HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maillot, F. Articles by Lee, P. J PubMed PubMed Citation Articles by Maillot, F. Articles by Lee, P. J Agricola Articles by Maillot, F. Articles by Lee, P. J

Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine^1,2

¹ From the Charles Dent Metabolic Unit, The National Hospital for Neurology & Neurosurgery, London, United Kingdom (FM, ML, JB, and PJL), and the Environmental Change Research Centre, University College London, London, United Kingdom (DWM)

² Reprints not available. Address correspondence to F Maillot, Charles Dent Metabolic Unit, Post Box 92, The National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom. E-mail: maillot{at}med.univ-tours.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Developmental delay in the offspring of women with phenylketonuria (PKU) can be prevented by maintaining maternal blood phenylalanine (Phe) within a target range (100–250 µmol/L).

Objective: We aimed to analyze outcomes in the offspring of women with PKU during pregnancy and to identify prognostic factors.

Design: Occipitofrontal circumference at birth (OFC-B); developmental scores [developmental quotient (DQ) and intelligence quotient (IQ)]at 1, 4, 8, and 14 y; and the time of starting a Phe-restricted diet (before or after conception) were collected. The influence of maternal Phe concentrations during pregnancy on offspring outcomes also was assessed.

Results: The study included 105 children born to 67 mothers with PKU. Mean (±SD) OFC-B z scores did not differ between the preconception and postconception diet groups (0.42 ± 1.24 and –0.96 ± 1.19, respectively). DQ at 1 y and IQ at 8 y were higher in offspring from the preconception diet group than in offspring from the postconception diet group [DQ: 107 ± 13.8 and 99.3 ± 13.3, respectively (P = 0.014); IQ: 110.6 ± 14.8 and 91.2 ± 23.9, respectively (P = 0.005)]. Maternal Phe concentrations correlated negatively with DQ and IQ scores, and variations (SD) in all maternal blood Phe correlated negatively with 4-, 8-, and 14-y IQ scores (r = –0.385, –0.433, and –0.712; P = 0.002, 0.008, and 0.031, respectively), even when concentrations were consistently within the target range.

Conclusions: The study suggests that women with PKU should start a Phe-restricted diet before conception. Maintenance of maternal blood Phe within the target range predicts good offspring outcomes, but variations even within that range should be avoided.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
High maternal phenylalanine (Phe) concentrations are associated with facial dysmorphism, microcephaly, development delay, learning difficulties, and congenital heart disease (CHD) in the offspring of women with phenylketonuria (PKU) (1, 2). Data from the prospective international Maternal PKU Collaborative Study [MPKUCS (3)], the French survey (4), and the United Kingdom PKU Registry (5) showed that many features of the maternal PKU syndrome are preventable when dietary phenylalanine intake is restricted before conception or soon afterward. Nevertheless, data from the United Kingdom PKU Registry also showed the lack of homogeneity in the care of pregnant PKU patients and showed that fetal outcome is better in pregnancies cared for by centers with more experience (5). Evaluating maternal PKU pregnancies followed at a single, experienced center specifically dedicated to the care of adults with inherited metabolic diseases is therefore of interest in helping define the specifics of management.

The practical management of maternal PKU at the Charles Dent Metabolic Unit was fully reported previously (6). Briefly, the policy is to advise that the Phe-restricted diet should start before conception and that the maternal blood Phe concentration should be maintained between 100 and 250 µmol/L before conception and throughout pregnancy (7). After intensive dietary education of the patients, fasting Phe concentrations are measured at home (by the patients) 2 times/wk before conception and 3 times/wk afterward. Postnatal management includes neurologic assessment of the infant at 4–8 wk and echocardiography for infants conceived while the mothers were not following the Phe-restricted diet. Subsequently, offspring are seen at 1, 4, 8, and 14 y for formal psychometric testing. Here we report an evaluation of the effect of the timing of diet induction—ie, before or after conception—and of maternal Phe concentrations during pregnancy on cardiac and neurodevelopmental outcomes of infants born to women with PKU who were followed in the Metabolic Unit from 1977 to 2005.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
A retrospective review of the pregnancies cared for in the Metabolic Unit at University College London Hospitals from January 1977 to June 2006 was performed by examining medical and dietetic notes. For the present study, we included live births between January 1977 and June 2005, so that all offspring had at least 1-y neuropsychometric assessments. Gestational variables included the timing of the start of the Phe-restricted diet (ie, before or after conception), gestational age, maternal weight change, and blood Phe concentrations throughout the pregnancy. Gestational age was expressed as the number of weeks after the last menstrual period.

Methods
Fasting Phe concentrations were collected by home monitoring and were recorded on a continuous scale of timing. Blood Phe was measured from blood spots by using the Guthrie method from January 1977 to July 1994, by using HPLC from August 1994 to 2004, and by using tandem mass spectrometry from 2004 through the remainder of the study period. The blood Phe target range was set at 100–250 µmol/L, according to Medical Research Council recommendations (7). Phe concentrations were assessed from several measurements: 1) the mean of all Phe concentrations recorded during the entire pregnancy; 2) the mean of all Phe concentrations recorded for each trimester of the pregnancy; 3) the percentage of time with Phe concentrations below, within, or above the target range; and 4) the variability of Phe concentrations during pregnancy, assessed by using the SDs of Phe concentrations during each pregnancy.

The offspring outcome variables were body weight (BW) and occipitofrontal circumference at birth (OFC-B). BW and OFC-B were collected from delivery records and expressed as z scores by using the EXCEL add-in IMSGROWTH software (version 2.12; Microsoft, Redmond, WA). The outcome measures after birth were developmental quotients (DQs) or intelligence quotients (IQs) (or both) at ages 1, 4, 8, and 14 y and the presence or absence of malformations or congenital heart disease (CHD). Developmental assessments were performed in each case by the same developmental psychologist (JB). Developmental outcome was assessed by means of the Griffiths Mental Development Scale at 1 y (for DQ) (8), the McCarthy Scales of Children's Abilities at 4 y [for General Cognitive Index (GCI)] (9), and the Weschler Intelligence Scale for Children–III (for IQ) at ages 8 and 14 y (10).

Statistical analysis
Data are expressed as means ± SDs unless indicated otherwise. To assess the differences in Phe concentrations and outcome measures between the 2 diet groups, 2-tailed unpaired t tests were used with a 95% significance level. To quantify whether there was a significant linear relation between Phe concentration and an individual outcome measure, the Pearson product-moment correlation coefficient (r) was calculated between the 2 sets of variables. The significance of these correlations was measured by calculating the associated P value. We carried out t tests by using MICROSOFT EXCEL 2002 (version 2002; Microsoft, Redmond, WA), and Pearson product-moment correlation coefficients were calculated by using MINITAB software (version 13.22; Minitab Inc, State College, PA). Statistical significance was set at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
From January 1977 to June 2005, 109 infants were born to 67 women with PKU: 37 women had 1 pregnancy, 21 had 2 pregnancies, 6 had 3 pregnancies, and 2 had 4 pregnancies; 2 pregnancies resulting in twins were excluded from the analyses, which left a total of 105 offspring. Of these, 73 (69.5%) were born to mothers who began the Phe-restricted diet before conception (preconception diet group) and 32 (30.5%) to mothers who began the diet after conception (postconception diet group). In the latter group, the time-point during gestation at which the Phe-restricted diet was begun was 9.88 ± 7.35 wk (median: 7 wk; minimum: 3 wk; maximum: 26 wk). When we divided the study period into decades, we found that the diet was begun before conception in 4 of 7 pregnancies (57.1%) from 1977 to 1986, in 37 of 43 pregnancies (86%) from 1987 to 1996, and in 34 of 55 pregnancies (61.8%) from 1997 to 2005. Data on maternal weight change were available from only 60 pregnancies, all of which were in the preconception diet group. Total weight gain was 9.2 ± 4.73 kg. Mean weight change was –0.4 ± 2.20, 4.9 ± 2.75, and 4.7 ± 2.68 kg in the first, second, and third trimester, respectively.

Mean blood Phe concentrations for entire pregnancies were lower when the diet was begun before conception than when it was begun after conception (203.5 ± 58 compared with 269 ± 115 µmol/L, respectively; P = 0.0003), especially during the first trimester (248.8 ± 86.6 compared with 493.6 ± 289.4 µmol/L; P < 0.0001). Phe also remained significantly lower in the preconception diet group than in the postconception diet group during the second (172.8 ± 59.4 and 253.1 ± 179.4 µmol/L, respectively; P = 0.0015) and third (183.4 ± 43.9 and 217 ± 64.2 µmol/L, respectively; P = 0.006) trimesters (Figure 1). The proportion of time when the Phe concentrations were within the target range (100–250 µmol/L) was greater in the preconception diet group than in the postconception diet group (62.4 ± 17.3 and 42.4 ± 16.6%, respectively; P = 0.00027). The proportion of time when the Phe concentrations were >250 µmol/L was less in the preconception diet group than in the postconception diet group (22.5 ± 15.9 and 48.4 ± 19%, respectively; P < 0.0001). There was no significant difference between the 2 diet groups with respect to the proportion of time when the Phe concentrations were <100 µmol/L (16.2 ± 12.44% compared with 10.72 ± 6.22%, respectively). The duration of gestation was longer when the diet was begun before conception than when it was begun after conception (39.8 ± 1.4 compared with 38 ± 3.21 wk, respectively; P = 0.0004).

View larger version (7K): [in this window] [in a new window]   FIGURE 1. Comparison (2-tailed unpaired t tests) of mean ± SD maternal blood phenylalanine concentrations in the preconception (, n = 73) and postconception (, n = 32) phenylalanine-restricted diet groups during the entire pregnancy (P = 0.0003) and during the first (P < 0.0001), second (P = 0.0015), and third (P = 0.006) trimesters. In the postconception diet group, data for the first and second trimesters were obtained from 25 pregnancies.

Table 1

Table 2

Table 3

Table 4

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The data presented here clearly indicate that women with PKU must start a Phe-restricted diet before conception to achieve metabolic control throughout pregnancy and, consequently, an optimal offspring outcome. Beginning the diet before conception leads to better metabolic PKU control: a higher proportion of Phe concentrations in the target range and of lower mean Phe concentrations were seen in each trimester in the preconception diet group than in the the postconception diet group. As shown in Table 2, all DQ and IQ scores were significantly higher when the diet was begun before conception, except 4-y GCI, which was not statistically significantly different (P = 0.10). Although different neuropsychometric assessments were used in the different age groups, all of the assessments are well validated in various populations for measuring DQ and IQ. Differences in relations with DQ and IQ could have to do with the different tests used, but we feel that they are more likely to be related to the metabolic environment. Beginning the Phe-restricted diet before conception also abolished the risk of CHD in the present cohort, although mild and clinically silent forms of CHD may have gone undetected, because systematic echocardiograms were not performed in the preconception diet group. Nevertheless, our data are concordant with the MPKUCS data, which showed that beginning the Phe-restricted diet before conception and achieving metabolic control (Phe < 900 µmol/L) no later than week 8 of gestation significantly reduced the incidence of CHD (12). In the present study, the 12% incidence of CHD in the postconception diet group was close to that described previously (12, 13). The 4 infants with CHD (Table 1) were born to mothers with PKU who had high untreated Phe concentrations and who began the Phe-restricted diet between weeks 7 and 18 of gestation.

OFC-B was larger when diet started before conception, but the comparison between diet groups was not statistically significant, although the numbers in the present study may have been insufficient to show such changes in comparison to larger studies (5). OFC-B is a marker of fetal brain growth, and, despite our findings, it is still an important outcome measure in maternal PKU. In evaluating maternal Phe concentrations in each trimester, we found that correlations with developmental scores were observed in the first trimester and to a lesser extent in the third trimester. Thus, with respect to neurodevelopment and the occurrence of CHD, metabolic PKU control is critical early in pregnancy, and it must be maintained throughout pregnancy to ensure satisfactory cognitive development.

The novel finding of this study was the effect of variations in blood Phe concentrations on offspring outcome. When we considered the entire pregnancy, using SD as a measure of variation in Phe, we found strong negative correlations with IQ scores at 4, 8 and 14 y, but this was not the case with mean Phe concentrations. The SD of Phe remained important even when mean Phe concentrations were consistently within the target range, which suggests not only that Phe concentrations should be kept within the target range, but also that they should be kept as consistent as possible within that range. This approach is in keeping with the good pregnancy outcome seen in women with untreated hyperphenylalaninemia, in whom Phe concentrations vary little (2). Variation in Phe concentrations expressed as SD was previously shown to relate to mothers' age and education and to the severity of phenylalanine hydroxylase mutation (14), but it has never previously been shown to influence fetal outcome. It is likely that more frequent monitoring could prevent these variations in Phe concentrations by allowing more responsive dietary advice. The current Medical Research Council recommendations are for twice-weekly Phe measurements before conception and thrice-weekly measurements afterward; this recommendation is supported by evidence from the United Kingdom PKU Registry and the MPKUCS. However, we are aware that some centers monitor less frequently, despite considerable fluctuations in Phe concentrations within a 24-h period (15).

Overall, the present study indicates that maintenance of Phe concentrations in the target range of 100–250 umol/L is associated with a good offspring outcome, which is the main goal of maternal PKU management. Nevertheless, questions remain as to what the optimal range is. Looking at the lower end of the range, we did not observe any adverse effect on DQ and IQ scores of periods when Phe concentrations were <100 umol/L. This finding suggests that low maternal Phe concentrations are not harmful but should be interpreted cautiously, because the time when Phe concentrations were <100 umol/L represented just 10% of the total time in both diet groups. Our own observations from twin pregnancies, a time during which keeping up with protein needs can be challenging, suggest that prolonged periods of low Phe concentrations are associated with poor neuropsychometric outcomes. Trying to define the upper threshold of Phe concentrations is also difficult, but our data indicate that the outcome is more likely to be negatively influenced when mean Phe concentrations during pregnancy are >300 µmol/L. That concentration is not very different from the 360 µmol/L threshold proposed by the MPKUCS investigators (3, 16).

Although the present study clearly shows that maternal Phe concentrations have a strong effect on offspring developmental outcome, other influencing factors cannot be excluded. Indeed, some offspring have good outcomes despite poor metabolic control of PKU, which suggests that important, as-yet-undetermined factors—placental, fetal, or maternal—may be protective (17). Data on potentially influencing factors such as maternal IQ, education, or social class were, unfortunately, not collected in our study and thus could not be investigated. The genotype of pregnant women with PKU has also been shown to affect offspring outcome by influencing the severity of PKU (18), but molecular analyses are not currently performed in our center. Just 37 of the offspring were the only children born to their mothers; the rest had 1 sibling that was included in the study. Those women who conceived while following the Phe-restricted diet and who maintained satisfactory metabolic control during the pregnancy were more likely to repeat this behavior in subsequent pregnancies. The converse is also true, and, thus, an overall potential sibling effect is likely to be diminished. The effect of this possibility and the effect of birth order on outcome should be considered, but, with such small numbers in the present study, those effects would have been difficult to evaluate. Adequate maternal nutrition and weight gain also are of interest, because they can influence the offspring's birth measurements (19). Those factors are regularly assessed in the Metabolic Unit, but the data show that women with PKU lost weight in the first trimester, which led to a total weight gain below that recommended, which normally is 11–16 kg by week 40 of gestation (20). Weight loss within the first trimester probably reflects an insufficient calorie intake related to the Phe-restricted diet itself (6, 11) or, in some cases, to the nausea and vomiting associated with pregnancy. The exact effect of maternal weight gain on fetal outcomes in this situation remains to be investigated further.

In conclusion, our data strongly support the concept that a Phe-restricted diet should start before conception to avoid malformations and CHD and to ensure the best possible developmental outcome for the offspring. Metabolic PKU control is important throughout pregnancy and essential during the first trimester. Not only is it important to aim to maintain maternal blood Phe concentrations of <300 µmol/L, but, also, variations in Phe concentrations should be minimized. Frequent monitoring of Phe concentrations is thus recommended.

	ACKNOWLEDGMENTS

 
We thank the women with PKU, their partners, and the children for their involvement in our Maternal PKU Programme. We are indebted to David Brenton for setting up this service 30 y ago.

The authors' responsibilities were as follows—FM: conception and design of the study, collection of data, and drafting, revision, and final approval of the manuscript; ML: dietetic management, collection of data, and revision and final approval of the manuscript; J Baudin: IQ/DQ assessments and revision and final approval of the manuscript; DWM: statistics and revision and final approval of the manuscript; and PJL: conception and design of the study, collection of data, revision and final approval of the manuscript. None of the authors had a personal or financial conflict of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Dent CE. The relation of biochemical abnormality to the development of mental defect in phenylketonuria. In: Etiologic factors in mental retardation: report of twenty-third Ross Pediatric Research Conference. Columbus, OH: Ross Laboratories, 1957:32–3.
2. Levy HL, Waisbren SE. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J Med 1983;309:1269–74.[Abstract]
3. Koch R, Hanley W, Levy H, et al. The Maternal Phenylketonuria International Study: 1984-2002. Pediatrics 2003;112:1523–9.[Abstract/Free Full Text]
4. Feillet F, Abadie V, Berthelot J, et al. Maternal phenylketonuria: the French survey. Eur J Pediatr 2004;163:540–6.[Medline]
5. Lee PJ, Ridout D, Walter JH, Cockburn F. Maternal phenylketonuria: report from the United Kingdom Registry 1978–97. Arch Dis Child 2005;90:143–6.[Abstract/Free Full Text]
6. Maillot F, Cook P, Lilburn M, Lee PJ. A practical approach to maternal phenylketonuria management. J Inherit Metab Dis 2007;30:198–201.[Medline]
7. Medical Research Council Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993;68:426–7.[Medline]
8. Huntley M. Griffiths Mental Development Scales (birth to 2 years). 1996 revision. Oxford, United Kingdom: The Test Agency Ltd, 2006.
9. McCarthy D. McCarthy scales of children's abilities. New York, NY: The Psychological Corporation, Harcourt Brace Jovanovich, 1972.
10. Wechsler D. Wechsler Intelligence Scale for Children Third Edition (WISC-III). London, United Kingdom: The Psychological Corporation Ltd, 1991.
11. Koch R, Friedman E, Azen C, et al. The International Collaborative Study of Maternal Phenylketonuria: status report 1998. Eur J Pediatr 2000;159(suppl):S156–60.[Medline]
12. Levy HL, Guldberg P, Güttler F, et al. Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study. Pediatr Res 2001;49:636–42.[Medline]
13. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia: an international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980;303:1202–8.[Abstract]
14. Widaman KF, Azen C. Relation of prenatal phenylalanine exposure to infant and childhood cognitive outcomes: results from the International Maternal PKU Collaborative Study. Pediatrics 2003;112:1537–43.[Abstract/Free Full Text]
15. MacDonald A, Rylance GW, Asplin D, Hall SK, Booth IW. Does a single plasma phenylalanine predict quality of control in phenylketonuria? Arch Dis Child 1998;78:122–6.[Abstract/Free Full Text]
16. Waisbren SE, Azen C. Cognitive and behavioral development in maternal phenylketonuria offspring. Pediatrics 2003;112:1544–7.[Abstract/Free Full Text]
17. Hanley WB, Azen C, Koch R, et al. Maternal Phenylketonuria Collaborative Study (MPUCS)—the "outliers." J Inherit Metab Dis 2004;27:711–23.[Medline]
18. Guttler F, Aen C, Guldberg P, et al. Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome. Pediatrics 2003;112:1530–3.[Abstract/Free Full Text]
19. Michals-Matalon K, Acosta PB, Azen C. Role of nutrition in pregnancy with phenylketonuria and birth defects. Pediatrics 2003;112:1534–6.[Abstract/Free Full Text]
20. Bishop J, Ford F, Thomas B. Pregnancy. In: Manual of dietetic practice. Oxford, United Kingdom: Blackwell Science, 2001:216–25.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maillot, F. Articles by Lee, P. J PubMed PubMed Citation Articles by Maillot, F. Articles by Lee, P. J Agricola Articles by Maillot, F. Articles by Lee, P. J