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Maternal phenylketonuria: the importance of early control during pregnancy
  1. R Koch
  1. Correspondence to:
    Dr R Koch
    Principal Investigator, Maternal PKU Collaborative Study, Los Angeles, California, USA;

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Commentary on the paper by Lee et al (see page 143)

Drs Lee, Ridout, Walters, and Cockburn have reviewed data on 228 pregnancies occurring in women with phenylketonuria (PKU).1 This paper provides important data which support the main findings of the Collaborative Maternal PKU Study sponsored by the National Institute of Child Health and Human Development in Bethesda, Maryland, USA.2 Despite the fact that the data of Dr Lee et al are based on pregnancies occurring only in the United Kingdom, the findings verify two of the most important findings in our longitudinal, prospective study, which collected data from three different countries: the United States, Canada, and Germany. In any international study such as the latter, cultural and social differences can always interfere with statistical analyses. Therefore the fact that both studies support and concur that pregnancies in control by the first 10 weeks of pregnancy resulted in normal intellectual development in the offspring at 6–8 years is important information. Furthermore, both studies observed that the occurrence of congenital heart disease in the offspring of women in good metabolic control very early in pregnancy was reduced to 1–2%, compared to 14–17% in those not in good control.

It is true that the numbers in the British study are smaller than those in the Collaborative Study and alone would not satisfy strong biostatistical evaluation. Only 32 offspring had IQ data at 8 years, whereas in the latter study, follow up data at 6–8 years of age were examined in 231 children.

It is also true that the two studies were organised in a different fashion and yet arrived at similar conclusions. The British study was based on a registry, which was analysed retrospectively for significant outcomes, whereas the Collaborative Study was longitudinal in nature and based on a specific protocol. It is remarkable that the results coincide on the major outcome data.

In reviewing both published studies, it is clear that a public health effort will have to be mounted to further improve outcome. For example, only some 50% of the women were treated before conception. While we currently look on this as significant progress, future studies will undoubtedly show more improvement as we begin to deal primarily with women of normal intelligence. The two reports involve a significant number of women with IQs of 85 or below. For discussion purposes, let us assume that the IQs in the British mothers were similar to those of mothers in the Collaborative Study. If so, 51% of the women with PKU reported in the Collaborative Study had documented IQ assessments of less than 85 on the Wechsler Adult Intelligence Scale. This significant reduction in maternal IQ in both studies is undoubtedly related to the diet discontinuation phase of treatment occurring in many countries during the period between 1965 and 1985. Today diet continuation for women with phenylketonuria is accepted procedure for most countries. Therefore future studies hopefully will be based on outcome in women with normal intelligence. It is my opinion that the availability of mutational data will aid us in selecting women with PKU who definitely must remain on a phenylalanine restricted diet, especially during their childbearing years.

The future use of tetrahydrobiopterin (BH4) in the treatment of pregnancies either alone or in combination with phenylalanine restriction in the mother’s diet also offers hope for improved fetal outcome. The IQ spread in the mothers evaluated in the Collaborative Study was 58–130. There were 48 women in the Collaborative Study who had mild hyperphenylalaninaemia. In the evaluation of the offspring of these 48 women, 40 of whom were untreated and eight of whom were treated with a phenylalanine restricted diet, Levy et al reported that the mean IQ of the 6–8 year old offspring was 102.3 No significant difference in IQ was found between the offspring of the women who were untreated and those who were treated. Future studies may document that treating women with PKU hopefully will produce a better fetal outcome in these pregnancies.

In conclusion, it is for future investigators to verify these new treatment modalities, and perhaps BH4 will prove useful in improving intellectual outcome even in women with classical PKU with two severe mutation of the phenylalanine hydroxylase gene.


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