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American Journal of Clinical Nutrition, Vol. 88, No. 2, 458-464, August 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Intake of antioxidant vitamins and trace elements during pregnancy and risk of advanced β cell autoimmunity in the child 1,2,3

Liisa Uusitalo, Mike G Kenward, Suvi M Virtanen, Ulla Uusitalo, Jaakko Nevalainen, Sari Niinistö, Carina Kronberg-Kippilä, Marja-Leena Ovaskainen, Liisa Marjamäki, Olli Simell, Jorma Ilonen, Riitta Veijola and Mikael Knip

1 From the Tampere School of Public Health, University of Tampere, Tampere, Finland (LU, SMV, JN, and LM); the Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland (LU, SMV, UU, JN, SN, CK-K, and M-LO); the Department of Epidemiology and Population Health, Medical Statistics Unit, London School of Hygiene & Tropical Medicine, London, United Kingdom (MGK); the Research Unit (SMV) and Department of Pediatrics (MK), Tampere University Hospital, Tampere, Finland; the Department of Public Health (SN) and the Hospital for Children and Adolescents (MK), University of Helsinki, Helsinki, Finland; the Department of Pediatrics (OS) and the Immunogenetics Laboratory (JI), University of Turku, Turku, Finland; the Juvenile Diabetes Research Foundation (JDRF) Center for Prevention of Type 1 Diabetes in Finland, Turku, Oulu, and Tampere, Finland (OS and MK); the Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland (JI); and the Department of Pediatrics, University of Oulu, Oulu, Finland (RV)

2 Supported by Academy of Finland (grants 63672, 79685,79686, 80846, 201988, 210632); Finnish Diabetes Association; Finnish Diabetes Research Foundation, Finnish Pediatric Research Foundation; Häme Foundation of the Finnish Culture Fund; Juho Vainio Foundation; Yrjö Jahnsson Foundation; Medical Research Funds; Turku, Oulu, and Tampere University Hospitals; JDRF (grants 197032, 4-1998-274, 4-1999-731, 4-2001-435); Novo Nordisk Foundation; EU Biomed 2 (BMH4-CT98-3314), Doctoral Programs for Public Health; Jalmari and Rauha Ahokas Foundation; and Orion-Farmos Research Foundation.

3 Address reprint requests to L Uusitalo, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: liisa.uusitalo{at}uta.fi.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Type 1 diabetes may have its origins in the fetal period of life. Free radicals were implicated in the cause of type 1 diabetes. It was hypothesized that antioxidant nutrients could protect against type 1 diabetes.

Objective: We assessed whether high maternal intake of selected dietary antioxidants during pregnancy is associated with a reduced risk of advanced β cell autoimmunity in the child, defined as repeated positivity for islet cell antibodies plus ≥1 other antibody, overt type 1 diabetes, or both.

Design: The study was carried out as part of the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project. The data comprised 4297 children with increased genetic susceptibility to type 1 diabetes, born at the University Hospital of Oulu or Tampere, Finland, between October 1997 and December 2002. The children were monitored for diabetes-associated autoantibodies from samples obtained at 3–12-mo intervals. Maternal antioxidant intake during pregnancy was assessed postnatally with a self-administered food-frequency questionnaire, which contained a question about consumption of dietary supplements.

Results: Maternal intake of none of the studied antioxidant nutrients showed association with the risk of advanced β cell autoimmunity in the child. The hazard ratios, indicating the change in risk per a 2-fold increase in the intake of each antioxidant, were nonsignificant and close to 1.

Conclusion: High maternal intake of retinol, β-carotene, vitamin C, vitamin E, selenium, zinc, or manganese does not protect the child from development of advanced β cell autoimmunity in early childhood.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Since the fetal origins hypothesis was widely introduced in the 1980s and 1990s (1), increased attention has been paid to the fetal period in search for the causes of chronic illnesses, including type 1 diabetes (2). Maternal dietary nitrite intake was associated with increased risk of type 1 diabetes in the offspring (3), and a strong inverse association was reported between maternal use of cod liver oil during pregnancy and the risk of type 1 diabetes in the child (4). Perinatal events were related to an increased risk of childhood type 1 diabetes (5).

Oxidative stress increases during pregnancy and birth. The high metabolic rate of the placenta leads to increased generation of free radicals, biomarkers of which were observed in maternal circulation (6). The concentration of lipoperoxides in cord blood is only 30% of that in maternal blood, suggesting that the placenta suppresses lipoperoxide formation or transplacental passage, protecting the fetus from the action of these free radicals (7). At birth, the neonate faces an increase in oxidative aggression and presents high concentrations of hydroperoxides in erythrocyte membranes, indicating oxidative stress (8).

Free radicals were implicated in the cause of type 1 diabetes (9), and it was hypothesized that antioxidant nutrients could protect against type 1 diabetes. Animal models of type 1 diabetes have indicated that dietary antioxidants may have protective effects in the disease process (10-12). Epidemiologic studies about associations with type 1 diabetes were published on vitamin C (13, 14), vitamin E (15, 16), selenium (15), and zinc (17), but the evidence was insufficient to draw conclusions about the possible protective role of dietary antioxidants against the disease.

Circulating concentrations of most dietary antioxidants in the newborn are correlated with respective maternal values and are thus likely to be influenced by maternal dietary intake. We hypothesized that high maternal intake of dietary antioxidants during pregnancy leads to high antioxidant status in the fetus and newborn, thereby reducing his or her risk of type 1 diabetes in early childhood. To test this hypothesis, we assessed whether maternal intake of selected dietary antioxidants during pregnancy was associated with a reduced risk of advanced β cell autoimmunity in the offspring, defined as repeated positivity for islet cell antibodies (ICAs) plus ≥1 other antibody, overt type 1 diabetes, or both.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
In the Type 1 Diabetes Prediction and Prevention (DIPP) Project, a prospective population-based cohort study, newborns at 3 university hospitals in Finland were screened for major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) conferred susceptibility to type 1 diabetes with the use of cord blood (18). Infants carrying increased genetic susceptibility (19) were monitored for diabetes-associated autoantibodies, growth, and viral infections at intervals of 3–12 mo. Study design and procedures were approved by the respective ethics committees, and the families signed an informed written consent.

The DIPP Nutrition Study falls within the framework of DIPP (20). The present series comprised 4297 children (79.4% of invited) born between 20 October 1997 and 31 December 2002 at the University Hospitals of Oulu and Tampere. Dietary data were available from mothers of 3723 of these children (86.6%), including 38 twins or triplets. Descriptive dietary information is based on a cohort of 3730 mothers, including 45 mothers whose child did not participate in the follow-up.

Of the 4 type 1 diabetes-associated autoantibodies analyzed, ICAs were used as the primary screening tool for β cell autoimmunity (18). When a child seroconverted to positivity for ICA for the first time, all his or her preceding and subsequent samples were analyzed for antibodies against insulin, 65-kDa isoform of glutamic acid decarboxylase, and islet antigen 2 antibodies. For the present analyses, autoantibodies were analyzed until 31 August 2006.

Dietary methods
Dietary intake during pregnancy was assessed postnatally by a self-administered, semiquantitative 181-item food-frequency questionnaire (FFQ), which was validated specifically for the present study against 10-d food records in a sample of pregnant Finnish women (21). Also in the validation study the questionnaire was completed after the delivery. The validity of the questionnaire for antioxidant nutrients was, in general, good; correlation coefficients between the 2 methods ranged from 0.45 for zinc to 0.71 for retinol. The only exception was vitamin E, for which the correlation was only 0.22. The FFQ was designed to assess the entire diet during the past month before the beginning of the maternity leave, ie, the 8th month of pregnancy. The respondents were asked to report the frequency of use in terms of natural units (eg, 1 apple), common household measures (eg, 1 glass of milk), or portions (eg, a portion of lasagna), for which typical portion sizes identified in earlier Finnish dietary studies were used in dietary calculations. The mothers received the FFQ by mail and returned it at the first visit to the study center when the infant was 3 mo old. A trained study doctor or nurse checked the FFQ and, if required, completed it in collaboration with the mother. All the returned FFQ forms were checked by a trained nutritionist. If there were ≥10 food items with missing frequency, the FFQ was rejected (n = 52, 1.4% of all FFQs). Other missing items were imputed with null (22). FFQ data were entered into a data file at a commercial data entry service. Daily energy intake and the intake of 7 selected antioxidant nutrients from foods were calculated with the use of the Finnish food composition database (23) by in-house software of the National Public Health Institute. The use of dietary supplements was assessed by a separate question on the FFQ form. The respondent was asked to write down the type, brand name, and manufacturer's name of all the dietary supplements used during the entire pregnancy, the amount of each supplement used per day or per week, and the weeks of pregnancy during which each supplement was used. The nutrient contents of the dietary supplements registered as drugs were obtained from the Finnish pharmacopoeia. Information on other dietary supplements was acquired from the National Food Administration, the manufacturer, or both. Average daily intakes of antioxidant nutrients from dietary supplements during the entire pregnancy were calculated as separate variables by in-house software of the National Public Health Institute.

Genetic methods
HLA-DQB1 alleles were analyzed as described earlier (19). In brief, a part of the second exon of the HLA-DQB1 gene was amplified with the use of a primer pair with a biotinylated 3' primer. The biotinylated polymerase chain reaction products were then transferred to streptavidin-coated microtitration plates, denatured, and hybridized with sequence-specific probes labeled with lanthanide chelates: europium, terbium, or samarium. Two hybridization mixtures were used, one containing probes hybridizing with DQB1*0602 and DQB1*0603, DQB1*0603 and DQB1*0604, and a consensus sequence, and the other containing probes specific to the DQB1*02, DQB1*0301, and DQB1*0302 alleles. After appropriate incubations and washings, the specific hybridization products were detected with the use of 3-color time-resolved fluorescence of the lanthanide chelates.

Immunologic methods
The detection of type 1 diabetes–associated autoantibodies was described in Virtanen et al (20). In brief, ICAs were quantified by a standard indirect immunofluorescence method on sections of frozen human pancreas from a blood group O donor (24). Serum antibodies against insulin were quantified with a microassay (25, 26) and glutamic acid decarboxylase and islet antigen 2 antibodies with specific radiobinding assays (27, 28). Transplacentally transferred autoantibodies, which were present in cord blood and thereafter disappeared from the infant's serum (29), were excluded from the analyses.

Background characteristics
Information on maternal age and education was registered with the use of a structured questionnaire completed after the delivery. In preliminary single covariate analyses, vocational education was more closely associated with dietary factors and with the endpoint variable than was basic education, and it was used in the multiple covariate models. In the questionnaire, vocational education was recorded on a 7-category scale corresponding to the Finnish education system. To achieve sufficient sample size in each category, the data were aggregated into 4 categories. Information on the number of earlier deliveries (parity), maternal smoking during pregnancy, and gestational age and weight and height of the newborn was received from the Medical Birth Registries of the Oulu and Tampere University Hospitals. Smoking during pregnancy was registered on a 3-category scale (nonsmoker, quit smoking during the first trimester, smoker). Because the number of quitters was small, they were aggregated with smokers. Ponderal index of the newborn was calculated by the formula (g/m3) x 100. Home municipality was coded as urban, semiurban, or rural according to the classification of Statistics Finland (30).

Statistical methods
Dietary variables
The intakes of the antioxidant nutrients from foods were adjusted for energy intake by the residual method (31). In the linear regression model used for energy adjustment, the variables are often transformed with the use of the ln to improve normality and homoscedasticity. However, when these ln-scale residuals are used as explanatory variables in a statistical model used to analyze the associations between dietary intake and an endpoint variable, the results may be difficult to interpret. If ln transformation had been used in the present study, the interpretation of the hazard ratio produced by the survival model would have been "the change in risk per a 2.7-fold increase in energy-adjusted intake of the nutrient." To achieve an interpretation of the hazard ratio that is intuitively more appealing, we used base-2 logarithmic (log2) transformation for the dietary variables instead of ln transformation. When a log2-transformed food or nutrient is used as an explanatory variable in the survival model, the interpretation of the hazard ratio is "the change in risk per a 2-fold increase in energy-adjusted intake of the nutrient." The total intake of each antioxidant was calculated by summing the intakes from foods and supplements. The total intakes were not adjusted for energy. The total intakes of all the antioxidants had distributions that were close to normal after log2 transformation, and these transformed values were used as explanatory variables in the survival models. Derived categorical variables were formed both from energy-adjusted intakes from foods and from total intakes from foods and supplements with the use of quartile values as cutoffs.

Associations of dietary variables with the endpoint variable
The endpoint of advanced β cell autoimmunity is interval censored. To accommodate this structure, a piecewise exponential survival model was used to analyze the associations of background characteristics and maternal antioxidant intake with the endpoint (20, 32), with constant hazard in the intervals 0–0.99, 1–1.99, 2–2.99, and ≥3 y. The models were fitted with the use of maximum likelihood in SAS PROC NLMIXED, with standard errors of estimates derived from the observed information matrix. SAS version 9.1.3 (SAS Institute, Cary, NC) was used in the analyses. There was no interval censoring in the diagnosis of clinical type 1 diabetes; therefore, the associations of antioxidant nutrients with the risk of clinical disease could be analyzed by Cox regression models with the use of SPSS 15.0 (SPSS, Chicago, IL). Cox regression analysis was also used to check the associations of categorical antioxidant intakes with advanced β cell autoimmunity and the associations of antioxidant intake with early endpoints (advanced β cell autoimmunity appearing before the age of 2.5 y). In etiologic analyses the effective sample size (ie, the number of children who had both maternal dietary data and endpoint data available) was 3723, including 138 cases with advanced β cell autoimmunity, 57 cases with advanced β cell autoimmunity appearing before the age of 2.5 y, and 55 cases with clinical type 1 diabetes.

Adjustment for potential confounding factors
The possible confounding by background characteristics was controlled by adding the background variables as covariates in the statistical models. Two sets of covariates were used, one including diabetes in a first-degree relative and genetic risk group, and the other including also sex, gestational age, maternal age, maternal parity, maternal education, maternal smoking during pregnancy, degree of urbanization of the home municipality, and region of birth (Oulu compared with Tampere area). All the background characteristics were categorical and were coded as binary indicator variables for model-fitting purposes.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Among the 4297 children, 144 (3.4%) were repeatedly positive for ICA plus ≥1 other antibody during the median follow-up time of 4.4 y (range: 0.2–8.8 y) since birth. Seventy-four children (1.7%) had progressed to clinical type 1 diabetes at a median age of 4.1 y (range: 1.0–7.9 y). Among those children, 53 were repeatedly positive for ICA plus ≥1 other autoantibody. Nine of the remaining 21 children had ≥1 autoantibody in one single sample before or at the time of diagnosis. Four persistently seronegative children had the last blood sample drawn 3.3–5.5 y before the diagnosis of diabetes. The remaining 8 children with diabetes had not provided serum samples for autoantibody follow-up. Therefore, we decided to include children who progressed to clinical type 1 diabetes in the group of children called later in the study as autoantibody-positive children. This resulted in 165 children (3.8% of all children) being positive for the ICA plus ≥1 other antibody endpoint, ie, having advanced β cell autoimmunity, which term will be used throughout the text for the endpoint. Cumulative incidence of advanced β cell autoimmunity was highest for children who had a first-degree relative with diabetes and for those with a high-risk genotype (Table 1Go). Gestational age was inversely associated with the risk of advanced β cell autoimmunity.


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  		TABLE 1. Distribution of background characteristics and cumulative incidence of advanced β cell autoimmunity among children with a genetic susceptibility to type 1 diabetes born at the University Hospital of Oulu or Tampere, Finland, 1997-20021

 
The intakes of the antioxidant nutrients had skewed distributions; therefore, average intakes are presented as medians (Table 2Go). The main sources of retinol were meat and milk products (Table 2Go). Organ meats supplied 43% and cheese 13% of the total dietary retinol intake. β-carotene came mainly from roots (65%). Juice was the main source of vitamin C, followed by fruit and vegetables (eg, cucumber, sweet pepper, and tomato; 10%) and citrus fruits (10%). Vitamin E was supplied mainly by vegetable oils and cereal products. The most important sources of selenium and zinc were meat, milk, and cereal products. Manganese was provided mainly by cereal products.


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  		TABLE 2. Intake of antioxidant nutrients and their dietary sources among 3730 pregnant women, who delivered an infant with genetic susceptibility to type 1 diabetes at the University Hospital of Oulu or Tampere, Finland, 1997-20021

 
The mean (maximum) daily supplementary intake was 18.1 µg (2141 µg) for retinol (1.9% of total intake), 261 µg (10 800 µg) for β-carotene (5.7% of total intake), 23.3 mg (1395 mg) for vitamin C (10.5% of total intake), 1.1 mg (191 mg) for vitamin E (7.3% of total intake), 6.3 µg (95 µg) for selenium (7.9% of total intake), 2.0 mg (30 mg) for zinc (10.6% of total intake), and 0.3 mg (18 mg) for manganese (4.8% of total intake). The minimum and median supplementary intake was zero for all the nutrients analyzed.

Maternal intake of any antioxidant nutrient in the study, analyzed with the use of a piecewise exponential survival model, was not significantly associated with the risk of advanced β cell autoimmunity in the offspring during the median follow-up time of 4.4 y (Table 3Go). For each nutrient, the hazard ratio, indicating the change in risk per 2-fold increase in the energy-adjusted intake of the nutrient, was nonsignificant and close to one. Hazard ratios were similar for energy-adjusted dietary intakes and for combined dietary and supplemental intakes. The inclusion of a broad set of background variables as covariates in the model, in addition to basic adjustment for genetic risk group and diabetes in the family, did not change the results.


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  		TABLE 3. Associations of maternal intake of antioxidant nutrients during pregnancy with the risk of advanced β cell autoimmunity among 3723 children with a genetic susceptibility to type 1 diabetes born at the University Hospital of Oulu or Tampere, Finland, 1997-20021

 
Antioxidant intake was not associated with the risk of advanced β cell autoimmunity appearing before the age of 2.5 y or with clinical type 1 diabetes. The hazard ratios were close to one, but the CIs tended to be wider than in the main analysis because of the smaller number of cases. Categorization of antioxidants into quarters of intake did not change the results (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this prospective cohort study with a reasonable number of endpoints, the maternal intake of retinol, β-carotene, vitamin C, vitamin E, selenium, zinc, or manganese during pregnancy was not associated with the risk of advanced β cell autoimmunity in the offspring with HLA-conferred susceptibility to type 1 diabetes. The presence of ≥2 type 1 diabetes-associated autoantibodies usually reflects a progressive process that only rarely reverts (33). Dietary intake was assessed by a FFQ developed and validated specifically for the purposes of the present study (21). The variation in the intakes of the analyzed nutrients was substantial. The difference between the 25th and 75th percentiles of intake from foods ranged from 46% for selenium to 147% for β-carotene. The mean intakes from dietary supplements covered only a small fraction of the total intakes, but the maximum supplementary intakes were large.

There are few previous studies on the association of retinol intake and type 1 diabetes. Retinol deficiency reduced diabetes in diabetes-prone BB rats (34). Because cod liver oil is rich in retinol, along with vitamin D and long-chain n–3 fatty acids, it may be hypothesized that retinol could be the main player in the inverse association that was observed between the use of cod liver oil during pregnancy and subsequent risk of type 1 diabetes in the offspring (4). The use of other kinds of vitamin D supplements was not associated with the risk of diabetes. The present findings do not support any association between maternal retinol intake and risk of prediabetes in the child. To our knowledge, β-carotene intake has not been analyzed in the context of type 1 diabetes. We found no association between maternal β-carotene intake and advanced β cell autoimmunity in the offspring.

A rat experiment suggested a protective effect of vitamin C against diabetes induced by interferon-{alpha} (11). Association of vitamin C with the risk of type 1 diabetes was also assessed in 2 epidemiologic analyses. Fewer children with type 1 diabetes than controls reported the use of vitamin C supplements for >1 mo, before the date of diagnosis of diabetes (13), whereas the intake of foods rich in vitamin C was not related to childhood type 1 diabetes in another case-control study (14). The present results show no association between vitamin C intake during pregnancy and the risk of advanced β cell autoimmunity in the child.

Animal models of type 1 diabetes have indicated that vitamin E may have protective effects against type 1 diabetes (9, 10, 35, 36). Serum {alpha}-tocopherol concentrations were inversely associated with type 1 diabetes in a nested case-control study within a 21-y follow-up of adult men (15). In a cohort of initially nondiabetic siblings of children with diabetes, we found an inverse relation of borderline significance between serum {alpha}-tocopherol concentrations and type 1 diabetes (16). In the present study, no evidence was observed of an association between maternal intake and advanced β cell autoimmunity in the offspring. However, because of the poor validity of the FFQ for vitamin E (21), we consider the data insufficient to rule out a possible protective role of maternal vitamin E intake against preclinical type 1 diabetes in the child.

In the nested case-control study referred to earlier (15), serum selenium was not associated with type 1 diabetes. Similarly, we found no association between maternal selenium intake and prediabetes in the offspring. Animal experiments have suggested a protective effect of zinc against developing type 1 diabetes (12, 37). A high groundwater concentration of zinc was associated with a reduced risk of type 1 diabetes in a case-control study (17). We found no significant association between maternal zinc intake and advanced β cell autoimmunity in the child. To our knowledge, there are no previous reports on the associations of manganese intake with type 1 diabetes. In the present study, we found no evidence of high maternal intake of manganese being protective against prediabetes in the offspring.

CIs for the hazards ratios tended to be wider for energy-adjusted nutrient intakes from foods than for the combined intakes from foods and supplements not adjusted for energy. Because the CIs for non–energy-adjusted intakes from foods and from combined sources were similar, this difference could not result from supplement use (data not shown). The discrepancy was largest for those nutrients that correlated most strongly with energy intake (vitamin E, zinc, and selenium). For these nutrients, the variances of the residuals produced by the energy adjustment method were considerably smaller than the variances of the absolute nutrient intakes. In the survival models with nutrient intakes as explanatory variables, a 1-unit change in residual implied a greater relative change on the range of nutrient intake among the study subjects than a 1-unit change in absolute intake, leading to larger standard errors of the estimate. Thus, the discrepancy in CIs for the hazard ratios may be considered an artifact created by the different scaling of energy-adjusted and absolute variables.

Antioxidant status of the fetus and newborn is likely to be influenced by maternal dietary intake. Although serum retinol and zinc concentrations are poor indicators of dietary intake (38), correlations were shown between maternal and cord blood concentrations of retinol (39) and zinc (40). Cord blood concentrations of β-carotene (41, 42), vitamin C (43, 44), selenium (45, 46), and manganese (47, 48) have shown positive correlations with maternal values. For vitamin E, positive correlations were observed for lipid-adjusted {alpha}-tocopherol concentrations and for erythrocyte {alpha}-tocopherol concentrations in cord and maternal blood (49, 50). However, the maternal antioxidant intake does not seem to protect the child from developing pre–type 1 diabetes in early childhood. One could speculate that the lack of association could be due to the short period of time when the infant faces oxidative stress while simultaneously being dependent on the antioxidants received from the mother. During the fetal period, the uterine environment may offer protection against oxidative stress (7). Free radical challenges increase at birth (8), but the newborn's own dietary intake may soon wipe out the effects of maternal intake. Therefore, studies on the associations between antioxidant intake in childhood and the risk of type 1 diabetes are warranted.


   ACKNOWLEDGMENTS
 
The author's responsibilities were as follows—LU: participated in designing the study, preparing, analyzing, and interpreting the data, and wrote the manuscript; MGK: participated in designing the study and planned the statistical analyses; SMV: participated in designing the study, planning the statistical analyses, and analyzing and interpreting the data;. UU: participated in designing the study and preparing the data; JN: participated in analyzing and interpreting the data; SN: participated in designing the study and preparing the data; CK-K and RV: participated in preparing the data; M-LO: participated in designing the study and interpreting the data; LM: participated in preparing the data; OS and JI: participated in conceiving and designing the study; MK: participated in conceiving and designing the study and interpreting the data. All authors participated in drafting or revising of the manuscript and approved the final version to be published. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication February 14, 2008. Accepted for publication May 12, 2008.





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