Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. METHODS: We pooled 10 case-control studies within the Pancreatic Cancer Case-control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. RESULTS: The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98-1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15-2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82-20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. CONCLUSIONS: This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.

Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

AIM: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. METHODS: Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. RESULTS: Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. CONCLUSIONS: Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation.

Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).

BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Consumption of untreated tank rainwater and gastroenteritis among young children in South Australia.

BACKGROUND: Tank rainwater is a source of untreated drinking water in Australia and elsewhere. The aim of this study was to determine whether the risk of gastroenteritis among children who drank tank rainwater differed from that of children who drank treated public mains water. METHODS: A cohort study of 1,016 4- to 6-year old children who drank rainwater or treated mains water in rural South Australia was undertaken in 1999. Parents kept a daily diary of their child's gastrointestinal symptoms and water consumption for a period of 6 weeks. Data on respiratory illness and other risk factors for gastroenteritis were also collected. RESULTS: The incidence of gastroenteritis among children was 3.8-5.3 episodes per child-year, but most episodes (60%) lasted just 1 day. No increase in odds of gastroenteritis was observed among children who drank rainwater compared with treated mains water. The adjusted odds ratio for gastroenteritis associated with rainwater consumption compared with mains consumption was 0.84 (95% confidence interval 0.63-1.13). CONCLUSIONS: Gastroenteritis was found to be a significant cause of morbidity among young children. Young children, who were regular consumers of tank rainwater, were at no greater odds of gastroenteritis than those who drank treated public mains water.

The binding of organic phosphates to human methaemoglobin A. Perturbation of the polymerization of proteins by effectors.

Theory is presented relating to the binding of an effector to two states of a protein acceptor coexisting in equilibrium. The problem is treated in terms of the four possible cases which specify relations between numbers of binding sites and intrinsic binding constants relevant to the acceptor states. It is shown that a distinction between these cases may be possible on the basis of the form of a plot of unbound effector concentration versus the constituent equilibrium coefficient which may be calculated from the sedimentation coefficient of the protein constituent. Particularly noteworthy in this respect is the finding that a turning point may exist in this plot for defined conditions with systems in which binding sites are not conserved (and binding affinities are altered) on polymer formation. The latter type of system is exemplified by studies on methaemoglobin A in 0.25 M sodium acetate, pH 5.4. In the absence of added organic phosphate effectors, a dimer-tetramer equilibrium operates governed by an association constant of 4.15 +/- 0.06 X 10(3) 1/mol, determined from sedimentation equilibrium results. Correlation of sedimentation velocity and equilibrium results shows that addition of adenosine 5'-triphosphate (ATP) results in its binding to one site on each of the dimeric (alpha beta) and tetrameric (alpha beta)2 species with intrinsic binding constants 1.03-10(3)-1.20-10(3) and 1.1-10(4)-2.1-10(4) 1/mol, respectively. It is also shown that 2,3-diphosphoglycerate perturbs the dimer-tetramer equilibrium in a similar way to ATP.

Antioxidant vitamins and low-density-lipoprotein oxidation.

Low-density-lipoprotein (LDL) oxidation was examined in 22 subjects (10 men, 12 women) after a daily dose of 18 mg beta-carotene, 900 mg vitamin C, and 200 mg alpha-tocopherol for 6 mo. Control subjects (12 men, 11 women) took no vitamin supplements. After 3-mo supplementation plasma concentrations of beta-carotene, alpha-tocopherol, and ascorbic acid increased fivefold (P < 0.001), 55% (P < 0.01), and 27% (P < 0.05), respectively. There was no difference from baseline in rate of oxidation or total amount of conjugated diene produced between subjects taking or not taking vitamins. Malondialdehyde in LDL before and after oxidation was not different between the two groups. Lag time before the onset of oxidation was significantly lengthened after antioxidant supplementation (28% and 35% after 3 and 6 mo, respectively, P < 0.001). There was a significant independent correlation between percent change in lag time and percent change in plasma alpha-tocopherol (r = 0.47, P < 0.01).

Diet, prolactin, and breast cancer.

Relationships between dietary nutrients and plasma prolactin concentration were studied in 249 women with a history of nonskin cancers among first-degree female relatives. For each quintile of nutrient density, the odds ratio (OR), relative to the lowest quintile, of having an elevated (above the median) prolactin concentration was estimated by logistic regression, taking into account parity, menopausal status, and current tobacco-smoking habits. For nutrient densities estimated from 24-h recall data there was a significant positive association between plasma prolactin concentration and increasing saturated fatty acid intake; the OR of elevated prolactin in the top quintile was 3.1 [95% confidence interval (CI) 1.2-8.1] and there was a negative association with vitamin C [OR in the top quintile 0.28, (95% CI 0.10-0.78)]. For usual nutrient densities (estimated by quantitative food frequency questionnaire) there was a statistically significant trend (P = 0.04) toward lower prolactin concentrations with increasing sodium density, and a marginally significant positive trend (P = 0.07) with increasing dietary density of refined sugars.

Lead in the placenta, membranes, and umbilical cord in relation to pregnancy outcome in a lead-smelter community.

As part of a cohort study of the effects of chronic exposure to lead on pregnancy outcome and child development, lead concentrations in the umbilical cord and placental tissues (body and membranes) from 9 late fetal deaths, 23 preterm births, and 18 births associated with premature rupture of the amniotic membranes were compared with the lead concentrations in the tissues obtained at 22 normal births. Modest elevations in lead concentration were found in the placental body of late fetal deaths (stillbirths) and preterm births as well as in the cord tissue associated with preterm births and premature rupture of membranes. The geometric mean lead concentration in the membranes from late fetal deaths was 2.73 micrograms/g of dry tissue (95% confidence limits 0.69-10.8), which was 3.5 times higher than the mean found in normal births (0.78 micrograms/g, 95% confidence limits 0.61-1.00). The concentration in the membranes of preterm births was also significantly high, being 1.24 micrograms/G (0.91-1.67). Low correlations of membrane and antenatal blood lead concentrations suggest that other factors in addition to exposure to environmental lead may influence the amount of lead accumulated in the placental membranes.

Public perceptions of the role of dietary and other environmental factors in cancer causation or prevention.

STUDY OBJECTIVE: The aim was to establish the public's perception of the relative importance of various environmental risk factors for cancer. DESIGN: A postal survey was undertaken using a questionnaire to assess the public's knowledge of cancer morbidity and mortality and the role of lifestyle and genetic risk factors. Sociodemographic data were also collected. SETTING: The survey was completed in the state of South Australia. PARTICIPANTS: A random sample of 1500 names were selected from the electoral rolls of the state. These rolls contain the names of all Australian citizens over the age of 18 years. A response rate of 73% was achieved. MEASUREMENTS AND MAIN RESULTS: The results of the survey showed that the knowledge base of the community was generally high, with few differences across sociodemographic groups. The relative importance of cancer as a contributor to mortality was, however, overestimated and the potential for "cure" underestimated. The role of both diet and cigarette smoking in cancer promotion was widely recognised but there was an overemphasis on the importance of pollution of the food supply compared to imbalance of nutrients. Respondents were more able to assign risk in relation to diet using a food based assessment, compared to a nutrient approach. There was wide acceptability that lifestyle change could have a profound effect on the cancer profile of the community. CONCLUSIONS: With the relatively high degree of awareness and acceptance of lifestyle factors as cancer risk determinants, campaigns which involve skill transfer and removal of barriers to change would appear to be the most relevant approach to improvement in community behaviour.

Demographic and dietary profiles of high and low fat consumers in Australia.

STUDY OBJECTIVE: To determine the socio-demographic, attitudinal, and dietary correlates of high and low fat consumption in the community. DESIGN: The study was undertaken using a postal survey format. A questionnaire was sent for self completion to a randomised sample of the adult population of two Australian states. PARTICIPANTS: Adult participants were selected randomly from the Electoral Rolls of the states of Victoria and South Australia. As voting at elections is compulsory in Australia, these rolls contain the names of all Australian citizens over the age of 18 years. Altogether 3209 respondents completed the survey giving a response rate of 67%. MAIN RESULTS: Lower than average fat consumption was more common in women. Age was a significant factor only in men. Occupation was not related to lower than average fat consumption but manual work and low occupational prestige were linked to higher than average consumption in men. People with a history of conditions related to heart disease were more likely to be low consumers but medical history did not distinguish high from average consumers. Low fat consumption was linked to higher refined and natural sugar consumption and higher alcohol consumption, but protein and complex carbohydrate consumption did not vary with fat consumption. Low fat diets also had higher densities of fibre and most vitamins and minerals, the exceptions being retinol, zinc, and vitamin B12, nutrients generally linked to meat and dairy consumption. Of the latter, only the low zinc concentrations, which are already borderline in the community, pose a potential nutritional problem. CONCLUSIONS: This study showed very strong links between dietary fat intake and the intake of nearly all other nutrients in the diet. The results highlight the need to consider relationships between nutrients not only for purposes of nutrition education but also in relation to nutritional epidemiology studies.

The Port Pirie cohort study: maternal blood lead and pregnancy outcome.

During a three-year period, 831 pregnant women in and around Port Pirie, South Australia--a lead smelter community with longstanding lead pollution--were enrolled in a cohort study to examine prospectively the relation between body lead burden and pregnancy outcome. Three-quarters of the enrolled women were residents of the Port Pirie municipality; the other women lived in adjacent towns and countryside. At 14-20 weeks' gestation, the Port Pirie resident women had a mean blood lead concentration of 10.6 micrograms/dl, while the mean in the other (non-Port Pirie) women was 7.6 micrograms/dl. Similar differences were observed in maternal blood samples taken at 30-36 weeks, at delivery, and from the umbilical cord. These blood lead measures, in conjunction with information collected on other risk factors, were then examined in relation to pregnancy outcome. Among 749 pregnancies followed to completion, pre-term delivery was statistically significantly associated, in a dose-response manner, with maternal blood lead concentration at delivery. Mothers of late fetal deaths (stillbirths) had blood lead concentrations at 14-20 weeks' gestation similar to those of all the other women but had lower concentrations at delivery than the other women. Outcomes of pregnancy for which no association with blood lead was detected were spontaneous abortion, low birthweight (for births at term), intrauterine growth retardation, premature rupture of the membranes, and congenital anomalies.

Port Pirie Cohort study: childhood blood lead and neuropsychological development at age two years.

The Port Pirie Cohort Study is an ongoing prospective study of the relationship between exposure to environmental lead within a lead smelter community, and neuropsychological development in early childhood. Over 600 children, originally recruited during antenatal life, underwent serial blood lead estimations up to two years of age. Systematic interview information was collected on a range of variables, and formal developmental assessment (Bayley Scales of Infant Development) was carried out at 24 months of age. Blood lead concentrations measured antenatally (maternal), at delivery (maternal and umbilical cord) and postnatally at 6, 15 and 24 months were negatively correlated (p less than 0.05) with mental development at 24 months of age. Geometric mean blood lead concentrations (microgram/dl) were 14.3, 20.8 and 21.2 at 6, 15 and 24 months of age respectively. When multiple covariates, including maternal IQ, were controlled for in multiple regression analysis, a statistically significant (p less than 0.01) inverse association was observed between blood lead concentration (PbB) measured at 6 months of age and mental development at 2 years of age. No such association was evident for psychomotor development. When the quality of the home environment (HOME Score) was added to the multiple regression model, the inverse association between blood lead concentration at 6 months of age and mental development at 2 years persisted, albeit less strongly (p = 0.07). From this analysis, it is estimated that a child with with PbB of 30 micrograms/dl at age 6 months will have a deficit of 3.3 points (approximately 3%) on the Bayley Mental Development Scale relative to a child with PbB of 10 micrograms/dl.

Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study.

Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.

Induction of micronuclei in cultured murine splenocytes exposed to elevated levels of ferrous ions, hydrogen peroxide and ultraviolet irradiation.

The frequency of micronuclei in cultured mouse splenocytes increased positively and in a dose-related manner to exposure to ferrous ions and ultraviolet irradiation, but not to hydrogen peroxide. Combined treatments, especially when ferrous ions were present with hydrogen peroxide or with ultraviolet irradiation, led to a synergistic enhancement in micronucleus frequency. The results indicate that a significant level of chromosome damage is associated with exposure to ultraviolet light and to general cellular pro-oxidative stress, and indicate that under these conditions the micronucleus assay can provide an effective in vitro model for the study of genotoxicity in relation to oxygen-derived free radicals.

Sociodemographic factors modifying the effect of environmental lead on neuropsychological development in early childhood.

A long-term prospective cohort study was conducted to examine the association between prenatal and postnatal exposure to environmental lead and childhood neuropsychological development. The possible interactive effects of blood lead and some covariates on early development were explored in this study. Our data suggest that gender of the child modifies the effect of lead on the neuropsychological development during early childhood. At the ages of 2 and 4 years, girls appear to be more sensitive than boys to the neuropsychological effects of lead. However, there is no significant modification of the effect of lead by some other covariates, such as parental smoking, socioeconomic status, home environment, birth weight, and the kind of infant feeding. Evidence of interactions between environmental lead exposure and other covariates in the causation of neuropsychological deficits in childhood underscores the desirability of considering both main effects and interactions in this area of research. Such effects, if confirmed, may have implications for public health intervention strategies.

Does breastfeeding at six months predict cognitive development?

There is controversy over whether the method of feeding in infancy affects intellectual development. We investigated the relationship between breastfeeding status at 6 months of age and long-term cognitive development in a cohort of 375 children born in Port Pirie, South Australia, between 1979 and 1982. Cognitive assessments were conducted at ages 2, 4, 7 and 11 to 13 years. After adjustment for sociodemographic, environmental and biomedical factors, a small, statistically non-significant, beneficial effect of breastfeeding on cognitive functioning was observed. Compared with the bottle-fed children, the breast-fed children had a 3.4 (95% CI -0.1 to 6.9), 1.3 (-2.3 to 4.9), 1.2 (-2.0 to 4.4) and 0.8 (-1.9 to 3.5) point advantage on the Bayley Mental Developmental Index at age 2 years, the McCarthy General Cognitive Index at age 4 years and the Wechsler Full-Scale IQ at ages 7 and 11 to 13 years, respectively. Our data suggest that any beneficial effect of breastfeeding on cognitive development is quite small in magnitude.