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GDM: Nonnutritive Sweeteners (2008)


Levy HL, Waisbren SW.  Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus.  N Engl J Med 1983;309(21):1269-1274.

PubMed ID: 6633585
Study Design:
Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To describe the mental and physical characteristics of the offspring of women with phenylketonuria and hyperphenylalaniemia.
Inclusion Criteria:
Women with maternal phenylketonuria or hyperphenylalaninemia screened by routine umbilical-cord blood specimens and their offspring.
Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment Umbilical-cord blood specimens were obtained on approximately 92% of all deliveries and screened for phenylalanine.  22 cases of phenylketonurira or hyperphenylalaninemia were identified from an analysis of 725,197 cord-blood specimens.  These families were contacted for biochemical and clinical evaluation, which included blood and urine specimens from the mother and physical examination of each child.

Design Cohort Study

Blinding used (if applicable): Not described

Intervention (if applicable):  not applicable.

Statistical Analysis  Not described.  Descriptive statistics and correlations reported.


Data Collection Summary:

Timing of Measurements Not Described

Dependent Variables:


  • Clinical Characteristics - Weschler Adult Intelligence Scale, Beery Visual Motor Integration Test or the Bender Gestalt Test
  • Pregnancy, Labor and Delivery - review of Medical Records


  • Perinatal Complications - review of medical records
  • Phenylketnuria or Hyperphenylalalninemia in offspring - newborn screening and physical examination
  • Head circumference - review of medical records, standardized growth charts
  • Birth and later weight - review of medical records, standardized growth charts
  • Intellectual Functioning - Bayley Scales of Infant Development, the McCarthy Scales of Children's Abilities, the Weschler Intelligence Scale for Children -- Revised, the Stanford-Binet Intelligence Test
  • Congenital heart disease and other congenital anomalies - review of medical records

Independent Variables

  • Maternal Phenylketonuria or Hyperphenylalaninemia

Control Variables None reported


Description of Actual Data Sample:

Initial N: 22 mothers, 53 offspring

Attrition (final N):  22 mothers , 53 offspring

Age: Mothers not specified, children 4 to 12 years of age at most recent examination

Ethnicity: White

Other relevant demographics: 2 mothers were identified as having classic phenylketonuria (>1200 umol per liter), 11 mothers were identified as having atypical phenylketonuria (594 to 1149 umol per liter) and 9 mothers were identified as having mild hyperphenylalaninemia (165 to 540 umol).  None of the mothers had been treated for phenylketonuria.  One mother with the classic form of the disorder was mentally retarded (IQ, 45), but the other mother with the classic form performed in the average range of intelligence (IQ, 94).  The mean IQ was 99.3+9.4 for women with atypical phenylketonuria, and 105.0+11.9 for those with mild hyperphenylalaninemia.  The blood tyrosine concentrations ranged from 26 to 78 umol per liter.  No other amino acid abnormalities were noted in the women.

Anthropometrics Head circumference and birth weight reported, differences among groups not described. 

Location: Massachusetts


Summary of Results:


Prenancy, Labor and Delivery - 59 untreated pregnancies occurred, 6 ended in spontaneous abortion.  Complications occurred in 5 pregnancies, including toxemia, hydramnios, placenta previa, abruptio placentae and premature rupture of the membranes.  The frequency of complications is comparable to that reported in the general white population.


Perinatal Complications - occurred in 3 births, including nuchal cord in 2 infants and an irregular heart beat in a 3rd.

Phenylketonuria or hyperphenylalaninemia - 6 offspring had either Phenylketonuria or hyperphenylalaninemia.  These occured in 2 familes and in each there was a child with PKU, at least one child with mild hyperphenylalalninmia and at least one child with a normal blood phenylalanine level.  In both families the mothers had mild hyperphenylalaninemia and the father had normal phenylalanine levels.

Head Circumference - 3 of the 4 children born to mothers with classic PKU had microcephaly at birth and at the most recent examination.  23% of offspring born to mothers with atypical phenylketonuria had microcephaly at birth, but only 1 had microcephaly at the most recent evaluation.  

Birth Weight - Children born to mothers with classic PKU had normal birth weight.  Only 2 of the offspring had a birth weight at or below 2500 g.  All but one had normal weight at the most recent examination.

Intellectual Functioning - the 6 children with PKU or hyperphenylalaninemia were excluded from analysis.  3 of the 4 chldren born to mothers with classic PKU had IQ scores between 64 and 69 (mild retardation) and the 4th scored 84 (borderline intelligence), with marked hyperactivity and hyperflexia.  These children had visual-motor coordination more than 2 years below age level and were in special classes.

The mean IQ in 13 children of mothers with atypical PKU was 95.2 + 13.4.  The mean IQ in 10 children of mothers with mild hyperphenylalaninemia had a mean IQ of 116.6+ 13.6 and all had scores in or above the average range of intelligence.  The DQ of the 10 younger children whose mothers had either atypical PKU or mild hyperphenylalanemia ranged from 90 to 135.  11% had more than a 2 year delay in visual-motor coordination.

Most of the children with visual-motor problems had general learning deficits.

Congenital Heart Disease - Only 1 child had congenital heart dx.  The mother of this child had atypical PKU.  There was a 7.5% frequency of congenital malformations which is higher frequency reported in childhood populations.

Correlations between Maternal Charcteristics and Offspring Characteristics in Maternal PKU and Hyperphenylalaninemia.





Blood Phenylalanine Levels


Blood Tyrosine Level

Offspring IQ

 r = .83, p <.001

(n= 26)

 r = -.82, p <.001


 r = .42, p <.013


Offspring Headcircumference at birth

 r = .24, p = NS


 r = -.49, p <.003


 r = .19, p = NS

(n = 30)

Offspring Birth Weight

r = .002, p = NS


r = -.17, p = NS


r = .30, p = .047

(n= 33)

In 5 families, an IQ score was available for the father as well as the mother.  In 4 of these families, the IQ in the offspring was closer to the mother's IQ than that of the fathers.


Author Conclusion:

Severe atypical or classic phenylketonuria (blood phenylalanine level, >1100 umol/liter) in the mother has a substantial cognitive effect on her offspring, but the effect of mild hyperphenylalalninmeia may have been overstated in the past.  Women with the classic and severe atypical forms of PKU should be treated with a low phenylalanine diet during pregnancy, preferably beginning before conception.  The decision to treat women with a less severe degree of atypical phenylketonuria during pregnancy may have to be consider in light of the possible risk to the fetus verses maintenance of the severe dietary restriction.

Microcephaly in offspring was consistently present only when the mother had classic PKU.

The occurrence of congenital heart disease and low birth weight as complications of maternal hyperphenylalaninmeia may have been overstated in past studies.

The carrier rate of of mutant phenylananine hydroxylase gene may be higher than previously anticipated. 

Funding Source:
Government: HRSA, NINDS, State Laboratory Institue Massachusetts Dept of Public Health
University/Hospital: Children's Hospital, Harvard Medical School, Massachusetts Department of Public Health
Reviewer Comments:

The potential for maternal PKU to negatively impact outcomes in offspring is unquestionable.  The authors raise an interesting question related to less severe atypical phenylketonuria and mild hyperphenylalaninemia and the need for strict diets in these mothers.

Key information related to the data anaylsis was missing as follows:

The authors did not report specific ages of data collection for either the mothers or the children.  This is particularly relevant with the children's data given the potential progression of PKU.

Different scales for visual-motor assessment used with no explanation given. 

The n reported in the correlation matrix varies greatly with no explanation given for missing or differing values.  Likewise Mothers' missing IQ scores and offspring's missing head-circumference data is not explained.

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) Yes
  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? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
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) Yes
  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.) N/A
  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.) N/A
  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? ???
  4.1. Were follow-up methods described and the same for all groups? ???
  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%.) ???
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? ???
  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? ???
  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.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  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? ???
  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? No
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  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? ???
  7.1. Were primary and secondary endpoints described and relevant to the question? ???
  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? ???
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? ???
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  8.2. Were correct statistical tests used and assumptions of test not violated? ???
  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)? N/A
  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? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? No
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? No
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