There is limited evidence regarding the impact of menstruation and hormonal fluctuation on metabolic control in UCDs. Two case reports describe menses-associated hyperammonemia in females with ARG (F.4753, F.4855). The first, published in 1994, described a 28-year-old with severe intellectual disability who developed cyclical, transient hyperammonemia correlated with menarche at age 18 years. Episodes improved with hormonal therapy for eight years and resolved following hysterectomy, with stability maintained over the 3.5-year follow-up period (F.4855). The second case, published in 2006, described a 24-year old with moderate intellectual disability who experienced monthly post-menstrual hyperammonemia with altered mental status. Her symptoms resolved once hormonal therapy suppressed menstruation, with five years follow-up data reported (F.4753).

Research in healthy women demonstrates a physiologic increase in energy expenditure during the luteal phase (after ovulation and before menses begin). In a controlled study using whole-room indirect calorimetry and polysomnography, nine healthy women showed a 6.9% increase in sleeping energy expenditure during the luteal phase compared with the follicular phase (from the beginning of menstration to ovulation) (L.462). This rise in metabolic rate occurred alongside higher core body temperature and reduced early-night heat dissipation, yet could not be explained by temperature changes alone. A 2020 systematic review and meta-analysis further supports these findings, showing that across 26 repeated-measures studies involving 318 women, resting metabolic rate was modestly higher in the luteal phase (standardized mean difference = 0.33; p < 0.001), indicating a hormone-associated elevation in baseline energy needs (L.460).

Menstrual cycle-related metabolic effects have also been observed in metabolic disorders. In a prospective 6-month study of women with classical phenylketonuria (PKU), twice-weekly dried blood spot monitoring showed fluctuations in metabolic control across the menstrual cycle despite stable energy and protein intake (L.461). Phenylalanine concentrations were lowest in the early luteal phase and highest in the early follicular phase around menstruation, with concentrations beginning to rise before menses onset. The authors recommended temporarily reducing protein intake and increasing energy intake shortly before menstruation in individuals with predictable cycles (L.461).

Together, these findings show that energy expenditure and metabolic parameters shift across the menstrual cycle, with increased energy needs and altered metabolic control during the luteal and perimenstrual phases. These physiological patterns may help explain menstruation-associated metabolic vulnerability in individuals with UCD. Furthermore, gray literature from the National Urea Cycle Foundation's Patient Survey Data indicates a shift toward earlier puberty, with females born between 1991 and 2008 experiencing pubertal onset at approximately 9.5 years of age compared with 13 years among those born between 1972 and 1990 (G.203). Thus, menstrual-related metabolic instability may begin at younger ages in contemporary UCD cohorts.

Delphi 2 Results

For pubertal, adolescent, and adult women, there was unanimous agreement to assess for signs and symptoms of hyperammonemia that coincide with the menstrual cycle. When such symptoms are identified, all respondents agreed that temporarily increasing energy intake and/or reducing protein intake is appropriate to prevent metabolic instability.

There was also consensus to consider hormonal birth control—in consultation with metabolic and primary care providers—for women who experience cyclical hyperammonemia.

Females with UCDs are at risk for metabolic decompensation during pregnancy, labor and delivery, and the postpartum period. Thus, routine, anticipatory counseling and educationfor females of childbearing age is critical and should include discussion of pregnancy-related metabolic risks, symptom recognition, and the need for early metabolic evaluation should pregnancy occur (F.5588, F.6128).

Considering these risks, pregnancy in individuals with inherited metabolic disorders, including UCDs, is ideally planned to allow for optimization of metabolic control and nutritional status prior to conception (F.5588). Preconception counseling and baseline nutritional assessment are recommended to identify and address potential nutrient deficiencies, with authors describing the importance of nutrition consultation and baseline laboratory evaluation before or early in pregnancy to support maternal health and reduce pregnancy-related metabolic risk (F.6128).

Several case reports (F.5581, F.5588, F.5932, F.6086, F.6128, F.7824, F.5513, F.6945, F.7526) and one systematic review (F.6262) also describe the role of genetic counseling and/or prenatal diagnosis during pregnancy for women with UCDs. Prenatal diagnosis offers the advantage of initiating medical and nutrition intervention as soon as possible after birth (F.5932, F.7824) or limiting unnecessary interventions that may otherwise be recommended due to family history (F.7824). Genetic counseling can help families understand inheritance risk, decide whether to proceed with prenatal testing during an existing pregnancy (F.6128), consider preimplantation genetic diagnosis (F.5588, F.6128), and review reproductive options if an affected fetus is identified (F.6128). Genetic counseling and familial testing can also help identify asymptomatic female OTC carriers in extended family members (F.6128, F.7824), which may improve maternal outcomes (F.6262) and offer the possibility of prenatal testing in their future offspring.

Delphi 1 Results

There was strong agreement (96%) that all females with UCD of childbearing age should receive counseling annually on the risk of maternal decompensation with pregnancy.

For females actively planning a pregnancy, there was strong agreement (96%) to assess the individual's nutritional status (e.g., dietary assessment, anthropometrics, and nutrition-focused laboratory testing).

Management during pregnancy, as described in case reports and case series, has included low-protein diet with or without EAA-based medical foods (F.4553, F.5581, F.5513, F.6128, F.6945, F.7362, F.7523, F.7526, F.7800), adequate non-protein calories (F.4553, F.7800), L-arginine or L-citrulline supplementation (F.4553, F.5513, F.5581, F.5588, F.6128, F.6945, F.7362, F.7523, F.7526, F.7800), nitrogen scavengers (F.4553, F.5513, F.5581, F.5588, F.6128, F.7362, F.7523), and avoidance/prompt treatment of metabolic triggers such as febrile illness, gastroenteritis, prolonged fasting, and protein loading (F.5581). While these interventions are also generally supported by a 2018 review (F.5937) and a 2019 systematic review article (F.6262), specific degree of protein restriction, calorie goals, or dosing information for amino acid supplements and/or nitrogen scavengers are rarely reported.

Consistent with non-UCD pregnancies, energy needs increase throughout gestation and adequate energy intake is necessary to prevent catabolism (F.5937, F.7963). FAO/WHO/UNU guidelines recommend additional energy intakes of 90, 287, and 466 calories per day in the first, second and third trimesters, respectively (F.7963), although other estimates suggest lower requirements of approximately 230 calories per day in the third trimester for singleton pregnancies (F.5937).

The 2012 European UCD guidelines emphasized avoiding protein deficiency, meeting pregnancy-specific nutritional needs, closely monitoring metabolic status during pregnancy, and establishing a registry to more systematically collect case examples (F.6373). These principles were reinforced in the 2019 revised European guidelines, which incorporated FAO/WHO/UNU recommendations for protein and energy requirements during pregnancy, specifying additional protein intakes of 1 g/day, 10 g/day, and 31 g/day in the first, second, and third trimesters, respectively (F.7963). For individuals following a low-protein diet, serial growth scans may be beneficial to ensure adequate fetal growth (F.5581).

Although protein requirements increase throughout pregnancy (F.5937, F.7963), the impact of these changes on protein tolerance in pregnant women with UCD has not been systematically studied. Case reports describe a wide range of tolerated protein intake, including intakes of 40 g/day (F.6128) and total protein intakes of 0.5-1 g/kg/day (F.4553, F.5469, F.7523) or 0.8-1 g/kg/day based on ideal body weight (F.7526). In one report, a 29-year-old woman increased her intact protein from 40 g/day at baseline to 60 g/day in the late third trimester (F.5581). Another publication described two women with OTC who increased protein intake to 75-85 g/day by the end of pregnancy, although baseline intake was reported for only one of the two individuals (45-60 g/day) (F.7362). In a woman with ASA, low protein intake early in pregnancy prompted introduction of an EAA-based medical food at 14 weeks' gestation to supply 20% of protein needs, increasing total intake from 0.46 g/kg/day (40-50 g/day) in the first trimester to 1.22 g/kg/day (70-80 g/day) by term (F.7526). This case also highlighted weekly follow-up with a dietitian and nurse throughout pregnancy to review plasma ammonia, plasma amino acids, and dietary records (F.7526). Given that physiologic metabolic adaptation to pregnancy may lower measured plasma amino acid concentrations (L.471) and pregnancy-specific reference standards are not available, plasma amino acids should be interpreted cautiously and in conjunction with clinical status, dietary intake, and longitudinal trends rather than absolute target values.

Furthermore, most micronutrient requirements increase during pregnancy compared with non-pregnant states, including choline, folate, iodine, iron, selenium, and zinc (L.466, L.467, L.468). Requirements for essential fatty acids, including linoleic acid and alpha-linolenic acid, also increase during pregnancy (L.469). The few published case reports describing micronutrient supplementation practices during pregnancy in women with UCDs have included multivitamins, DHA/EPA (omega-3) supplements, and calcium (F.5581, F.7362, F.7526). Given the risk for micronutrient deficiencies in individuals with UCDs following low-protein diets, preconception nutrition evaluation is beneficial when feasible (F.5588). See Recommendation 2.5.1 for guidance on individualized supplementation to prevent deficiencies.

Delphi 1 Results

The following treatment practices during pregnancy received unanimous agreement:

• The metabolic team should coordinate treatment plans with a high-risk OB during pregnancy and delivery.
• Guided by frequent laboratory monitoring and nutrition assessment, protein and calorie intake should be increased throughout pregnancy to meet increased requirements.
• Vitamin and mineral supplementation should be evaluated individually based on the specific medical food prescribed, dietary adherence, and the pregnant individual's laboratory assessment.

Frequency of Biochemical Monitoring During Pregnancy:

SEVERE UCD:

• Ammonia: Reported monitoring frequency varied, with respondents divided between weekly (30%), biweekly (26%), and monthly (26%), suggesting a practical monitoring range of every 1-4 weeks.
• Plasma amino acids: Dietitians more frequently preferred weekly monitoring (45%), whereas most other providers (67%) preferred monthly monitoring.
• Comprehensive metabolic panel: Most respondents reported either monthly (30%) or once per trimester (48%).
• Nutrition-focused biochemical markers (e.g., vitamin B12 status, folate status, zinc, iron studies, 25-hydroxy vitamin D): Most respondents recommended assessment once per trimester (52-70%) or once during pregnancy (22-39%). Approximately half of respondents (45%) supported testing free/total carnitine once per trimester, while 36% preferred testing once during pregnancy.

MILD UCD:

• Ammonia: While there was no agreement on a single interval, most respondents supported a monitoring range of every 1-4 weeks (82%).
• Plasma amino acids: Most respondents favored monitoring either monthly (50%) or once per trimester (27%).
• Comprehensive metabolic panel: Most respondents indicated assessment either monthly (30%) or once per trimester (48%).
• Nutrition-focused biochemical markers (e.g., vitamin B12 status, folate status, zinc, iron studies, 25-hydroxy vitamin D, and free/total carnitine): Respondents most commonly recommended testing once per trimester (18-45%) or once during pregnancy (45-57%).

Delphi 2 Results

There was strong agreement (96%) to provide an individualized nutrition prescription for pregnant women to meet pregnancy-specific nutrient goals and prevent catabolism, including titrating protein intake to approach the DRI for the stage of pregnancy based on individual tolerance and guided by ongoing nutrition assessments and laboratory monitoring.

Coordinated care between the metabolic team and a high-risk obstetrician is essential throughout pregnancy to ensure early recognition and timely management of hyperammonemia in individuals with UCDs. Pregnancy-related nausea and emesis can compromise oral intake and precipitate hyperammonemic crises (F.5588, F.5937, F.6262, F.7715). Clinicians should recognize that hyperammonemia may present with symptoms commonly attributed to pregnancy, including nausea, vomiting, headaches, mood disturbances, and seizures (F.5937, F.6128, F.6262); therefore, these symptoms should not be dismissed. Because seizures may occur in both hyperammonemia and eclampsia, routine blood pressure monitoring is recommended to support early detection and management of pre-eclampsia (F.5581, F.6128).

Females previously undiagnosed with UCD may first present hyperammonemia during pregnancy (F.7326, F.5287, F.5513, F.6262, F.4553, F.7715, F.7800) with potential progression to hyperammonemic coma (F.5287, F.5513, F.6262) or even death (F.6262, F.7715) in the absence of adequate and timely intervention. While details of acute management in pregnancy are often limited, successful cases have included parenteral calories via IV dextrose and/or lipids (F.5513, F.7362), gradual reintroduction of protein via parenteral amino acids and/or enteral feeds (F.5513), IV and/or oral L-arginine (F.4553, F.5513, F.7362), oral L-citrulline (F.7362, F.5513, F.5287), nitrogen scavengers (F.4553, F.5513, F.5287), and continuous venovenous hemodiafiltration (F.5513).

Delphi 1 Results

There was unanimous agreement that poor nutrient intake due to pregnancy-related nausea and vomiting should be treated aggressively (e.g., antiemetics, nutritional strategies, and/or hospitalization) to prevent endogenous protein catabolism.

The catabolic processes of labor and delivery increase risk for metabolic decompensation. To mitigate this risk, coordinated care between the metabolic team and a high-risk obstetrician is essential, with a comprehensive management plan established prior to delivery to guide monitoring and interventions throughout labor and delivery (F.5581). Early epidural initiation can help reduce catabolism (F.5581, F.7362), and planned elective deliveries can help ensure specialist availability (F.5581, F.6128, F.6262) and allow for timely intervention as indicated.

Emesis is common during labor and delivery and can be managed with prescribed antiemetics (F.5581, F.7362). Hydration should be maintained with intravenous fluids that include dextrose to minimize catabolism (F.4553, F.5469, F.5581, F.5588, F.6128, F.6262, F.7362). Reported approaches to IV dextrose administration vary, including 2 mL/kg/hr without specified concentration (F.5588), 5-10% dextrose at 125 mL/hr (F.6128), D10% with 0.45% saline at 144 mL/hr (F.7362), and D10% without specified rate (F.4553, F.7362). Intravenous lipid emulsion has also been used during delivery to provide additional protein-free calories (F.7362). For scheduled cesarean sections, IV dextrose should begin during the required fasting period to avoid catabolism and potential hyperammonemia before the procedure (F.6128, F.6276).

In addition to intravenous dextrose and/or lipids to mitigate catabolism, oral or intravenous nitrogen scavengers (F.4553, F.5469, F.5932) and L-arginine (F.4553,F.5932, F.7362) have been used to help mitigate hyperammonemia during labor and delivery. Any hyperammonemia that develops during delivery should be treated promptly. Based on available case reports, management strategies have included oral or intravenous nitrogen scavengers (F.6128, F.7523), intravenous L-arginine (F.6128), and escalation to hemodialysis when standard interventions are insufficient (F.6128).

Delphi 1 Results

The following treatment practices during delivery received unanimous agreement:

• During active labor and delivery, individuals with a UCD should be placed on IV dextrose at 150 mL/hr (i.e., 1.5 times maintenance) to prevent catabolism.
• Provide adequate energy (100-120% DRI) during delivery and for six weeks postpartum to prevent catabolism.

Biochemical monitoring can help specialists adjust interventions as needed throughout labor and delivery to prevent or mitigate hyperammonemia. Recommendations from case series and case reports support monitoring plasma ammonia concentrations every 4-6 hours throughout labor and delivery (F.6128, F.6262, F.6276, F.7362). Increased monitoring is warranted if ammonia concentrations begin to rise and/or should symptoms of hyperammonemia develop (F.6128). Case series and case reports have also suggested routine blood glucose monitoring every 1-4 hours throughout labor and delivery (F.6128, F.6276, F.7526, F.7362) with administration of IV insulin as needed to prevent hyperglycemia without decreasing energy administration (F.6128, F.7362).

This topic was not included in the Delphi consensus process.

The risk for metabolic decompensation during the postpartum period is well documented (F.4578, F.4737, F.5087, F.5232, F.5469, F.5581, F.5588, F.5923, F.6262, F.6276, F.6489, F.6528, F.6935, F.7086, F.7282, F.7313, F.7362, F.7963). The risk is thought to driven primarily by metabolic stress (F.4578, F.5588) and the increased protein load from the involution of the uterus (F.5469, F.5588, F.5581, F.6528), which occurs most rapidly in the first 10-14 days postpartum (F.5937). Most reported cases of postpartum hyperammonemia have occurred within 2-14 days after delivery (F.4578, F.5087, F.5232, F.5469, F.5588, F.6276, F.6489, F.6935, F.7086, F.7282, F.7313, F.7362), with some publications identifying high-risk windows within the first 5 days (F.7963), 2-8 days (F.6262), or 3-10 days postpartum (F.5581). However, cases have been reported up to one month postpartum (F.5232), and some authors note decompensation can occur up to 6-8 weeks post-partum (F.5581). Given this risk, a 2019 systematic review comparing outcomes in 36 cases of maternal OTC highlighted the importance of proactively instructing all women with a known UCD diagnosis on symptoms and risk of hyperammonemia (F.6262).

The risk of hyperammonemia is especially concerning for previously undiagnosed individuals, for whom preventive measures such as monitoring blood ammonia concentrations are unlikely to be in place (F.4578, F.4737, F.5232, F.6262, F.6489, F.6528, F.6935). Without early recognition, postpartum hyperammonemia can progress to seizures (F.5232, F.6489, F.7313), coma (F.4578, F.5232, F.5923, F.6528, F.6935) and/or death (F.5232, F.5923, F.6528, F.7313). Symptoms may overlap with postpartum psychosis and/or depression (F.4578, F.4737, F.5087, F.5232, F.5588, F.6528); therefore, these presumed diagnoses should prompt evaluation of metabolic status (F.4578, F.5232, F.5588, F.6276, F.6528). Acute hyperammonemic events in the postpartum period have been reported in individuals with OTC (F.4737, F.5232, F.5469, F.5581, F.5588, F.6276, F.6935, F.7362), CPS (F.5087, F.5923, F.6276, F.7086), and CIT-I (F.4578, F.7282), as well as citrullinemia type 2 (F.6489).

Proactive monitoring of ammonia during the postpartum period allows for early detection and intervention when indicated (F.5469, F.5581, F.6262, F.6276, F.7362, F.7963). Monitoring may be considered for up to six weeks postpartum, corresponding to the timeframe in which the uterus typically returns to pre-pregnancy size (F.5937). A 2010 case series and an unpublished clinic protocol suggested that women with OTC remain in hospital for at least 72 hours postpartum and undergo evaluation at their metabolic center within two days of discharge (F.6128, G.187), while another unpublished report recommended inpatient monitoring for approximately five days postpartum until protein tolerance is established, with outpatient follow-up within one week of discharge (G.195). Although individuals with mild phenotypes or distal UCDs, such as ASA, may be at lower risk for hyperammonemia, postpartum monitoring is still recommended (F.5788, F.7526).

Delphi 2 Results

There was strong agreement (96%) for the proposed frequency of nutrition encounters during the postpartum period (see TABLE #2, Monitoring the Nutritional Management of an Individual with UCD when Well), including those associated with a clinic visit (in-person or telemedicine) as well as interim telephone encounters.

Preventive strategies to reduce the risk of postpartum metabolic decompensation include temporary protein restriction (F.4553, F.4737, F.5469, F.5581, F.6276), adequate non-protein energy to prevent catabolism (F.4553, F.4737, F.5581, F.5588, F.6276, F.7362), L-arginine or L-citrulline (F.4553, F.4737, F.6276, F.7362), and nitrogen scavengers (F.4553, F.4737, F.5469, F.5581, F.6276, F.7362). A case series and review also emphasize the importance of dietitian involvement during the postpartum period to prevent both catabolism and excess protein intake (F.6128, F.6262).

Intravenous dextrose is a central strategy for meeting postpartum energy needs and preventing catabolism. Continuous infusion of 5-10% dextrose at maintenance rates has been used during labor and the immediate postpartum period (F.4553, F.5581, F.6276, F.7326), with glucose monitoring and insulin administration as needed to maintain normal blood glucose (F.6128). One clinic's standards of practice described 10% dextrose at twice maintenance until meeting energy needs orally (G.187). In published cases, dextrose infusions were typically continued until adequate oral intake was re-established postpartum (F.5581, F.7362). Additional caloric support has included intravenous lipid emulsion, although total energy goals were not specified (F.4737, F.6276, F.7362). One case maintained energy intake above 2,000 kcal/day using intravenous dextrose and an oral glucose polymer, with glucose polymers reintroduced postpartum in response to rising ammonia concentrations (F.5581). Despite consistent emphasis on maintaining adequate energy intake, recommendations for postpartum energy requirements, routes of delivery, and timing of transition to oral intake are not well described in the literature.

Specific recommendations on postpartum protein intake are limited to a few case studies. Two published and one unpublished reports describe restricting protein immediately after delivery, followed by gradual increases to usual intake (F.5581, F.6276, G.195). In one case, a patient with OTC experienced rising ammonia concentrations that were managed with oral glucose, increased sodium benzoate, and a low protein diet, with protein gradually returned to baseline over three weeks (F.5581). Another case described a patient managed with IV dextrose and prophylactic protein restriction of 50 g/day and increased to 1.2 g/kg/day by postpartum day 3 to support lactation (F.6276). An unpublished report described institutional practice consisting of a 24-hour protein-free diet supported by intravenous fluids, followed by stepwise advancement to the prescribed metabolic diet while intravenous fluids were reduced over the next 12-24 hours (G.195). A 2010 case series also reported postpartum management in six women with OTC, with two cases showing stable ammonia concentrations following discharge on protein intakes of 40 g/day and 0.8 g/kg/day (F.6128).

Regarding patients who experience hyperammonemia in the postpartum period, one case report in a female with unknown OTC restricted protein to less than 5 g/day with intravenous 10% dextrose and 20% lipid, intravenous L-arginine, and sodium benzoate with ammonia concentrations and behavioral abnormalities improving over the first 24-48 hours (F.4737). If hyperammonemia occurs and does not adequately respond to primary nutrition and medical intervention, dialysis may be necessary (F.5232, F.6276, F.6489, F.6935, F.7086, F.7313).

Delphi 1 Results

There was unanimous agreement for the following:

• Provide adequate energy (100-120% DRI) during delivery and for six weeks postpartum to prevent catabolism.
• After delivery, women with a UCD should continue to receive IV dextrose until tolerating normal oral intake.

There was strong consensus (96%) that, after delivery, protein intake should return to pre-pregnancy goals, unless the individual with a UCD is breastfeeding.

It is well established that human milk confers important health benefits to infants, including reduced risks of infection, necrotizing enterocolitis, and sudden infant death. Lactation also provides substantial maternal health benefits, including lower risks of myocardial infarction, diabetes, hypertension, and breast cancer (L.463).

Pregnancy and lactation are both periods of increased micronutrient demand; however, lactation places unique and, for some nutrients, greater requirements on the mother to support human milk production. According to FAO/WHO/UNU, energy and protein requirements increase during lactation by approximately 669 kcal/day and 19 g/day, respectively, during the first six months, and by 460 kcal/day and 13 g/day thereafter (F.7963). Micronutrient requirements during lactation may exceed those of pregnancy and non-pregnant states, particularly for iodine, vitamin A, choline, and certain B vitamins (L.466, L.468). Furthermore, maternal intake and body stores of several nutrients directly influence human milk composition (e.g., iodine, selenium, choline, vitamins A, B12, and D, and DHA) (L.464). In contrast, for some nutrients, such as calcium and iron, milk concentrations less responsive to maternal intake, though severe deficiency may still compromise maternal status. In the general population, routine supplementation during lactation is recommended when dietary intake is insufficient, maternal deficiency is present, or requirements are unlikely to be met through diet alone, with particular attention to vitamin B12, vitamin D, choline, and DHA (L.464).

In women with UCD, successful lactation is feasible in the setting of adequate energy and nutrient intake (F.5937, F.7526). However, there is limited published information specific to lactation-related nutritional needs in UCDs. In a 2010 case report of a known OTC female who successfully initiated breastfeeding, protein intake was restricted to 50 g protein/day immediately after delivery and then increased to 1.2 g protein/kg/day by postpartum day three, along with slight increases in L-citrulline and sodium benzoate doses. She was discharged on day seven without metabolic decompensation (F.6276). A 2014 case report of CIT-I described continuation of arginine supplementation during breastfeeding with plans to gradually reduce the dose while closely monitoring of plasma ammonia and amino acids (F.7800). Specific micronutrient supplementation during lactation is not well described in the literature, though risks for nutrient deficiencies in individuals with UCD following a low protein diet are discussed under Recommendation 2.5.

Delphi 1 Results

The following treatment practices during pregnancy received unanimous agreement:

• A woman with a severe UCD should be supported to breastfeed if desired.
• A woman with a mild UCD should be supported to breastfeed if desired.