This study described current dietary management practices of pregnant PKU patients at Vancouver General Hospital, BC, Canada, while demonstrating that adherence to phenylalanine intake recommendations worked to achieve metabolic control before 8 wk pregnant, as per recommendations from the Maternal PKU Collaborative Study (15, 20). Though current counselling on the importance of preconception control is provided, this study highlights the importance of continuing to search for new strategies, as the mean phenylalanine concentrations in blood spots were above the recommended range preconception. Few patients in our analysis obtained control prior to conception, despite the policy of discussing the need to plan pregnancy at every visit. Our analysis also indicated a more rapid increase in phenylalanine tolerance around 20 wk gestation, highlighting the importance of continued monitoring of patients as the pregnancies progress so that blood phenylalanine levels don’t drop too low.
The rise in phenylalanine tolerance throughout PKU pregnancies has been documented in previous studies. Phenylalanine tolerance refers to the quantity of phenylalanine PKU patients can consume while maintaining target plasma phenylalanine concentrations (120–360 umol/L). However, it has also been recorded that the rise in phenylalanine tolerance was reduced in pregnancies where the fetus also has PKU, paired with a greater likelihood of having elevated phenylalanine concentrations in blood (21). This suggests that PAH activity in the fetus plays a role in maternal metabolic control, and that a smaller increase in phenylalanine tolerance towards latter stages of pregnancy may indicate fetal PKU. No offspring were diagnosed with PKU from the 16 pregnancies reported in this study. We did not have access to the PAH genotype responsible for the PAH mutation, or the patients’ original diagnosis. Therefore, differences among the patients’ phenylalanine tolerance slope throughout pregnancy could be affected by differences among their ability, as well as their fetus’ ability, to metabolize phenylalanine.
Previously, our laboratory determined the minimum dietary phenylalanine (in the presence of excess tyrosine at 65 mg·kg− 1·d− 1) requirement for healthy pregnant women using stable isotope-based techniques. During early pregnancy (13–19 wk), we found the mean requirement to be 15 mg·kg− 1·d− 1, which is 65% higher than what has previously been determined in adult males (11, 22). Comparing healthy pregnancy data to non-pregnant adult data highlights that the requirement for phenylalanine increases even in early pregnancy. The mean requirement for phenylalanine during late pregnancy (33-39wk) is 21 mg·kg− 1·d− 1, which is 40% higher than the mean requirement for early pregnancy (11). These results provide insight into aromatic amino acid requirements and metabolism during pregnancy, having implications for future studies and current clinical practices for women with PKU in pregnancy. The increase in the dietary requirement for phenylalanine throughout pregnancy corresponds to an increase in nitrogen retention and tissue synthesis. When comparing against the data collected from the current study, at 13–19 wk pregnant, PKU patients were consuming approximately 50% less phenylalanine than the previously determined requirement (15 mg·kg− 1·d− 1) in healthy pregnant women (11). At 33–39 wk pregnant, the difference was narrower, with patients consuming 16% less phenylalanine than the previously determined requirement of 21 mg·kg− 1·d− 1 (11). A rationale for why these patients consumed less phenylalanine than the requirements in healthy pregnant women while maintaining good metabolic control may be due to obligatory oxidation of phenylalanine to tyrosine when PAH is functioning properly. This remains true even when healthy women are provided with excess tyrosine in the diet, which allows for saturation of the body’s tyrosine pool, meaning there will be a decrease in loss of phenylalanine from conversion to tyrosine in PKU patients (23). There is data to support that some obligatory oxidation of phenylalanine through conversion to tyrosine occurs in healthy human populations, varying depending on method of determination and life stage, with previous studies showing a wide range of 2–26% (22–25). While obligatory phenylalanine oxidation has not been measured during pregnancy, there is no way of knowing if it is affected during different stages of gestation. However, this may explain the lower phenylalanine intake in comparison to previously determined requirements. Another potential rationale is that with the increase in phenylalanine levels seen in blood spots between 8 and 12 wks, the dietitians are recommending very low phenylalanine intakes to ensure the patients achieve metabolic control during this critical stage of development. The fetus also grows significantly in size in the second trimester. Lastly, though unknown, the decrease in percent difference from 50–16% in phenylalanine intake compared to requirements may be due to the maturing fetus’s phenylalanine utilization and PAH capabilities, allowing for more conversion of phenylalanine to tyrosine.
Mean protein intake, as a function of kg of body weight, increased throughout the pregnancies. This corresponds well to what we know about dietary protein requirements during pregnancy, as there are increases in nitrogen retention and tissue accretion throughout pregnancy (12, 26). It is important to remember that the total protein values we report are estimated from phenylalanine intake and added to what is consumed as medical food. There was negligible percent difference (less than 5%) between protein intake at 13–19 wk and 33–39 wk when compared to the previously determined protein requirement in healthy pregnant women. Having a protein intake in excess of the requirement in all PKU patients is recommended, since low phenylalanine intake can limit protein synthesis (27). Our laboratory has shown earlier that children with PKU have a mean protein requirement of 1.85 g·kg− 1·d− 1, which is substantially higher than the recommendations for PKU children of 1.33 g·kg− 1·d− 1 (28). While PKU protein requirements in pregnancy are yet to be determined, ideally, protein and other amino acids should not be limiting, further decreasing the potential for adequate protein synthesis (17). The current DRI recommendation is 0.88–1.1 g·kg− 1·d− 1 throughout all of pregnancy (13), and in general PKU management the target is to achieve 120–140% above this recommendation which is also typically applied in pregnant patients with PKU. In the current study PKU women were consuming a mean protein intake of 1.2 and 1.6 g/kg/d in early and late gestation, and very similar to our determined mean requirement of 1.2 and 1.52 g/kg/d in healthy pregnancy. With the advancement of formulas, including Glycomacropeptide (GMP) products where a large component of this protein source is low phenylalanine intact protein, there is a need to determine protein requirements in PKU during different gestation stages to explore if they meet optimal protein intake recommendations.
Recently, a research group in Baltimore performed a retrospective analysis of pregnant PKU patients (n = 35) and determined that women who achieved metabolic control of phenylalanine prior to conception had improved phenylalanine plasma concentrations for the remainder of their pregnancy, similar to previously published studies (29–31). This indicated that early metabolic control was a good predictor for overall control throughout pregnancy. In the current study, we found that both those who had good metabolic control (consistent phenylalanine blood levels between 120 and 360 umol/L) and those who didn’t (consistent phenylalanine levels > 360umol/L) both managed to achieve good metabolic control during the pregnancy by 8 wks. Another publication, from the Charles Dent Metabolic Unit in London, described their clinic’s current PKU management in pregnancy. Similarly, they highlight the importance of pre pregnancy control, emphasizing that natural sources of dietary protein should be greatly restricted (32). As well, a research group in Turkey retrospectively analyzed data from pregnant PKU patients (n = 71) (33). They determined that metabolic control worsens during the late first trimester, and that more frequent monitoring during this period may be one of the keys to improving metabolic control and birth outcomes. A similar trend is seen in our current analysis, where mean phenylalanine concentrations in blood increased around 8–12 wk pregnancy, while staying below 360 umol/L, and then reduced and stabilized. However, our findings also highlight the importance of continued monitoring during late stages of pregnancy, where phenylalanine tolerance rises at a higher rate (Fig. 2). Continuing to diligently monitor these patients after 20 wk will prevent phenylalanine concentrations from dropping too low, which can increase the risk of complications such as intrauterine growth restriction (34).
Maintaining proper tyrosine levels is also important in pregnant women with PKU. Tyrosine is the precursor for catecholamines, thyroid hormones, and melanin, with both low and high levels of tyrosine having potential health impacts on the mother and fetus (35). Tyrosine monitoring and supplementation occurs in PKU patients to reduce/mitigate any potential negative effects, though they are poorly understood. During PKU pregnancies, a tyrosine deficiency may be particularly harmful to the fetus; not only is the mother unable to synthesize tyrosine, but the fetus also has reduced tyrosine synthesizing capacity due to its increased risk of having PKU and its premature hepatic enzymatic abilities (36, 37). Therefore, it is currently recommended that if multiple low tyrosine concentrations in blood spots are observed, supplementation should be initiated (17, 36, 38, 39). Though currently there is no evidence for tyrosine toxicity in PKU pregnancies from overconsumption, there are arguments for preventing blood concentrations from rising too high (39). Active transport of placental tyrosine to the fetal compartment will allow fetal blood tyrosine concentrations to be 1.8 to 3.3 times greater than maternal concentrations (40). These high concentrations have unknown consequences on fetal development. As well, due to competitive inhibition of placental transporters that carry both phenylalanine and tyrosine, fetal phenylalanine concentrations may be lowered (41). In comparison with previous publications, the blood spot tyrosine values observed in our analysis indicate good monitoring and control of tyrosine, and will contribute to the body of reference values currently available for PKU pregnancies (36, 38, 42).
Our retrospective analysis has limitations. Firstly, we did not have access to the health records of the babies to allow us to analyze any long-term effects. We recognize this would have broadened the scope of our study, as the long-term complications of uncontrolled or unmanaged PKU in pregnancy are well documented. It is difficult to determine if the current management mitigates these risks without including this piece of information. As well, our sample size was small, though this is a common problem with inherited metabolic disease studies. Lastly, we had to extrapolate both natural dietary protein intake and weight was estimated at each stage of pregnancy.
In conclusion, the current dietary management practices described in this retrospective analysis of pregnant PKU patients from Vancouver General Hospital, Vancouver, are sufficient to achieve targeted metabolic control. Mean phenylalanine and tyrosine concentrations in blood are within the target range by 8 wk gestation. The findings highlight the importance of early intervention with good metabolic control and continued diligent management throughout pregnancy to ensure phenylalanine and tyrosine levels remain in the target range throughout the pregnancy. Recent evidence on Phe requirements in healthy pregnant individuals clearly show that Phe requirements increase 65% by ~ 16wk compared to non-pregnant individuals, suggesting an increased demand for Phe by the placental-fetal unit. Whether pregnant PKU individuals needs for phenylalanine are increased early in pregnancy needs to be determined in future. When metabolic control is poor pre-conception, our study also highlights that good metabolic control of phenylalanine can be achieved quickly with proper management. This study provides a wealth of reference values to allow for comparison between clinics, an understanding of how well our own practices are working at the Adult Metabolic Diseases Unit, and provides a basis for future experimental studies in our pregnant PKU population.