Nutritive and Non-Nutritive Sweeteners



Bunin GR, Kushi LH, Gallagher PR, Rorke-Adams LB, McBride ML, Cnaan A. Maternal diet during pregnancy and its association with medulloblastoma in children: a children's oncology group study (United States). Cancer Causes Control. 2005 Sep; 16 (7): 877-891. 

PubMed ID: 16132798
Study Design:
Case-control study.
C - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
  • To replicate previous findings (by same author) that frequent consumption of fruits, vegetables, vitamin C and folate during pregnancy was associated with decreased risk of medulloblastoma and primitive neuroectodermal tumors (PNET) in the offspring
  • To investigate comprehensively the role of maternal diet (as related to medulloblastoma and PNET).
Inclusion Criteria:
  • Children with central nervous system medulloblastoma or PNET diagnosed before six years of age during 1991 to 1997*
  • Children registered with the Children's Cancer Group
  • Physician consent to contact family.

* Diagnosis of medulloblastoma or PNET was confirmed by an independent pathologist when slides or blocks of the tumor were available; about half of the final case sample was reviewed. Those subjects with misdiagnosis were excluded.  It was estimated that 5% of the final case sample of 318 were not medulloblastoma or PNET.


Exclusion Criteria:
  • Another cancer diagnosis before or concurrent with medulloblastoma and PNET
  • Biological mother not available for interview
  • Language barrier
  • No household phone
  • Residence outside of North America
  • Unable to locate families and parents
  • No response from letter
  • Actively refused.
Description of Study Protocol:


  • Case subjects were registered with the Children's Cancer Group
  • Physicians gave consent to contact families of potential case subjects
  • Random-digit dialing was used to identify control subjects
  • Participants contacted were asked to give verbal consent for the telephone interview.


  • Case-control study
  • Telephone interviews conducted with the biological mothers of case and control subjects
  • From food frequency questionnaire, total number of servings per day was calculated for eight food groups:  Dairy; fruit, not including juices; fruit including juices; citrus fruit and juices; vegetables, not including juices or soups; vegetables, including juices and soups; cured meat and fish; fresh meat
  • Macronutrient and select micronutrients were calculated assuming standard portion size of servings.

Statistical Analysis

  • Odds ratio (OR) was calculated for weekly or greater intake of the individual food items compared with less frequent intake 
  • Means for cases and controls were compared by T-tests
  • If the OR was statistically significant (P<0.05) or the difference in the means was statistically significant, further analysis was done on the food item
  • Tests were done to evaluate evidence of dose-response relationships.
Data Collection Summary:
  • Timing of measurements: Trained interviewers conducted telephone interviews with mothers of case subjects and control subjects
  • Dependent variables: Variables included diagnosis of medulloblastoma or PNET
  • Independent variables: Intake of 112 food items was completed in two time periods during pregnancy: The year before pregnancy and the second trimester in pregnancy.

Control Variables

  • Total calories
  • Mother's race
  • Date of interview
  • Child's age at interview
  • Income level
  • Number of cigarettes per day
  • Weight gain due to nausea and vomiting.
Description of Actual Data Sample:

Initial N

  • 318 case subjects
  • 315 control subjects.

Attrition (Final N)

  • 315 case subjects
  • 315 control subjects.


  • Case subjects 4.9±2.1 years
  • Control subjects 5.6±2.3 years.


  • Case subjects 82% white
  • Control subjects 84% white.

Other Relevant Demographics

  • 84% case mothers were married at time of interviews
  • 81% control mothers were married at time of interviews.


Case and control mothers were similar in most demographics and pregnancy characteristics except case mothers were significantly more likely to have gained weight as result of nausea or vomiting; case mothers were less likely to have smoked.


Not discussed.


Summary of Results:

The odds of case subjects consuming diet soda was no different than the odds of control subjects consuming diet soda as shown by the adjusted odds ratio confidence intervals (contains one). Questions pertaining to diet soda intake did not specifically assess for aspartame. Aspartame was the most widely used artificial sweetener in diet sodas during the gestational time period of the subjects.

Odds Ratio for Diet Soda Consumption in Relation to Medulloblastoma/PNET


Periconception Results Mid-Pregnancy Results Mid-Pregnancy: Crude Results
(95% CI)

Periconception:  Adjusted Results

Mid-Pregnancy Month 1: Crude Results
(95% CI)

Mid-Pregnancy: Adjusted Results

Less than 1 per Month







>1 per Month to 1 per Day

1.3 (0.9, 2.1)

1.2 (0.7, 2.1)


1.7 (1.0, 2.7)*

1.5 (0.8, 2.6)

>2 per Day

1.6 (1.0, 2.3)*

1.3 (0.8, 2.4)


1.2 (0.7, 2.0)

1.3 (0.7, 2.5)


Trend P-Value 0.03 0.35 0.51 0.44


Other Findings

  • Modest, inverse association for fruits or juices: OR (for highest compared to lowest category)=0.6 (95% CI=0.3, 1.1)
  • Modest, inverse association for Vitamin C: OR=0.6 (95% CI=0.4, 1.1)
  • Folate and vegetables showed no association (in contrast to the author's previous study)
  • Cured meats showed no association with this type of tumor (in contrast to other childhood brain tumors)
  • Inverse association with non-fresh peaches and similar fruits was noted: OR=0.5 (95% CI=0.3, 0.8)
  • Positive association with non-chocolate candy was noted: OR=1.7 (95% CI=1.0, 3.0)
  • French fries and chili peppers were associated with medulloblastoma/PNET: OR=2.4 (95% CI=1.2, 4.9) and OR=1.8 (95% CI=1.0, 3.0), respectively.
Author Conclusion:

The authors conclude the results generally do not support an association with aspartame; some aspects of diet are worthy of further research in relation to brain tumors and other cancers in children. 

Funding Source:
Government: National Cancer Institute
Reviewer Comments:
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) ???
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? N/A
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? N/A
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes