A general review of pregnancy planning for women with IMD suggested the need for genetic counseling, establishment of metabolic control through diet, discussion of the use of medications and what to expect during pregnancy (“normal factors”) (F.616). Although it would be optimal for women with MSUD to have and comprehend this information prior to conceiving, several published case studies described women for whom individualized pregnancy management planning began either late in the first trimester (F.3481, F.3482) or in the second trimester or later (F.3481, F.49). A comprehensive plan for coordinating maternal and fetal monitoring and intervention between the metabolic clinic and the high risk obstetrical gynecological service was implemented in two recent case reports (F.3482, F.4423). These plans included contingencies should more aggressive treatments be necessary due to either metabolic decompensation or obstetrical complications.

Delphi 1:

There was consensus (100% of RD and 83% of MD respondents agreed) that the recommendations for vitamin and mineral intake should be individualized based on the pregnant woman's prescribed medical food, dietary adherence and laboratory assessment.

Statements were not included in the surveys about recommendations for coordinated pregnancy planning.

Most studies indicated goals for blood LEU concentrations throughout pregnancy at 100-300 µM (F.3487, F.3483, F.78), with VAL and ILE in the upper range of normal (F.78). For women whose blood BCAA were not in the desired treatment range at presentation, dietary changes were implemented to quickly bring them into range (F.78, F.3483, F.3481). Although only one woman was reported to have had mild nausea and vomiting that affected dietary intake in early pregnancy (F.3482), two other pregnant women (F.3481) had acute illnesses (unrelated to pregnancy) that required hospitalization to manage the increased blood BCAA related to their metabolic decompensation. During the second half of pregnancy, increased LEU tolerance (e.g., greater LEU or intact PRO intake without corresponding rise in plasma LEU) has been observed, related to protein synthesis (maternal and fetal) and BCAA metabolism by the fetus (F.78, F.102, F.4423, G.50, G.30). Goal plasma BCAA levels of “as close to normal as possible” are recommended (G.50). Possible slowed fetal growth, when plasma BCAA levels were low, was observed in one study (F.102).

Delphi 2:

There was consensus (83% of respondents agreed) that BCAA levels should be maintained in the normal treatment ranges.

There were no reported teratogenic effects of elevated LEU or the other BCAA on the developing fetus (F.78, F.3481, F.3482, F.3483, F.4423, F.102). This was especially noteworthy in the healthy and normally developing infants of a few women who did not have optimal control of maternal plasma BCAA. In most cases, fetal growth was followed by ultrasound and found to be normal. Apgar scores for all infants were 9, 9 or 9, 10 at 5 and 10 minutes, respectively. Infant and child evaluations, done at various times from 8 months to 3 years of age, identified no developmental delays.

Delphi 2:

There was consensus (83% of all respondents respondents agreed) that blood BCAA concentrations should be maintained in the normal treatment ranges during pregnancy

The starting point for the recommendations for optimal dietary intake of BCAA, PRO and energy during a woman’s early pregnancy were the same as the recommendations of these same nutrients prior to her pregnancy, with frequent blood BCAA monitoring to guide increases in dietary BCAA intake, and use of appropriate medical food (F.78, F.3481, F.3482, F.3483). Supplemental ILE and VAL were reported as necessary in one case to maintain blood BCAA within the recommended ranges and help lower the blood LEU (F.3482). One author, with experience with six pregnancies in women with MSUD, stated that supplementation with ILE and/or VAL may not be necessary in most cases, as the increased (intact) protein intake recommended throughout gestation usually provides sufficient amount of these amino acids (G.6). Also see TABLE #4, Recommended Dietary PRO, BCAA and Energy Intake, TABLE #6, Recommendations for the Nutritional Monitoring of Individuals with MSUD, TABLE #7, Classification of Medical Foods for MSUD.

Delphi 1 and 2:

There was consensus (100% of all respondents agreed or completely agreed) that, guided by frequent laboratory monitoring, BCAA and protein intake should be increased to meet increased needs during pregnancy.

In all the case studies, it was reported that the women with MSUD had an increased demand for dietary LEU ( and all BCAA) by at least the second half of pregnancy. The increase of natural or intact PRO (to provide LEU) ranged from 2.5- to 7-fold over pre-pregnancy recommendations (F.78, F.3481, F.3482, F.3483,F.4423, F.102). These increased demands for LEU come from the maternal anabolic processes as well as growth of the fetus. In addition, a heterozygous fetus has sufficient BCKA in later gestation to oxidize small amounts of BCAA from the maternal circulation. It was suggested that reaching these LEU intake goals may involve replacing low protein modified products with regular baked goods and cereals/grains (F.3483). In addition, eggs and dairy products may be easier to introduce, incorporate and accept in the diet than fish and meats (F.3483).

Delphi 1 and 2:

There was consensus (100% agreement among all respondents) that, guided by frequent laboratory monitoring, BCAA and PRO intake should be increased throughout pregnancy to meet increased requirements

Vitamin and mineral intake recommendations for women with MSUD during pregnancy did not differ from those of pregnant women in the general population (F.78, F.3481, F.3482, F.3483, F.102).  However, the type and amount of medical food consumed by the woman with MSUD influences the amount of supplemental or pre-natal vitamins/minerals she may require. Both assessment of intake and biochemical monitoring are essential for final decisions about the need for vitamin and mineral supplementation (F.616, F.4423).

Delphi 1:

There was consensus (100% RD and 83% MD respondents agreed) that vitamin and mineral supplementation should be evaluated individually based on specific medical food prescribed, dietary adherence and the pregnant woman's laboratory assessment.

Delphi 2:

There was consensus (100% agreement among all respondents) that monitoring is essential to ensure the meeting of the extra nutrient needs of pregnancy.

Low concentrations of free carnitine were reported in one patient during pregnancy, and 50 mg carnitine/day was prescribed (F.102). As the woman’s pre-pregnancy free carnitine concentrations were not reported, it is not known if the low concentration was merely that seen in most pregnancies due to volume dilution (L.288) or a true deficiency. While it has been reported that carnitine may exert an antioxidant effect in individuals with MSUD (L.287), routine carnitine supplementation in MSUD pregnancies has not been systematically studied nor reported.

Delphi 1:

There was no consensus (82% of RD and 33% of MD respondents agreed) that carnitine should be supplemented if plasma free carnitine is below the normal range.

Comments: one MD commented asked, "what is the normal range?". Both MD and RD respondents commented that they have not observed low free carnitine in this population. One MD stated that he felt that carnitine is not a concern in MSUD.

A baseline assessment of the woman’s nutritional status and current nutrient intake in the pre-pregnancy and/or early pregnancy stages should follow the routine monitoring recommendations given in TABLE #6, Recommendations for the Nutritional Monitoring of Individuals with MSUD. During labor, delivery and the early post-partum period, specific monitoring has been proposed (F.102, F.3482, F.3481, F.4423). This includes: daily Chem 7, plasma amino acids, electrolytes, venous blood gases; and 3-4 times daily urinary electrolytes and ketones. Intercurrent illnesses that occur during pregnancy or the post-partum period require more frequent monitoring and follow recommendations outlined in  Q#1, Topic 1.3.1  of this guideline.

Delphi 1:

There was very little consensus among the respondents about type and frequency of laboratory monitoring during pregnancy; several respondents noted that they would base recommendations on clinical indicators as well:

Complete blood count (CBC): 29% of respondents would measure CBC monthly, 65% would measure once per trimester, and 6% would never use this indicator.

Comprehensive metabolic panel: Most respondents would measure this monthly (35%) or once per trimester (59%); 6% would never measure this.

Plasma amino acids: Respondents felt plasma amino acids should be monitored frequently: 29% would check plasma amino acids weekly, 29% biweekly, 29% monthly, 6% once per trimester, and 6% never.

Plasma carnitine, free, esterified and total: 6% would measure this monthly, 29% once per trimester, 24% once during pregnancy, and 41% would never measure plasma carnitine.

Plasma transthyretin: 29% would measure transthyretin (prealbumin) monthly, 41% once per trimester, 12% once during pregnancy, and 18% would never measure transthyretin.

Folate (erythrocyte): 6% would measure folate monthly, 65% once per trimester, 12% once during pregnancy, and 18% would never measure folate.

Urine organic acids: 23% of respondents would measure urine organic acids monthly, 18% once per trimester, 18% once during pregnancy, and 41% would never measure urine organic acids.

Pregnant women with MSUD experience the same pregnancy-related problems with emesis and nausea as those without MSUD, but have the added risk of a catabolic crisis. Therefore, the general recommendations for management of the complications of pregnancy apply with the additional recommendations for MSUD management as described in these guidelines. Among the seven reported case studies, there were only two women who were reported to have mild nausea and emesis that affected dietary intake in early pregnancy (F.3482, F.4423). Approximately 1-2% of all pregnant women experience hyperemesis gravidarum. Diagnostic criteria include intractable vomiting, weight loss, and ketosis. For pregnant women with MSUD, weight loss and catabolism require aggressive treatment including hospitalization and possible hyperalimentation (F.616). See Q #1 for details of management during acute illness.

 Delphi 1 and Delphi 2:

There was consensus (100% agreement among the respondents) that poor nutrient intake due to pregnancy-related nausea and vomiting should be aggressively treated to prevent endogenous protein catabolism.

Two out of seven cases studies described women with MSUD who had acute illnesses, unrelated to pregnancy (F.3481). These were managed using usual illness protocols such as described in Research Question 1 and medical management focused on preventing and/or minimizing metabolic crises. These interventions included some or all of the following: counseling and education, adjustment of oral intake including intact PRO, supplementation with VAL and ILE, BCAA-free medical food, and tube-feeding or parenteral nutrition.

Delphi 2:

There was not consensus (56% of RD and 83% MD respondents agreed) that the usual illness protocols should be used for maternal MSUD.

Comments: one respondent commented that the intervention should be more aggressive with closer monitoring

As it is not possible to predict when and where labor may begin, advance preparation for possible early or prolonged labor and/or complicated delivery has been shown to be necessary (F.3481, F.3482, F.4423). Some women were provided with patient-specific, detailed, printed instructions to give to the local obstetrical team, in case delivery was not at the planned birthing hospital. These instructions included contact information for the patient’s usual metabolic and obstetrical teams.  During labor and delivery, IV glucose (± insulin) has often been used to control catabolism: 220 g glucose/24 hours (F.3483); but a plan to provide fluids, medications and additional nutrients parenterally, if needed, has also been included (F.3481, F.3482, F.3483, F.4423).

Delphi 1:

There was consensus (100% agreement among respondents) that adequate energy should be provided during labor, delivery and the post-partum period to prevent catabolism.

Delphi 2:

There was consensus (100% agreement among all respondents) that IV lipids and glucose should be available for use during labor and delivery.

There have been reports of metabolic decompensation and/or rapid rise of plasma LEU concentrations in the post-partum period in women with MSUD (F.78, F.102, F.3481). After delivery, additional LEU is no longer required for the anabolic processes of the pregnancy and growth of the fetus. It has been recommended that maternal LEU intake should return to that of her pre-pregnancy period (F.3483)  unless she is breastfeeding - see below. There have been reported a need for additional short-term (12-24 hours) LEU (or intact PRO) restriction during the rapid involution of the uterus and readjustment of blood volume (F.3481, F.3482, F.3487, F.4423).

Adequate energy intake is necessary to prevent the catabolic buildup of BCAA. It has been shown that severe LEU restriction in the immediate postpartum period may not be necessary if sufficient energy is given to prevent endogenous catabolism (F.3481, F.3483). Parenteral nutrition (including glucose and fluids) has been used for 12-24 hours (F.102, F.3481, F.3483), or given and gradually reduced when at least 50% of nutrient requirements has been consumed orally (F.616, F.3482). Additional VAL and ILE were given in one case for 10 days post-partum to reduce blood LEU concentrations (F.3482). BCAA-free parenteral amino acids, in place of BCAA-free medical food, as well as glucose (10% dextrose) ± insulin, IV lipids (20%), fluids and electrolytes, may be used if complications prevent sufficient oral intake – see Research Question 1.

Delphi 1:

There was was consensus (100% of RD and 83% of MD respondents agreed) that close monitoring of metabolic labs should continue for at least 6 weeks post-partum.

There was consensus among all respondents that, unless breast-feeding, the MSUD mother should soon return to her pre-pregnancy PRO recommendations (for both intact PRO and medical food).

Delphi 2:

There was a discrepancy between the RD and MD respondents regarding complete restriction of LEU for 24-48 hours post- delivery, with 100% agreement among physicians, and 64% agreement among dietitians. Dietitians remarked on their lack of experience with pregnancy among women with MSUD.

Breast feeding by a woman with MSUD has been documented in at least 3 published case reports (F.78, F.3482, F.3483). Exact BCAA and PRO requirements for lactation varied from case to case, but a general starting point was the recommendation given to all healthy lactating women: intake approximately the same as that required in the third trimester of pregnancy. One woman breast fed for 4 weeks, but little information about her nutrient intake was given (F.78). Two of the women breast fed for at least 6 months. One required at least 1500 mg LEU per day (3 to 5 times her pre-pregnancy intake) to maintain appropriate maternal blood LEU concentrations (F.3483); the other required 1500-2100 mg LEU (2-3 times her pre-pregnancy intake) (F.3482). Data on the infants who breast fed for 6 mos or more indicated excellent outcomes (F.3482, F.3483). Infant growth at 7 months was normal on World Health Organization Child Growth Standards,with length and weight at the 25th percentile and head circumference at the 75th percentile for age, and the Bayley Scales of Infant and Toddler Development Cognitive Composite Score was 120, indicating above-average abilities (F.3482).

Delphi 2:

There was no consensus (73% agreement among RD and 66% among MD respondents) that nutrient requirements for protein, BCAA, and energy of lactating women with MSUD will be similar to nutrient requirements during the third trimester of pregnancy.

There was consensus (100% agreement among all respondents) that close clinical and biochemical monitoring will be needed to adjust for postpartum changes in the mother and increased nutrient needs of her (breastfeeding) infant.