High maternal blood PHE is a fetal teratogen resulting in the maternal PKU syndrome (MPKUS) that includes microcephaly, low birth weight (LBW), congenital heart disease (CHD), and intellectual disability in children born to mothers with untreated PKU during pregnancy (L.163). The NIH Consensus Statement in 2001 recommended maternal blood PHE be maintained between 120-360 µmol/L before conception and during pregnancy to prevent the MPKUS (L.130). This recommendation was based on preliminary evidence from the MPKU Collaborative Study (MPKUCS) of 413 live births in 382 women from the US, Canada, and Germany, Switzerland and Austria. Subsequent analysis of the MPKUCS findings (L.157) as well as reported experience of other countries, including England (F.2560, F.2528), France (F.2473), Ireland (F.1291) and Australia (F.2585) indicates that better control of maternal blood PHE is associated with the best cognitive outcomes in offspring. The recommended treatment range for blood PHE varies slightly from country to country: England 100-250 µmol/L, France 120-300 µmol/L, and Germany 60-240 µmol/L. These lower concentrations are based on two premises: that blood PHE is concentrated across the placental gradient such that fetal exposure is about 1.6-1.8 times maternal blood PHE, and that there is a linear dose-response effect causing defects common to the MPKUS. Analysis of the MPKUCS showed that the relationship between maternal PHE and offspring cognitive outcomes is not linear, and that a blood PHE of 360 μmol/L is the threshold at which cognition begins to be impaired (L.165). The relationship between maternal blood PHE and cognitive outcome in the offspring is linear at blood PHE >360 µmol/L. The timing of control of maternal blood PHE (defined as the number of weeks gestation before blood PHE was consistently <600 µmol/L, was associated with cognitive development of offspring measured at age 4 and 7 years. Women who achieved metabolic control by 10 weeks gestation had children with normal birth outcomes (L.157), and children born to mothers who were treated prior to pregnancy had the best outcomes, with a mean General Cognitive Index score of 99, compared with 107 in non-PKU controls, and 59 in those who had not achieved dietary control by 20 weeks gestation (F.2515). Children born to mothers who did not achieve early metabolic control had behavioral problems such as aggression, hyperactivity, and poor impulse control (F.2585, F.2243).

Throughout the consensus process, there was very strong agreement that blood PHE be maintained between 120-360 µmol/L before and during pregnancy. Disagreement tended to be by those who recommended a stricter upper limit of 240 µmol/L.

In Delphi 1, 94% of all respondents agreed the upper limit of blood PHE treatment range should be 360 µmol/L. Those who did not commented that the upper limit should be 240 µmol/L.

In Delphi 2, 71% of all respondents agreed the upper limit of blood PHE treatment range shoulc be more strict at <240 μmol/L (87% RD and 33% MD).

In the Nominal Group, 63% of participants agreed with an upper limit for blood PHE during pregnancy of <360 µmol/L, and 38% were neutral. Discussion suggested an upper limit lower than 360 µmol/L may be preferable.

In a survey of children at risk for MPKUS, cardiac defects were found in about 12% of children born to women who were not on diet during pregnancy and had blood PHE above 1200 µmol/L (L.163). The extent and timing of control of blood PHE was related to the incidence of cardiac defects. Of 31 children in the MPKUCS who had cardiac defects, 26 (80.6%) were born to mothers whose blood PHE was >900 µmol/L at 8 weeks gestation, 5 (16.1%) to mothers with blood PHE of 601-900 µmol/L, 1 (3.2%) to a mother whose blood PHE was 361-600 µmol/L, and none to mothers whose blood PHE was 120-360 µmol/L or to mothers with untreated HPA (L.166). The critical period for embryogenesis of the heart is 5-8 weeks gestation (F.1230). Given that no cardiac defects were noted when blood PHE was < 360 µmol/L, women with hyperphenylalaninemia (HPA) who have untreated blood PHE of 360-600 µmol/L should be treated during pregnancy. Cognitive outcomes have been normal in children born to women with HPA whose blood PHE is 360-600 µmol/L without diet restriction (F.2468). Facial dysmorphology is also a feature in offspring of mothers with untreated PKU. In one study, occurrence of facial dysmorphology was related to first trimester maternal blood PHE (F.1527).

This topic was not addressed in the consensus process.

Recommendations for a lower limit of blood PHE during pregnancy varies. While in the US this limit has historically been 120 µmol/L (L.130), in Europe and Australia a lower limit of 60-100 µmol/L is recommended (F.2560, F.2585). The ACMG guidelines now recommend 60 µmol/L as a safe lower blood PHE in MPKU (F.2626), based in part on evidence from the British experience showing normal outcomes when blood PHE was <100 µmol/L. However, in this study the lower blood PHE occurred <10% of the time (F.2528). One study (F.1518) concludes that low blood PHE is associated with intrauterine growth retardation (IUGR). In this study, incidence of IUGR was correlated with increased length of time with blood PHE <120 µmol/L.

In Delphi I, there was strong consensus (100%) for a lower limit of blood PHE of 120 µmol/L during pregnancy, but comments included support for safety below this limit. 

In Delphi 2, there was strong agreement (95% of all respondents) that blood PHE in pregnancy can safely be lower than120 µmol/L but should not be <60 µmol/L. 

In the Nominal Group, only a minority of participants (12%) believed the lower limit for blood PHE treatment range during pregnancy should be <120 µmol/L.

Monitoring of a woman with PKU by a metabolic team before and during pregnancy is critical to outcome of the pregnancy, since treatment must be frequently modified to ensure adequate nutrition is being provided. A schedule of assessments was derived from the NIH Working Group for the NIH Consensus Review, and includes the domains to monitor, frequency of monitoring, and special circumstances to consider (F.2627, F.2629). For each domain, further published evidence regarding monitoring women with PKU during pregnancy is included. For biochemical monitoring, laboratory norms (excluding blood PHE) for pregnant women should be used. Because of hemodiluton associated with pregnancy, some parameters, including plasma amino acids, normally decrease during pregnancy. See TABLE #8, Monitoring Nutritional Management of PKU for monitoring recommendations during pregnancy and the post-partum period.

This topic was not included in the consensus process.

Recommended dietary PHE intake during pregnancy depends on inherent PHE tolerance prior to conception and into the first trimester with a range of 225-770 mg/day. By the second trimester, PHE tolerance increases due to increased protein synthesis in the mother and the fetus, with recommended intakes ranging from 770-2275 mg/day during this period (F.2627, G.103).  PHE tolerance during lactation is approximately the same as during the third trimester (F.2627, G.83). In the MPKUCS, mean PHE intake approximately doubled from the first to third trimester in women who were in good metabolic control (F.1245). Dietary PHE intake in the MPKUCS was not correlated to any outcome measure, however severity of PKU correlated with blood PHE during pregnancy and with outcomes (F.1527). See TABLE #3, Recommended intakes of PHE, TYR and Protein for PKU for range of recommended PHE intake during pregnancy and lactation

Typical methods of tracking dietary PHE intake, including counting milligrams or exchanges of PHE, or grams of PRO, are appropriate during pregnancy (F.2627) as long as frequent monitoring assures that blood PHE is in the recommended treatment range. Since tolerance for PHE increases rapidly in pregnancy, especially in conjunction with periods of rapid maternal weight gain, avoiding hypophenylalaninemia is important (F.1518), and large increases in PHE intake (25-50%) may be needed (G.88).

In Delphi 1, 81% of respondents agreed with the following PHE intake requirements: 

1st trimester 265-770 mg PHE/day; 2nd trimester 400-1650 mg PHE/day; 3rd Trimester and lactation 700-2275 mg PHE/day.

Individuals with PKU do not metabolize PHE to TYR normally, so TYR becomes an essential amino acid in PKU. There is no consensus regarding TYR supplementation during pregnancy in women with PKU (F.1518) and there was no relationship found between dietary intake of TYR or blood TYR and outcomes in the MPKUCS (F.2627). TYR is provided in the PKU diet primarily from medical foods. One review article suggests that the amount of TYR added to medical food may not optimal and may result in overnight deficiencies or daytime excesses of TYR (due to diurnal variations in blood TYR) that possibly put the fetus at risk for TYR toxicity (F.1225).

In Delphi 1, 81% of respondents agreed with a daily TYR requirement of 6000-7600 mg/day throughout pregnancy and lactation.

In Delphi 2, 86% of respondents agreed that when blood TYR concentrations are less than 30 μmol/L , subsequent testing should be done to determine if this is due to the known diurnal variation in blood TYR. Comments were that when blood TYR is low, medical food intake should be examined closely to determine if the individual is consuming all prescribed medical food and mixing medical food correctly.

In the MPKUCS, maternal PRO intakes were negatively correlated with blood PHE throughout all trimesters of pregnancy (F.1245). Adequate PRO and energy intake is needed to support proliferation of maternal reproductive tissues, fetal growth and development, and to prevent catabolism. PRO needs increase by 50% during pregnancy. In the general population, this represents an increase from 46 to 71 g/day during the second and third trimester (Y.12). For women with PKU who are pregnant, PRO needs are met through the use of medical foods, since intake of natural protein is limited (F.2629). When PRO is provided as L-amino acids it is oxidized more rapidly, and the recommended PRO intake is increased by approximately 20% to compensate (F.2627). See TABLE #3, Recommended intakes of PHE, TYR and Protein for PKU for the recommended PRO intake during pregnancy.

Medical food provides approximately 80% of PRO needs in individuals with classic PKU who are receiving treatment. This remains unchanged in women with PKU during preconception and early pregnancy, when tolerance for natural PRO is very limited. Medical foods vary widely with respect to PRO source, PRO:Kcal ratio, fat, and vitamin and mineral content. All current outcome data for MPKUS is based on women who were consuming medical food containing L-amino acids as the protein source. However, newer medical foods providing only LNAA, or GMP supplemented with L-amino acids are now available. In the AHRQ report, as well as other published guidelines, LNAA therapy alone is contraindicated in pregnancy because it is used in combination with a more liberal dietary PHE intake and blood PHE concentrations cannot be maintained in the recommended treatment range (F.2626, F.2627, F.2629). Theoretically GMP as a PRO source can support normal fetal growth and development, however concern about whether intake of GMP-based medical foods can produce a sufficient increase in plasma amino acids to support normal growth has been raised (G.107), and there are no reports in the literature of GMP use in pregnancy. Poor adherence to medical food prescription, or intake of medical foods devoid of vitamin, mineral and fat, increase the risk of nutritional deficiencies during pregnancy (F.2627). Conversely, over-prescription and/or over-consumption of medical food, sometimes used to provide additional protein or energy, can lead to nutrient excesses (F.2560).

In Delphi 2, 71% of  all participants agreed that PRO requirements in PKU should be 20-40% above the DRI. Of the MDs surveyed, 67% were either neutral or disagree with this recommendation, but offered no comments to explain their opinion. 62% of respondents agreed the recommended total PRO intake should be higher when the amino acid-based medical food to total PRO ratio is higher.

The MPKUCS showed that maternal energy intakes in women with PKU were negatively correlated with blood PHE throughout pregnancy and adequate energy intake and adequate weight gain were associated with better pregnancy outcomes (F.2627). The DRI for energy intake during pregnancy is an additional 340 kcal in second trimester and 452 kcal in third trimester above pre-pregnancy energy needs (Y.12). The recommended energy intake during pregnancy for the woman with PKU is no different than that for women without PKU. Adjustments in energy intake should be made as necessary to promote weight gain goals for pregnancy as established by the Institute of Medicine: underweight (BMI <18.5) 28–40 pounds, normal weight (BMI 18.5-24.9) 25–35 pounds, overweight (BMI 25.0-29.9) 15–25 pounds, and obese (BMI >30.0) 11-20 pounds (L.193).

Additional sources of energy to meet increased energy needs during pregnancy are often required, especially when natural PRO is very limited and/or when medical food has a high PRO:Kcal ratio. Frequently used sources of energy include modified low protein foods, fats, simple carbohydrates, and in some cases protein-free medical foods, such as glucose polymers (G.101).

In Delphi 1, 81% of respondents agreed with a daily energy requirement of 2000-3000 kcal throughout pregnancy and lactation.

Fat intake during pregnancy provides a source of energy, essential fatty acids, and cholesterol. The recommended fat intake during pregnancy (Acceptable Macronutrient Distribution Range expressed as % of energy intake) is 20-35% for total fat, 5-10% for linoleic acid, and 0.6-1.2% for α-linolenic acid (Y.12). No guideline is established for cholesterol intake (Y.12). In the MPKUCS, mean fat intake for all subjects was <30% of energy, and higher fat intake was associated with lower blood PHE in all trimesters (F.1245). Fat and essential fatty acid intakes and cholesterol may be low in women with PKU during pregnancy, especially if the medical food contains little or no fat (F.2627). DHA intake of 200–300 mg/day is recommended for all pregnant women with PKU, since low PHE diets often contain inadequate amounts of precursor α-linolenic acid (F.2627, G.88). Low blood cholesterol has been associated with spontaneous abortions (F.2629).

In Delphi 2, 80% of respondents agreed with providing a DHA supplement of 200-300 mg/day for pregnant women with PKU.

Vitamin and mineral intake should meet the DRI for pregnancy but not exceed tolerable upper intake (Y.12). Excessive vitamin A is a known teratogen (F.2629). Vitamin B₁₂ deficiency increased the risk of CHD in the MPKUCS (F.1189, F.2627). The primary source for most vitamins and minerals is the medical food or vitamin supplementation if the medical food is low or devoid of vitamins and minerals (F.2627).

Prenatal vitamin and mineral supplementation may be used if intakes are inadequate (G.101). Care must be taken to maintain vitamin A intake (from supplements plus medical foods) within the safe limit of <3000 μg/d (Y.12) in order to avoid hypervitaminosis A. Only pre-formed sources of vitamin A (not vitamin A from beta-carotene) must be included in the calculation of vitamin A intake (G.88).

In Delphi 1, there was strong agreement (91% RD and 100% MD respondents) that supplemental vitamins and minerals should be considered when individuals are consuming an incomplete medical food. Comments included statements that clinical and laboratory monitoring may reveal the need for specific supplementation in some individuals, especially if they are not adherent to dietary recommendations (including adequate medical food intake).

LNAA as monotherapy is contraindicated in women with PKU during pregnancy because it is not effective in lowering blood PHE to within the treatment range considered safe for pregnancy (120-360 μmol/L) (F.2176).

In Delphi I, there was strong agreement (100% RD and 80% MD) that LNAA products should not be used in an MPKU pregnancy.

Sapropterin is a Class C medication, which means “animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks”. There is limited evidence on sapropterin use during pregnancy. One study showed normal birth outcome in a woman who was given a low dose (40-100 mg/d) of sapropterin during pregnancy (F.1237). The ACMG guideline concludes that, given the known adverse effects of elevated maternal blood PHE on pregnancy outcomes, and because sapropterin may be effective in lowering blood PHE, its use should be considered on a case-by-case basis (F.2626, F.2627. F.2629). There is no data on sapropterin use during lactation (F.2629).

An FDA mandated post-marketing study of sapropterin use during pregnancy is underway. Preliminary evidence from this study (personal communication G.112) includes data on 27 pregnancies in 23 women. In 19 pregnancies women were taking sapropterin during pregnancy (18 of these were on sapropterin prior to conception, 1 started during pregnancy). Outcomes of these pregnancies were 14 live births, 2 SAB, and 3 ongoing pregnancies. In 8 pregnancies, women had taken sapropterin in the past but not during pregnancy. Outcomes of these pregnancies were 3 live births, 2 SAB and 3 ongoing pregnancies. Median dose of saproterin was 20 mg/kg at the start of pregnancy, with no adjustment for weight gain during pregnancy. A group of women taking sapropterin had lower blood PHE than a group who were not currently taking sapropterin, though no statistical analysis of differences was done. There were no differences in birth anthropometric measurements or Apgar scores noted between groups. Adverse events included premature labor, SABs, and gastrointestinal side effects. Sapropterin was not discontinued in any pregnancy reported. Cleft palate occurred in one offspring of a mother on sapropterin who did not have good blood PHE control during early pregnancy.

In the consensus process, sapropterin use in pregnancy was generally regarded as favorable, recognizing that high maternal PHE is a known teratogen and all efforts to keep blood PHE in control during pregnancy should be considered.

In Delphi 2, there was overall agreement (81%) with appropriateness of sampropterin use in pregnancy (RD 87% and MD 66%). Agreement increased with respect to women with PKU who were pregnant but not able to control blood PHE (87% RD and 100% MD).

In the Nomimal Group, 50% of participants agreed and 50% were neutral regarding appropriateness of sapropterin use in pregnancy. Those who were neutral commented on having a lack of experience with the drug.

In Delphi 1, there was 100% agreement among all respondents that psychosocial support improves adherence to treatment recommendations for individuals with PKU. In addition there was 100% agreement that individuals with PKU need access to care, medical foods, and psychosocial services.

Achieving metabolic control before conception, or as rapidly as possible during pregnancy, is especially important because of the risk high maternal blood PHE poses to the developing fetus if the diet is not well maintained. Over the past several decades, dietary adherence in MPKU has improved, possibly due to improvement in diet palatability or to increased education regarding the risks for MPKUS (F.1189). In the MPKUCS, only 10% of women were in good metabolic control by 10 weeks gestation (L.157). In a more recent study of women with MPKU; 55% in the US and UK, 79% in Germany, and 88% in France (F.1518) achieved treatment range blood PHE goals by 10 weeks gestation (F.1189). Adherence to diet does not improve in subsequent pregnancies compared to the first pregnancy (F.2525). In the MPKUCS maternal factors associated with better control of blood PHE included higher maternal age, level of education, socio-economic status, IQ, and having a less severe form of PKU. The severity of PKU had the highest correlation to blood PHE concentrations (L.165). In one center, women who are off diet when they conceive are hospitalized to rapidly lower blood PHE and those for whom gestation is >12 weeks are offered termination (F.2560)

This topic was not addressed in the consensus process.

Despite the fact that the unbound PHE content of breast milk is higher than normal, women with PKU may safely breastfeed their infants (F.2629). If the infant also has PKU, breastmilk can be used in combination with PHE-free medical food. Closely monitoring both maternal and infant blood PHE is especially important for managing therapy when a woman with PKU breastfeeds an infant with PKU. See research question 3.3 for further information on breast-feeding an infant with PKU.

While elevated maternal blood PHE does not preclude breastfeeding, adherence to PHE restricted dietary therapy is recommended for the health and well being of mother and baby (F.2629). See next section.

This topic was not addressed in the consensus process.

It is recommended that women with PKU should continue a PHE-restricted diet after pregnancy (F.2627). In the past, most women with MPKU (71% and 91% in two studies) discontinued diet therapy after pregnancy (F.1189). Diet discontinuation is associated with an increased risk of psychiatric symptoms, such as thought and mood disorders, that may impair parenting ability (F.1189), and it has been reported that the home environment has a greater impact on development of a child measured at 1 year of age than the timing of maternal metabolic control during pregnancy (F.2525). Recommended intakes of PRO, energy, and PHE in the post-partum period are the same as those recommended for the last trimester of pregnancy.  See TABLE #3, Recommended intakes of PHE, TYR and Protein for PKU for intake recommendations.

This topic was not addressed in the consensus process.

For a woman with PKU who is carrying twins, one recommendation is that PRO intake be increased by 10 grams in the first trimester and then adjusted as blood PRO status is monitored. Another recommendation for multiple fetuses is to provide stated PRO needs of 0.9 g/kg/day plus an additional 12 g/day, and energy needs at 700 kcal/day per fetus. Guidance for other nutritional requirements of pregnancy in non-PKU women applies. Providing sufficient energy to promote adequate weight gain is essential, especially early in pregnancy when nutrient stores are laid down for the third trimester. In reported experience from two clinicians, PHE tolerance increased from 300 to 1500 mg/d for one twin pregnancy, and from 550 to 1000 mg/day in another (G.88).

This topic was not addressed in the consensus process.

Suggestions regarding diet management for gestational diabetes include providing 30 grams of carbohydrate at breakfast, 60 grams at lunch and dinner, and 15-30 grams for snacks depending on activity level of the individual with PKU. Medical food chosen should be low in carbohydrate, and additional energy from medical food may be needed (G.85).

This topic was not addressed in the consensus process.