exposure >/= 4 ppm (RR = 1.42, 95% CI = 0.92 to 2.18, 48 deaths, Ptrend = 0.12) and for myeloid leukemia and peak exposure >/= 4 ppm (RR = 1.78, 95% CI = 0.87 to 3.64, 19 deaths, Ptrend = 0.13; trends among exposed person-years). No associations were found with cumulative or average exposure. An excess of leukemia, especially myeloid leukemia, was also found among garment workers in the large NIOSH cohort (Pinkerton et al. 2004), but not in the British chemical workers cohort (Coggon et al. 2003). In the NIOSH cohort, risks for leukemia, myeloid leukemia, and acute myeloid leukemia were higher among workers with longer duration of exposure (10+ yrs), longer time since first exposure (20+ years), and among those exposed prior to 1963 (when formaldehyde exposure was thought to be higher) (Pinkerton et al. 2004). In the smaller industrial cohort studies, some studies reported excesses for all lymphohematopoietic cancers combined among formaldehyde-exposed workers (Bertazzi et al. 1989, Stellman et al. 1998) or leukemia (Hansen and Olsen 1995, 1996), but others observed no association for all lymphohematopoietic cancers combined (Andjelkovich et al. 1995, Stern 2003, Pinkerton et al. 2004) or leukemia (Andjelkovich et al. 1995, Stellman et al. 1998, Stern 2003). Each of the six cohort studies of health professionals, and the nested case-control study of embalmers from three of these studies, found elevated mortality for lymphohematopoietic cancers. Hall et al. (1991), Hayes et al. (1990), Stroup et al. (1986), Levine et al. (1984) and Walrath and Fraumeni (1983, 1984) reported increases in risk for all lymphohematopoietic cancers combined and for leukemia. Most estimates were statistically nonsignificant with the exception of the studies of Hayes et al. (1990) and Stroup et al. (1986), where statistically significant excess mortality was found for all leukemia combined or for myeloid leukemia in association with formaldehyde exposure. In the nested case-control study by Hauptmann et al. (2009), sufficient numbers of cases of lymphohematopoietic cancer deaths among embalmers and funeral directors were identified to enable evaluation of exposure-response relationships, using models of potential formaldehyde exposure. A significant increase in nonlymphoid lymphohematopoietic cancers was observed among ever-embalmers (OR = 3.0, 95% CI = 1.0 to 9.5, 44 exposed cases), and significant increases in risk were observed at the highest levels of cumulative, average, and peak exposure. Most of the increase was attributable to myeloid leukemia, which was significantly elevated among ever-embalmers (OR = 11.2, 95% CI = 1.3 to 95.6, 33 exposed cases) and showed significant trends with duration of exposure and peak exposure, and a more attenuated trend with 8-hour time-weighted average intensity of exposure. In further analyses of non-lymphoid lymphohematopoietic cancers using workers with < 500 lifetime embalmings as the reference group, statistically significant increases in relative risks were found among workers with the longest duration of working in jobs with embalming, the highest number of lifetime embalmings, and the highest cumulative exposure to formaldehyde. With respect to other case-control studies, a population-based study found no clear association between leukemia and exposure to formaldehyde (Blair et al. 2001), and two nested case-control studies reported statistically nonsignificant increases in leukemia risk based on small numbers of exposed cases (Partanen et al. 1993, Ott et al. 1989). Few cohort or case-control studies reported findings for subtypes of lymphohematopoietic cancers other than leukemia. Most of the cohort studies had relatively low power to detect effects, and either did not report findings or did not evaluate exposure-response relationships. For Hodgkin’s lymphoma, the NCI study was the only cohort or case-control study that reported an increase in risk. In an external analysis, an SMR of 1.42 (95% CI = 0.96 to 2.10, 25 deaths) was observed among formaldehyde-exposed workers and, in internal analyses, statistically significant exposure-response relationships were observed with peak (Ptrend = 0.01 among the exposed group) and average exposure (Ptrend = 0.05 among the exposed group), but not with cumulative exposure (Beane Freeman et al. 2009). For non-Hodgkin’s lymphoma, statistically non-significant increases in risks were observed in one cohort study (Hayes et al. 1990), and in most of the population-based or nested case-control studies (Partanen et al. 1993, Ott et al. 1989, Richardson et al. 2008, Wang et al. 2009a, Tatham et al. 1997, Blair et al. 1993). The risk of non-Hodgkin’s lymphoma (large B cell type) increased with increasing probability of exposure (Ptrend < 0.01) in a large case-control incidence study of U.S. women (Wang et al. 2009a). No increase in non-Hodgkin’s lymphoma was reported in the population-based case-control study by Gérin et al. (1989), or in the nested case-control study of embalmers by Hauptmann et al. (2009). For multiple myeloma, peak exposure of >/= 4 ppm was associated with a statistically significant increase in risk in the NCI cohort (RR = 2.04, 95% CI = 1.01 to 4.12, 21 deaths, Ptrend = 0.08 among the exposed group) (Beane Freeman et al. 2009), although an increase in risk was also seen among unexposed workers for this endpoint. Increased risks also were seen among British chemical workers (Coggon et al. 2003), abrasive materials workers (Edling et al. 1987b), and U.S. embalmers (Hayes et al. 1990). Other cohort studies did not find associations, based on small numbers of observed deaths or cases, or did not report findings. Among case-control studies, statistically nonsignificant increases in risks were observed by Boffetta et al. (1989), Pottern et al. (1992) (women only), and Hauptmann et al. (2009), but not by Heineman et al. (1992) (men only). Several meta-analyses were available. (Hauptmann et al. [2009] was not available for any of the analyses.) Statistically significant risks were reported for all lymphohematopoietic cancers and leukemia among cohort studies of health professionals by Bosetti et al. (2008) (RR = 1.31, 95% CI = 1.16 to 1.47, 263 deaths for all lymphohematopoietic cancers; and RR = 1.39, 95% CI = 1.15 to 1.68, 106 deaths for leukemia) and among studies of occupations with known high formaldehyde exposure by Zhang et al. (2009a), (mRR = 1.25, 95% CI = 1.09 to 1.43, 19 studies for all lymphohematopoietic cancers combined; mRR = 1.54, 95% CI = 1.18 to 2.00, P < 0.001, 15 studies for leukemia; and mRR = 1.90, 95% CI = 1.31 to 2.76, P = 0.001, 6 studies for myeloid leukemia. A statistically nonsignificant increase in leukemia risk was also estimated among the combined studies of health professional workers by Bachand et al. (2010). No increased risks for leukemia were found in the available meta-analyses of industrial cohorts (Bosetti et al. 2008, Bachand et al. 2010), or combined cohort and case-control studies (Collins and Lineker 2004). Other cancer sites: With the exception of brain and central nervous system cancers, few of the cohort studies reported consistently elevated risks for cancers at other sites. Few case-control studies of other cancer endpoints have been conducted. Excess mortality from brain and central nervous system cancers has been reported in each of the six cohort studies of health professionals, with statistically significant SMRs/PMRs (1.94 to 2.7) reported in three studies (Stroup et al. 1986, Walrath and Fraumeni 1983, 1984). However, in the nested case-control analysis of brain cancers among embalmers and funeral directors by Hauptmann et al. (2009), which used subjects from cohort studies of Hayes et al. (1990) and Walrath and Fraumeni (1983, 1984), a statistically nonsignificant increase in brain cancers was observed in association with ever-embalming (OR = 1.9, 95% CI = 0.7 to 5.3, 42 exposed cases). There were no clear exposure-response patterns with duration of employment in embalming jobs, or estimated cumulative, peak, or average exposure to formaldehyde, however. No increases in brain and central nervous system cancers have been observed in the industrial cohort studies that have reported findings. A meta-analysis by Bosetti et al. (2008) reported a statistically significant increase in the risk of brain cancer among health professional workers (RR = 1.56, 95% CI = 1.24 to 1.96, 74 deaths), but not among industrial workers. Several industrial studies have reported increases in one or more of stomach, colon, rectal, and kidney cancers, and a case-control study of pancreatic cancer (Kernan et al. 1999) suggested an increase in this endpoint at higher levels of formaldehyde exposure. Two meta-analyses of pancreatic cancer (Ojajärvi et al. 2000, Collins et al. 2001) showed no consistent increase in risk across studies, however, with the exception of a borderline statistically significant increase among pathologists, anatomists and embalmers. Studies in Experimental Animals: Formaldehyde has been tested for carcinogenicity in mice, rats, and hamsters. Studies reviewed include chronic and subchronic inhalation studies in mice, rats, and hamsters; chronic and subchronic drinking-water studies in rats; and one chronic skin-application study in mice. No chronic studies in primates were found, but one subchronic inhalation study and one acute/subacute inhalation study in monkeys was reviewed. [Several of these studies were limited by a small number of animals per group, short exposure duration, short study duration, incomplete pathology or data reporting, and/or incomplete statistical analysis.] Formaldehyde exposure resulted in nasal tumors (primarily the extremely rare squamous-cell carcinoma) in several strains of rats when administered chronically by inhalation (Kerns et al. 1983a, Sellakumar et al. 1985, Appelman et al. 1988, Woutersen et al. 1989, Monticello et al. 1996, Kamala et al. 1997). Only two inhalation studies in mice or hamsters were found. No tumors were reported in C3H mice exposed to formaldehyde at 200 mg/m3 [163 ppm] for 1 hour/day, 3 days/week, for 35 weeks (Horton et al. 1963), but squamous-cell carcinoma of the nasal cavity occurred in 2 of 17 B6C3F1 male mice exposed at 14.3 ppm for 6 hours/day, 5 days/week, and sacrificed at 24 months (Kerns et al. 1983a). Although the increase was not statistically significant, the authors concluded that the tumors were exposure-related. [Biological significance is implied because these tumors are extremely rare in non-exposed mice and rats; no nasal squamous-cell carcinomas have been observed in more than 2,800 B6C3F1 mice and 2,800 F344 rats used as controls in NTP inhalation studies.] No tumors were reported in Syrian golden hamsters exposed at 10 ppm 5 hours/day, 5 days/week for life (Dalbey 1982) or at 2.95 ppm 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983). No tumors occurred in male cynomolgus monkeys exposed at 2.95 ppm for 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983) or in male rhesus monkeys exposed at 6 ppm for 6 hours/day, 5 days/week for 6 weeks (Monticello et al. 1989); however, squamous metaplasia and hyperplasia in the nasal passages and respiratory epithelia of the trachea and major bronchi occurred. Male Wistar rats administered formaldehyde in drinking water at 5,000 ppm for 32 weeks developed forestomach tumors (squamous-cell papillomas) in one study (Takahashi et al. 1986); however, in two other drinking-water studies, no tumors were reported in either male or female Wistar rats administered formaldehyde at concentrations ranging from 20 to 5,000 ppm for two years (Til et al. 1989, Tobe et al. 1989). In another study, male and female Sprague-Dawley breeder rats administered formaldehyde at 2,500 ppm in drinking water. Offspring of these breeder rats exposed transplacentally beginning on gestation day 13 and postnatally via drinking water for life showed increased incidences of benign and malignant tumors of the gastrointestinal tract, particularly intestinal leiomyosarcoma (a very rare tumor). Male Sprague-Dawley rats administered formaldehyde at concentrations up to 1,500 ppm showed increased incidences (compared with control groups given tap water) of the number of animals bearing malignant tumors, hemolymphoreticular neoplasms (leukemia and lymphoma combined), and testicular tumors (interstitial-cell adenoma) (Soffritti et al. 2002a). Compared with the vehicle control group (tap water containing 15 mg/L methanol), the incidence of testicular tumors was significantly higher in the 1,000-ppm exposure group, and the incidence of hemolymphoreticular tumors was higher in the 1,500-ppm exposure group. Female rats in the 1,500-ppm exposure group showed higher incidences of malignant mammary-gland tumors and hemolymphoreticular neoplasms than the tap-water control group; however, the incidences were not significantly higher than in the vehicle control group. In addition, some rare stomach and intestinal tumors occurred in a few male and female rats in the exposed groups but not in the control groups. Other studies examined the promoting effects of formaldehyde when administered after initiation with DBMA, DEN, MNU, or MNNG or cocarcinogenic effects when administered with coal tar, benzo[a]pyrene, wood dust, and hydrogen chloride. Some of these studies did not show an enhanced tumor response. However, a few studies, including a skin-painting study in mice (Iverson et al. 1986), a drinking-water study in rats (Takahashi et al. 1986), and inhalation studies in rats (Albert et al. 1982, Holmström et al. 1989a) and hamsters (Dalbey et al. 1986), indicated that formaldehyde could act as a tumor promoter or act as a co-carcinogen when administered with other substances. Adsorption, distribution, metabolism, and excretion: Formaldehyde is a metabolic intermediate that is essential for the biosynthesis of purines, thymidine, and some amino acids. The metabolism of formaldehyde is similar in all mammalian species studied. Differences in distribution following inhalation exposure can be related to anatomical differences. For example, rats are obligate nose breathers while monkeys and humans are oronasal breathers. Thus, in humans, some inhaled formaldehyde will bypass the nasal passages and deposit directly into the lower respiratory tract. The endogenous concentrations in the blood of humans, rats, and monkeys are about 2 to 3 mug/g and do not increase after ingestion or inhalation of formaldehyde from exogenous sources (Casanova et al. 1988, Heck et al. 1985, Heck and Casonova 2004). Although formaldehyde is rapidly and almost completely absorbed from the respiratory or gastrointestinal tracts, it is poorly absorbed from intact skin. When absorbed after inhalation or ingestion, very little formaldehyde reaches the systemic circulation because it is rapidly metabolized by glutathione-dependent formaldehyde dehydrogenase and S-formyl-glutathione hydrolase to formic acid, which is excreted in the urine or oxidized to carbon dioxide and exhaled (IARC 2006). Formaldehyde reaching the circulation is rapidly hydrated to methanediol, which is the predominant form in the circulation (Fox et al. 1985). Although the metabolic pathways are the same in all tissues, the data indicate that the route of absorption does affect the route of elimination. When inhaled, exhalation is the primary route of elimination; however, when ingested, urinary excretion as formate is more important. Unmetabolized formaldehyde reacts non-enzymatically with sulfhydryl groups or urea, binds to tetrahydrofolate and enters the single-carbon intermediary metabolic pool, reacts with macromolecules to form DNA and protein adducts, or forms crosslinks primarily between protein and single-stranded DNA (Bolt 1987). Toxic effects: Formaldehyde is a highly reactive chemical that causes tissue irritation and damage on contact. Formaldehyde concentrations that have been associated with various toxic effects in humans show wide interindividual variation and are route dependent. Symptoms are rare at concentrations below 0.5 ppm; however, upper airway and eye irritation, changes in odor threshold, and neurophysiological effects (e.g., insomnia, memory loss, mood alterations, nausea, fatigue) have been reported at concentrations </= 0.1 ppm. The most commonly reported effects include eye, nose, throat, and skin irritation. Other effects include allergic contact dermatitis, histopathological abnormalities (e.g., hyperplasia, squamous metaplasia, and mild dysplasia) of the nasal mucosa, occupational asthma, reduced lung function, altered immune response, and hemotoxicity (IARC 2006). Some studies of Chinese workers suggest that long-term exposure to formaldehyde can cause leucopenia, and one study reported that a significantly higher percentage of formaldehyde-exposed workers had blood cell abnormalities (leucopenia, thrombocytopenia, and depressed serum hemoglobin levels) compared with unexposed controls (reviewed by Tang et al. 2009). Zhang et al. (2010) reported that Chinese factory workers exposed to high levels of formaldehyde had significantly lower counts of white blood cells, granulocytes, platelets, red blood cells and lymphocytes than unexposed controls. In vitro studies indicated that formaldehyde exposure caused a significant, dose-related decrease in colony forming progenitor cells (Zhang et al. 2010). Other studies have shown that formaldehyde exposure affects changes in the percentage of lymphocyte subsets (Ying et al. 1999, Ye et al. 2005). Higher rates of spontaneous abortion and low birth weights have been reported among women occupationally exposed to formaldehyde (IARC 2006, Saurel-Cubizolles et al. 1994). Oral exposure is rare, but there have been several apparent suicides and attempted suicides in which individuals drank formaldehyde. These data indicate that the lethal dose is 60 to 90 mL (Bartone et al. 1968, Yanagawa et al. 2007). Formaldehyde ingestion results in severe corrosive damage to the gastrointestinal tract followed by CNS depression, myocardial depression, circulatory collapse, metabolic acidosis, and multiple organ failure. The toxic effects of formaldehyde in experimental animals include irritation, cytotoxicity, and cell proliferation in the upper respiratory tract, ocular irritation, pulmonary hyperactivity, bronchoconstriction, gastrointestinal irritation, and skin sensitization. Other reported effects include oxidative stress, neurotoxicity, neurobehavioral effects, immunotoxicity, testicular toxicity, and decreased liver, thyroid gland, and testis weights (IARC 2006, Aslan et al. 2006, Sarsilmaz et al. 2007, Golalipour et al. 2008, Ozen et al. 2005, Majumder and Kumar 1995). In vitro studies have demonstrated that formaldehyde is directly cytotoxic and affects cell viability, cell differentiation and growth, cell proliferation, gene expression, membrane integrity, mucociliary action, apoptosis, and thiol and ion homeostasis (IARC 2006). Since metabolism of formaldehyde is glutathione-dependent, cells depleted of glutathione are more susceptible to formaldehyde toxicity (Ku and Killings 1984). Carcinogenicity of metabolites and analogues Formic acid (formate + H+), the major metabolite of formaldehyde, has not been tested for carcinogenic effects. Acetaldehyde, an analogue of formaldehyde, is listed as reasonably anticipated to be a human carcinogen by the NTP (2004). Acetaldehyde induced respiratory tract tumors in rats (adenocarcinoma and squamous-cell carcinoma of the nasal mucosa) and laryngeal carcinoma in hamsters. In addition, epidemiological studies have reported increased risks of cancers of the upper digestive tract (esophagus, oral cavity, and pharynx) and upper respiratory tract (larynx and bronchi) in humans (Salaspuro 2009). Glutaraldehyde and benzaldehyde have also been tested for carcinogenicity in 2-year bioassays by the NTP. Glutaraldehyde was not considered to be carcinogenic in rats or mice, and benzaldehyde was not considered to be carcinogenic in rats. The NTP concluded that there was some evidence of carcinogenicity for benzaldehyde in mice based on an increased incidence of squamous-cell papilloma and hyperplasia in the forestomachs of male and female mice (NTP 1999). Genetic and related effects: Formaldehyde is a direct-acting genotoxic compound that affects multiple gene expression pathways, including those involved in DNA synthesis and repair and regulation of cell proliferation. Most studies in bacteria were positive for forward or reverse mutations without metabolic activation and for microsatellite induction (Mu and Harris 1988). Studies in non-mammalian eukaryotes and plants also were positive for forward and reverse mutations, dominant lethal and sex-linked recessive lethal mutations, and DNA single-strand breaks (Conaway et al. 1996, IARC 2006). In vitro studies with mammalian and human cells were positive for DNA adducts, DNA-protein crosslinks, DNA-DNA crosslinks, unscheduled DNA synthesis, single-strand breaks, mutations, and cytogenetic effects (chromosomal aberrations, sister chromatid exchange, and micronucleus induction). In in vivo studies in rats, formaldehyde caused DNA-protein crosslinks (in the nasal mucosa and fetal liver but not bone marrow) (Casanova-Schmitz et al. 1994a, Wang and Liu 2006), DNA strand breaks (lymphocytes and liver) (Im et al. 2006, Wang and Liu 2006), dominant lethal mutations (Kitaeva et al. 1990, Odegiah 1997), chromosomal aberrations (pulmonary lavage cells and bone marrow in one of two studies) (Dallas et al. 1992, Kitaeva et al. 1990), and micronucleus induction in the gastrointestinal tract (Migliore et al. 1989). However, it did not induce sister chromatid exchange or chromosomal aberrations in lymphocytes or micronucleus formation in peripheral blood (Kilgerman et al. 1984, Speit et al. 2009). Mutations in the p53 gene were detected in nasal squamous-cell carcinomas from rats (Recio et al. 1992). Inhalation exposure to formaldehyde also induced DNA-protein crosslinks in the nasal turbinates, nasopharynx, trachea, and bronchi of rhesus monkeys (Casanova et al. 1991). In mice, formaldehyde exposure did not cause dominant lethal mutations (Epstein et al. 1972, Epstein and Shafner 1968), micronucleus induction (Gocke et al. 1981), or chromosomal aberrations (Fontignie-Houbrechts 1981, Natarajan et al. 1983) when exposed by intraperitoneal injection or induce micronuclei by intravenous or oral exposure (Morita et al. 1997), but did induce heritable mutations when exposed by inhalation (Liu et al. 2009b). In studies of lymphocytes from health professional workers exposed to formaldehyde, higher levels of formaldehyde-albumin adducts were found in workers exposed to relatively high concentrations compared with workers exposed to lower concentrations (Pala et al. 2008) and higher levels of DNA-protein crosslinks, strand breaks, and pantropic p53 protein levels were found in exposed workers compared with unexposed workers (Shaham et al. 2003). Wang et al. (2009) found higher levels of DNA adducts (N6-hydroxymethyldeoxyadenosine [N6 HOMe dAdo]) among smokers compared with non-smokers; however, the source of formaldehyde is not clear (for example, it could be formaldehyde in tobacco or a metabolite of a tobacco-specific compound). Numerous studies have evaluated chromosomal aberrations and sister chromatid exchange in lymphocytes and micronucleus induction in lymphocytes, or nasal or oral epithelial cells from humans exposed to formaldehyde (primarily health professionals, but also industrial workers, volunteers and subjects exposed from environmental sources). Among formaldehyde-exposed subjects, statistically significant increased frequencies (compared with unexposed, low exposure or pre- exposure vs. post-exposure) of cytogenetic damage in lymphocytes were observed for chromosomal aberrations in 7 of 12 reviewed studies, sister chromatid exchanges in 6 of 12 studies and micronuclei induction in 5 of 7 studies reviewed. In addition to these studies, Zhang et al. (2010) reported that lymphocytes from workers exposed to high levels of formaldehyde had statistically increased frequency of monosomy of chromosome 7 and trisomy of chromosome 8. Statistically significant increased frequencies of micronuclei were also observed in the buccal cavity or oral epithelium in four of five reviewed studies and in the nasal epithelium in all five available studies (Note that findings from two studies, Suruda et al. [1993] and Tikenko-Holland et al. [1996], evaluating the same study participants are treated as one study in this count). In addition to these studies, a review of cytogenetic studies in the Chinese literature on formaldehyde-exposed workers reported increased incidences of chromosomal aberrations in lymphocytes (one study) and micronuclei in lymphocytes and nasal epithelial cells (one study each); however, two studies did find increases in sister chromatid exchanges in lymphocytes. Regulation of gene expression by formaldehyde was investigated in eight studies. Formaldehyde exposure increased expression of genes involved in intracellular adhesion, inflammation, xenobiotic metabolism, nucleic acid metabolism, cell-cycle regulation, apoptosis, and DNA repair. Thus, multiple biochemical pathways are affected by formaldehyde exposure. Mechanistic considerations: Although the biological mechanisms associated with formaldehyde-induced cancer are not completely understood, it is important to recognize that chemicals can act through multiple toxicity pathways and mechanisms to induce cancer or other health effects (Guyton et al. 2009). Potential carcinogenic modes of actions for formaldehyde include DNA reactivity (covalent binding), gene mutation, chromosomal breakage, aneuploidy, and epigenetic effects. Studies evaluating nasal tumors in rats have shown that regional dosimetry, genotoxicity, and cytotoxicity are believed to be important factors. Computational fluid dynamics models have been developed to predict and compare local flux values in the nasal passages of rats (Kimbrell et al. 1993, 1997), monkeys (Kepler et al. 1998), and humans (Subramaniam et al. 1998). Regions of the nasal passages with the highest flux values are the regions most likely affected by formaldehyde exposure. Similar flux values were predicted for rats and monkeys for regions of the nasal passages with elevated cell proliferation rates, thus providing support for the hypothesis that formaldehyde flux is a key factor for determining toxic response. Furthermore, DNA-protein crosslinks and cell-proliferation rates are correlated with the site specificity of tumors (Pala et al. 2008). Cell proliferation is stimulated by the cytotoxic effects of formaldehyde. Increased cell proliferation may contribute to carcinogenesis by increasing the probability of spontaneous or chemically induced mutations. The dose-response curves for DNA-protein crosslinks, cell proliferation, and tumor formation show similar patterns with sharp increases in slope at concentrations greater than 6 ppm. The observed sequence of nasal lesions is as follows: rhinitis, epithelial dysplasia, squamous metaplasia and hyperplasia, and squamous-cell carcinoma. Biological mechanisms have been proposed for the possible association between lymphohematopoietic cancers and formaldehyde exposure. Proposed mechanisms for formaldehyde-induced leukemia are: (1) direct damage to stem cells in the bone marrow, (2) damage to circulating stem cells, and (3) damage to pluripotent stem cells present in the nasal turbinate or olfactory mucosa (Zhang et al. 2009a,b). Evidence in support of the potential for DNA damage to circulating hematopoietic stem cells is that DNA-protein crosslinks have been identified in the nasal passages of laboratory animals exposed to formaldehyde, and increased micronuclei have been identified in the nasal and oral mucosa of formaldehyde-exposed humans. In addition, olfactory epithelial cells obtained from rat nasal passages contain hematopoietic stem cells, which have been shown to re-populate the hematopoietic tissue of irradiated rats (Murrell et al. 2005). However, some authors have questioned the biological plausibility of an association between formaldehyde exposure and leukemia, because formaldehyde is rapidly metabolized, and it would not be expected to enter the systemic circulation (Cole and Axten 2004, Golden et al. 2006, Heck and Casanova 2004, Pyatt et al. 2008). They stated that formaldehyde does not cause bone marrow toxicity or pancytopenia, which are common features of known leukemogens, and that the genotoxic and carcinogenic effects in animals and humans are limited to local effects. [The recent reports of adducts in leukocytes of smokers (Wang et al. 2009b), albumin adducts in medical research workers (Pala et al. 2008), DNA-protein crosslinks measured in peripheral blood cells of hospital workers (Shaham et al. 2003), and the hematologic changes measured by Zhang et al. (2010) suggest that formaldehyde might enter the systemic circulation of humans exposed to formaldehyde.].

    PMID: 20737003 [PubMed – as supplied by publisher]

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    PLoS Med. 2009 Dec;6(12):e1000191. Epub 2009 Dec 1.

    The APPLe study: a randomized, community-based, placebo-controlled trial of azithromycin for the prevention of preterm birth, with meta-analysis.

    van den Broek NR, White SA, Goodall M, Ntonya C, Kayira E, Kafulafula G, Neilson JP.

    Liverpool School of Tropical Medicine, Liverpool, United Kingdom.


    BACKGROUND: Premature birth is the major cause of perinatal mortality and morbidity in both high- and low-income countries. The causes of preterm labour are multiple but infection is important. We have previously described an unusually high incidence of preterm birth (20%) in an ultrasound-dated, rural, pregnant population in Southern Malawi with high burdens of infective morbidity. We have now studied the impact of routine prophylaxis with azithromycin as directly observed, single-dose therapy at two gestational windows to try to decrease the incidence of preterm birth.

    METHODS AND FINDINGS: We randomized 2,297 pregnant women attending three rural and one peri-urban health centres in Southern Malawi to a placebo-controlled trial of oral azithromycin (1 g) given at 16-24 and 28-32 wk gestation. Gestational age was determined by ultrasound before 24 wk. Women and their infants were followed up until 6 wk post delivery. The primary outcome was incidence of preterm delivery, defined as <37 wk. Secondary outcomes were mean gestational age at delivery, perinatal mortality, birthweight, maternal malaria, and anaemia. Analysis was by intention to treat. There were no significant differences in outcome between the azithromycin group (n = 1,096) and the placebo group (n = 1,087) in respect of preterm birth (16.8% versus 17.4%), odds ratio (OR) 0.96, 95% confidence interval (0.76-1.21); mean gestational age at delivery (38.5 versus 38.4 weeks), mean difference 0.16 (-0.08 to 0.40); mean birthweight (3.03 versus 2.99 kg), mean difference 0.04 (-0.005 to 0.08); perinatal deaths (4.3% versus 5.0%), OR 0.85 (0.53-1.38); or maternal malarial parasitaemia (11.5% versus 10.1%), OR 1.11 (0.84-1.49) and anaemia (44.1% versus 41.3%) at 28-32 weeks, OR 1.07 (0.88-1.30). Meta-analysis of the primary outcome results with seven other studies of routine antibiotic prophylaxis in pregnancy (>6,200 pregnancies) shows no effect on preterm birth (relative risk 1.02, 95% confidence interval 0.86-1.22).

    CONCLUSIONS: This study provides no support for the use of antibiotics as routine prophylaxis to prevent preterm birth in high risk populations; prevention of preterm birth requires alternative strategies.

    TRIAL REGISTRATION: Current Controlled Trials ISRCTN84023116

    PMID: 19956761 [PubMed – indexed for MEDLINE]PMCID: PMC2776277Free PMC Article

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    Ultrasound Obstet Gynecol. 2009 Dec;34(6):653-9.

    Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.

    O’Brien JM, Defranco EA, Adair CD, Lewis DF, Hall DR, How H, Bsharat M, Creasy GW; Progesterone Vaginal Gel Study Group.

    Collaborators (48)

    Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, KY 40503, USA.


    OBJECTIVES: To determine whether progesterone supplementation alters cervical shortening in women at increased risk for preterm birth.

    METHODS: We performed a planned secondary analysis from a large, multinational preterm birth prevention trial of daily intravaginal progesterone gel, 90 mg, compared with placebo in women with a history of spontaneous preterm birth or premature cervical shortening. Transvaginal cervical length measurements were obtained in all randomized patients at baseline (18 + 0 to 22 + 6 weeks’ gestation) and at 28 weeks’ gestation. For this secondary analysis, the difference in cervical length between these time points was compared for the study population with a history of spontaneous preterm birth and for a population with premature cervical shortening (< or = 30 mm) at randomization. Differences between groups in cervical length for the 28-week examination were analyzed using ANCOVA, including adjustment for relevant clinical parameters and maternal characteristics.

    RESULTS: Data were analyzed from 547 randomized patients with a history of preterm birth. The progesterone-treated patients had significantly less cervical shortening than the placebo group (difference 1.6 (95% CI, 0.3-3.0) mm; P = 0.02, ANCOVA). In the population of 104 subjects with premature cervical shortening at randomization, the cervical length also differed significantly on multivariable analysis, with the treatment group preserving more cervical length than the placebo group (difference 3.3 (95% CI, 0.3-6.2) mm; P = 0.03, ANCOVA), with adjustment for differences in cervical length at screening. A significant difference was also observed between groups for categorical outcomes including the frequency of cervical length progression to < or = 25 mm and a > or = 50% reduction in cervical length from baseline in this subpopulation.

    CONCLUSIONS: Intravaginal progesterone enhances preservation of cervical length in women at high risk for preterm birth.

    PMID: 19918965 [PubMed – indexed for MEDLINE]

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    Int J Epidemiol. 2009 Oct;38(5):1380-9. Epub 2009 Jul 3.

    Maternal anaemia and preterm birth: a prospective cohort study.

    Zhang Q, Ananth CV, Li Z, Smulian JC.

    Merck & Co, Inc, Whitehouse Station, NJ, USA.


    BACKGROUND: The role of maternal anaemia in preterm birth remains poorly defined, and the association between anaemia and preterm birth clinical subtypes remain unclear. We examined if maternal anaemia exposure both within and across trimesters during gestation is associated with preterm birth.

    METHODS: This was a secondary analysis of data from a population-based prospective cohort study in 13 counties of East China (1993-96). All singleton live births delivered at 20-44 weeks to women with at least one haemoglobin measure during pregnancy were included (n = 160 700). Risk of preterm birth (<37 weeks) was examined by clinical subtypes, namely, preterm premature rupture of membranes (PROM), spontaneous preterm labour and medically indicated preterm birth. Haemoglobin changes across trimesters were assessed as proxy of haemo-dilution and haemo-concentration. Multivariable Cox proportional hazards regression models were fitted.

    RESULTS: Preterm birth rates of preterm birth were 4.1% for anaemic and 5% for non-anaemic women (P < 0.05). Compared with haemoglobin of 11 g/dl (reference), values <or=5 g/dl in the first trimester were associated with increased risk for preterm PROM [hazard ratio (HR) 3.3, 95% confidence interval (CI) 1.4-7.7], whereas low haemoglobin in the third trimester was associated with reduced risk of spontaneous preterm labour. Haemodilution was associated with reduced risk for preterm birth.

    CONCLUSIONS: Anaemia in early pregnancy was found to be associated with increased risk for preterm PROM, whereas exposure in late pregnancy was associated with reduced risk for spontaneous preterm labour.

    PMID: 19578127 [PubMed – indexed for MEDLINE]

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    Health Technol Assess. 2009 Sep;13(43):1-627.

    Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, Roberts TE, Barton PM, Jowett SM, Hyde CJ, Khan KS.

    Birmingham Women’s Hospital and Department of Obstetrics and Gynaecology, University of Birmingham, UK.


    OBJECTIVES: To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth.

    DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion.

    REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness.

    RESULTS: Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance.

    CONCLUSIONS: For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

    PMID: 19796569 [PubMed – indexed for MEDLINE]Free Article

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    Obstet Gynecol. 2009 Sep;114(3):516-22.

    Heterogeneity of preterm birth subtypes in relation to neonatal death.

    Chen A, Feresu SA, Barsoom MJ.

    Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.


    OBJECTIVE: To investigate the heterogeneity of preterm labor, preterm premature rupture of membranes (PROM), and indicated preterm birth in overall and gestational-age-specific neonatal death risk.

    METHODS: We used 2001 U.S. linked birth/infant death (birth cohort) data sets for this analysis. We categorized three preterm birth subtypes according to reported preterm PROM, induction of labor, cesarean delivery, and pregnancy and labor complications. We used Cox proportional hazard models to calculate covariates adjusted hazard ratios (HRs) for neonatal death (0-27 days of life) among preterm neonates born at 24-27, 28-31, 32-33, and 34-36 weeks of gestation, with preterm labor being the referent.

    RESULTS: There were 3,763,306 singleton live births at 24-44 weeks of gestation in the data set. Preterm PROM, indicated preterm birth, and preterm labor had neonatal death risk of 2.7%, 1.8%, and 1.1%, respectively. Compared with preterm labor, preterm PROM had shorter gestational age and lower birth weight, so did indicated preterm birth but to a lesser extent. Preterm PROM and indicated preterm birth after 28 weeks of gestation were associated with higher neonatal death risk than preterm labor. At 34-36 weeks of gestation, the HR of preterm PROM was 1.53 (95% confidence interval 1.20-1.95), and the HR of indicated preterm birth was 2.06 (95% confidence interval 1.83-2.33). The increased risk from preterm PROM and indicated preterm birth was not limited to early neonatal death in the first 7 days.

    CONCLUSION: Preterm PROM and indicated preterm birth had higher risk of neonatal death than preterm labor, indicating heterogeneity in gestational age distribution and gestational-age-specific neonatal death risk.


    PMID: 19701029 [PubMed – indexed for MEDLINE]

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    Lancet. 2009 Jun 13;373(9680):2034-40.

    Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.

    Norman JE, Mackenzie F, Owen P, Mactier H, Hanretty K, Cooper S, Calder A, Mires G, Danielian P, Sturgiss S, MacLennan G, Tydeman G, Thornton S, Martin B, Thornton JG, Neilson JP, Norrie J.

    Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK.

    Comment in:


    BACKGROUND: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy.

    METHODS: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks’ gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks’ gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks’ gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581.

    FINDINGS: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51).

    INTERPRETATION: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy.

    FUNDING: Chief Scientist Office of the Scottish Government Health Directorate.

    PMID: 19523680 [PubMed – indexed for MEDLINE]

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    BJOG. 2009 May;116(6):780-8.

    World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries.

    Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc N, Anthony J, De Greeff A, Poston L, Shennan A; WHO Vitamin C and Vitamin E trial group.

    Collaborators (60)

    Nuffield Department of Obstetrics and Gynaecology, Oxford Maternal and Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, UK.

    Comment in:


    OBJECTIVE: To determine if vitamin C and E supplementation in high-risk pregnant women with low nutritional status reduces pre-eclampsia.

    DESIGN: Multicentred, randomised, controlled, double-blinded trial.

    SETTING: Antenatal care clinics and Hospitals in four countries.

    POPULATION: Pregnant women between 14 and 22 weeks’ gestation.

    METHOD: Randomised women received 1000 mg vitamin C and 400 iu of vitamin E or placebo daily until delivery.

    MAIN OUTCOME MEASURES: Pre-eclampsia, low birthweight, small for gestational age and perinatal death.

    RESULTS: Six hundred and eighty-seven women were randomised to the vitamin group and 678 to the placebo group. Groups had similar gestational ages (18.1; SD 2.4 weeks), socio-economic, clinical and demographical characteristics and blood pressure at trial entry. Risk factors for eligibility were similar, except for multiple pregnancies: placebo group (14.7%), vitamins group (11.8%). Previous pre-eclampsia, or its complications, was the most common risk factor at entry (vitamins 41.6%, placebo 41.3%). Treatment compliance was 87% in the two groups and loss to follow-up was low (vitamins 2.0%, placebo 1.3%). Supplementation was not associated with a reduction of pre-eclampsia (RR: 1.0; 95% CI: 0.9-1.3), eclampsia (RR: 1.5; 95% CI: 0.3-8.9), gestational hypertension (RR: 1.2; 95% CI: 0.9-1.7), nor any other maternal outcome. Low birthweight (RR: 0.9; 95% CI: 0.8-1.1), small for gestational age (RR: 0.9; 95% CI: 0.8-1.1) and perinatal deaths (RR: 0.8; 95% CI: 0.6-1.2) were also unaffected.

    CONCLUSION: Vitamins C and E at the doses used did not prevent pre-eclampsia in these high-risk women.

    PMID: 19432566 [PubMed – indexed for MEDLINE]

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    Evid Rep Technol Assess (Full Rep). 2009 Mar;(176):1-257.

    Maternal and neonatal outcomes of elective induction of labor.

    Caughey AB, Sundaram V, Kaimal AJ, Cheng YW, Gienger A, Little SE, Lee JF, Wong L, Shaffer BL, Tran SH, Padula A, McDonald KM, Long EF, Owens DK, Bravata DM.


    BACKGROUND: Induction of labor is on the rise in the U.S., increasing from 9.5 percent in 1990 to 22.1 percent in 2004. Although, it is not entirely clear what proportion of these inductions are elective (i.e. without a medical indication), the overall rate of induction of labor is rising faster than the rate of pregnancy complications that would lead to a medically indicated induction. However, the maternal and neonatal effects of induction of labor are unclear. Many studies compare women with induction of labor to those in spontaneous labor. This is problematic, because at any point in the management of the woman with a term gestation, the clinician has the choice between induction of labor and expectant management, not spontaneous labor. Expectant management of the pregnancy involves nonintervention at any particular point in time and allowing the pregnancy to progress to a future gestational age. Thus, women undergoing expectant management may go into spontaneous labor or may require indicated induction of labor at a future gestational age.

    OBJECTIVES: The Stanford-UCSF Evidence-Based Practice Center examined the evidence regarding four Key Questions: What evidence describes the maternal risks of elective induction versus expectant management? What evidence describes the fetal/neonatal risks of elective induction versus expectant management? What is the evidence that certain physical conditions/patient characteristics are predictive of a successful induction of labor? How is a failed induction defined?

    METHODS: We performed a systematic review to answer the Key Questions. We searched MEDLINE(1966-2007) and bibliographies of prior systematic reviews and the included studies for English language studies of maternal and fetal outcomes after elective induction of labor. We evaluated the quality of included studies. When possible, we synthesized study data using random effects models. We also evaluated the potential clinical outcomes and cost-effectiveness of elective induction of labor versus expectant management of pregnancy labor at 41, 40, and 39 weeks’ gestation using decision-analytic models.

    RESULTS: Our searches identified 3,722 potentially relevant articles, of which 76 articles met inclusion criteria. Nine RCTs compared expectant management with elective induction of labor. We found that overall, expectant management of pregnancy was associated with an approximately 22 percent higher odds of cesarean delivery than elective induction of labor (OR 1.22, 95 percent CI 1.07-1.39; absolute risk difference 1.9, 95 percent CI: 0.2-3.7 percent). The majority of these studies were in women at or beyond 41 weeks of gestation (OR 1.21, 95 percent CI 1.01-1.46). In studies of women at or beyond 41 weeks of gestation, the evidence was rated as moderate because of the size and number of studies and consistency of the findings. Among women less than 41 weeks of gestation, there were three trials which reported no difference in risk of cesarean delivery among women who were induced as compared to expectant management (OR 1.73; 95 percent CI: 0.67-4.5, P=0.26), but all of these trials were small, non-U.S., older, and of poor quality. When we stratified the analysis by country, we found that the odds of cesarean delivery were higher in women who were expectantly managed compared to elective induction of labor in studies conducted outside the U.S. (OR 1.22; 95 percent CI 1.05-1.40) but were not statistically different in studies conducted in the U.S. (OR 1.28; 95 percent CI 0.65-2.49). Women who were expectantly managed were also more likely to have meconium-stained amniotic fluid than those who were electively induced (OR 2.04; 95 percent CI: 1.34-3.09). Observational studies reported a consistently lower risk of cesarean delivery among women who underwent spontaneous labor (6 percent) compared with women who had an elective induction of labor (8 percent) with a statistically significant decrease when combined (OR 0.63; 95 percent CI: 0.49-0.79), but again utilized the wrong control group and did not appropriately adjust for gestational age. We found moderate to high quality evidence that increased parity, a more favorable cervical status as assessed by a higher Bishop score, and decreased gestational age were associated with successful labor induction (58 percent of the included studies defined success as achieving a vaginal delivery anytime after the onset of the induction of labor; in these instances, induction was considered a failure when it led to a cesarean delivery). In the decision analytic model, we utilized a baseline assumption of no difference in cesarean delivery between the two arms as there was no statistically significant difference in the U.S. studies or in women prior to 41 0/7 weeks of gestation. In each of the models, women who were electively induced had better overall outcomes among both mothers and neonates as estimated by total quality-adjusted life years (QALYs) as well as by reduction in specific perinatal outcomes such as shoulder dystocia, meconium aspiration syndrome, and preeclampsia. Additionally, induction of labor was cost-effective at $10,789 per QALY with elective induction of labor at 41 weeks of gestation, $9,932 per QALY at 40 weeks of gestation, and $20,222 per QALY at 39 weeks of gestation utilizing a cost-effectiveness threshold of $50,000 per QALY. At 41 weeks of gestation, these results were generally robust to variations in the assumed ranges in univariate and multi-way sensitivity analyses. However, the findings of cost-effectiveness at 40 and 39 weeks of gestation were not robust to the ranges of the assumptions. In addition, the strength of evidence for some model inputs was low, therefore our analyses are exploratory rather than definitive.

    CONCLUSIONS: Randomized controlled trials suggest that elective induction of labor at 41 weeks of gestation and beyond may be associated with a decrease in both the risk of cesarean delivery and of meconium-stained amniotic fluid. The evidence regarding elective induction of labor prior to 41 weeks of gestation is insufficient to draw any conclusion. There is a paucity of information from prospective RCTs examining other maternal or neonatal outcomes in the setting of elective induction of labor. Observational studies found higher rates of cesarean delivery with elective induction of labor, but compared women undergoing induction of labor to women in spontaneous labor and were subject to potential confounding bias, particularly from gestational age. Such studies do not inform the question of how elective induction of labor affects maternal or neonatal outcomes. Elective induction of labor at 41 weeks of gestation and potentially earlier also appears to be a cost-effective intervention, but because of the need for further data to populate these models our analyses are not definitive. Despite the evidence from the prospective, RCTs reported above, there are concerns about the translation of such findings into actual practice, thus, there is a great need for studying the translation of such research into settings where the majority of obstetric care is provided.

    PMID: 19408970 [PubMed – indexed for MEDLINE]Free Article

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    BMC Pregnancy Childbirth. 2009 Feb 24;9:6.

    Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial.

    Dodd JM, Crowther CA, McPhee AJ, Flenady V, Robinson JS.

    Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, SA, Australia.


    BACKGROUND: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity during infancy and childhood. Survivors of preterm birth continue to remain at considerable risk of both chronic lung disease and long-term neurological handicap. Progesterone is involved in the maintenance of uterine quiescence through modulation of the calcium-calmodulin-myosin-light-chain-kinase system in smooth muscle cells. The withdrawal of progesterone, either actual or functional is thought to be an antecedent to the onset of labour. While there have been recent reports of progesterone supplementation for women at risk of preterm birth which show promise in this intervention, there is currently insufficient data on clinically important outcomes for both women and infants to enable informed clinical decision-making. The aims of this randomised, double blind, placebo controlled trial are to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth will reduce the risk and severity of respiratory distress syndrome, so improving their infant’s health, without increasing maternal risks.

    METHODS: Design: Multicentered randomised, double blind, placebo-controlled trial. Inclusion Criteria: pregnant women with a live fetus, and a history of prior preterm birth at less than 37 weeks gestation and greater than 20 weeks gestation in the immediately preceding pregnancy, where onset of labour occurred spontaneously, or in association with cervical incompetence, or following preterm prelabour ruptured membranes. Trial Entry & Randomisation: After obtaining written informed consent, eligible women will be randomised between 18 and 23+6 weeks gestation using a central telephone randomisation service. The randomisation schedule prepared by non clinical research staff will use balanced variable blocks, with stratification according to plurality of the pregnancy and centre where planned to give birth. Eligible women will be randomised to either vaginal progesterone or vaginal placebo. Study Medication & Treatment Schedules: Treatment packs will appear identical. Woman, caregivers and research staff will be blinded to treatment allocation. Primary Study Outcome: Neonatal Respiratory Distress Syndrome (defined by incidence and severity). Sample Size: of 984 women to show a 40% reduction in respiratory distress syndrome from 15% to 9% (p = 0.05, 80% power).

    DISCUSSION: This is a protocol for a randomised trial.

    PMID: 19239712 [PubMed – indexed for MEDLINE]PMCID: PMC2653463Free PMC Article

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    Obstet Gynecol. 2009 Feb;113(2 Pt 1):285-92.

    Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.

    Caritis SN, Rouse DJ, Peaceman AM, Sciscione A, Momirova V, Spong CY, Iams JD, Wapner RJ, Varner M, Carpenter M, Lo J, Thorp J, Mercer BM, Sorokin Y, Harper M, Ramin S, Anderson G; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU).

    Departments of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA 15213, USA.


    OBJECTIVE: To assess whether 17 alpha-hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets.

    METHODS: We performed this randomized, double-blinded, placebo-controlled trial in 14 centers. Healthy women with triplets were randomly assigned to weekly intramuscular injections of either 250 mg of 17 alpha-hydroxyprogesterone caproate or matching placebo, starting at 16-20 weeks and ending at delivery or 35 weeks of gestation. The primary study outcome was delivery or fetal loss before 35 weeks.

    RESULTS: One hundred thirty-four women were assigned, 71 to 17 alpha-hydroxyprogesterone caproate and 63 to placebo; none were lost to follow-up. Baseline demographic data were similar in the two groups. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss before 35 0/7 weeks) was similar in the two treatment groups: 83% of pregnancies in the 17 alpha-hydroxyprogesterone caproate group and 84% in the placebo group, relative risk 1.0, 95% confidence interval 0.9-1.1. The lack of benefit of 17 alpha-hydroxyprogesterone caproate was evident regardless of the conception method or whether a gestational age cutoff for delivery was set at 32 or 28 weeks.

    CONCLUSION: Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations.



    PMID: 19155896 [PubMed – indexed for MEDLINE]PMCID: PMC2790283Free PMC Article

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    Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support

    Publication Types:

    MeSH Terms:


    Secondary Source ID:

    Grant Support:

    Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02120, USA.


    CONTEXT: Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer.

    OBJECTIVE: To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men.

    DESIGN, SETTING, AND PARTICIPANTS: The Physicians’ Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled.

    INTERVENTION: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.

    MAIN OUTCOME MEASURES: Prostate and total cancer.

    RESULTS: During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.

    CONCLUSIONS: In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.



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