There is no data in the formal or gray literature regarding nutritional therapies and outcomes in VLCAD with respect to menstruation; however, several case studies report the onset of exercise intolerance and rhabdomyolysis in the premenarchal period. A case of a pre-pubescent female who experienced 10 hospitalizations for rhabdomyolysis in the year preceding menarche was reported in a conference abstract (G.129). During this time, dietary modifications of fatty acids (LCF, MCT) did not ameliorate the decompensations and she required "near continuous" enteral and parenteral nutrition in order to achieve anabolism. On average, her CK was 16,657 IU pre-menarche, and 8,517 IU post-menarche. Prior to this set of episodes, she had been clinically stable and following menarche she required only 3 hospitalizations. (G.129). In a retrospective review including 5 women diagnosed with VLCAD as adults, all had exercise intolerance beginning at age 9 to 11 years (F.617). A case report of homozygotic twin sisters diagnosed with VLCAD in their late forties provided another longitudinal picture of VLCAD. Both had exercise-induced muscle pain and stiffness of increasing severity at puberty. The women learned that restriction of physical activities and consumption of low fat, high carbohydrate meals minimized episodes. Their episodes were most severe in puberty and decreased after menopause (F.6).

Nominal Group

There was consensus that there is a possibility of increased risk for complications during premenarche/menstruation, and that providers should be aware of this potential risk and monitor patients accordingly.

When planning for pregnancy, issues to consider by the woman and her metabolic and obstetrical teams include VLCAD severity and risks associated with pregnancy: adherence to dietary management, MCT and carnitine supplementation; adequate energy intake as needs increase during pregnancy; and biochemical and clinical monitoring for rhabdomyolysis (F.3795, F.4411).

The literature included commentary on delivery method (vaginal vs. Cesarean delivery), emergency contingencies for complications that could arise with respect to energy needs during prolonged labor, changes in C14:1 acylcarnitine concentrations, effects of epidural anesthesia, and scheduled Cesarean-section (C-section) with appropriate anesthesia (F.617, F.3795, F.4411).

In one case report the authors concluded that patients and clinicians should remain alert to potential complications and individualize a comprehensive and multidisciplinary plan of care based on the patient's clinical course, genotype, and non-pregnant phenotype (F.3795).

Questions on this topic were not included in the Delphi surveys.

Three case reports detail the pregnancy, intrapartum and postpartum management of women with VLCAD (F.3795, F.3816, F.4411). At all stages, the goal was to prevent acute metabolic decompensation and precipitation of rhabdomyolysis.

A 21-year-old presented prior to conception with a prescribed diet emphasizing carbohydrate with MCT and L-carnitine supplementation, although specifics of macronutrient distribution and dosing were not provided. Prior to pregnancy, she experienced difficulty adhering to these recommendations and required hospitalizations for rhabdomyolysis with elevated CK concentrations every 2-3 months. Following counseling regarding risk, she became pregnant; however, specific details about her diet during pregnancy were not delineated (F.3795).

Another case report of a 17-year-old describes her preconception treatment with a low-fat diet supplemented with MCT including formula and oral L-carnitine, without further details. She began prenatal care at 29 weeks gestation, but no specifics regarding her diet or L-carnitine dose during pregnancy were provided (F.4411).

In a clinical, biochemical and molecular study of 13 adults (7 females), most with late diagnosed VLCAD, five women (mean age of diagnosis 30 years) had a total of nine pregnancies and two miscarriages. Three women suffered from myalgias after the first delivery or myoglobinuria with CK concentrations as high as 17,000 U/L. No information was reported regarding diet during the pregnancies, but the use of supplements (MCT, L-carnitine, and coenzyme Q10) by some was noted (F.617).

Delphi 1

There was no consensus on whether a pregnant woman who is asymptomatic should follow a diet restricted in LCF, however over 50% agreed LCF restriction should be prescribed for moderate and severe phenotypes. One MD recommended "25 to 30% of energy from total fat for those with mild/moderate phenotypes".

There was good consensus (100% MD/85.7% RD) that an asymptomatic pregnant woman with a severe phenotype should follow a diet supplemented with MCT. RDs reached 85.7% consensus that MCT supplementation would be needed for a moderate phenotype. There was neither MD nor RD consensus for MCT use in a mild phenotype.

Responses to fasting questions indicated support for 9 to 12 hours duration for mild, 6 to 10 hours for moderate, and 6 to 8 hours for severe phenotypes for the pregnant woman who is eating well and is asymptomatic.

Nominal Group

There was consensus among participants that pregnancy presents additional challenges:  Energy needs may be 20% higher than usual.  A patient should maintain the same ratio of LCF/MCT as prescribed for her prepregnancy diet, but increase total fat as energy needs increase during the pregnancy.  Emphasize carbohydrate and protein as needs increase during the 2nd and 3rd trimester. Micronutrient recommendations would be similar to that prescribed for normal pregnancy.  Fasting times may need to be reduced due to increased metabolic stress.

Complications during pregnancy were reported in two (F.4411, F.3816) of 12 pregnancies described in the formal VLCAD literature. The other 10 pregnancies were uncomplicated (F.617, F.3795), although one woman had two miscarriages before a term pregnancy (F.617).

A 17-year-old experienced severe myalgia and rhabdomyolysis with elevated CK by week 25 when she found out she was pregnant (F.4411). Intervention included 5% IV dextrose and bed rest. Due to a short cervix, she was admitted at week 28 and placed on bed rest until week 35. She was then allowed short walks and showers. She was discharged home but was quickly readmitted due to myalgia and elevated CK. She remained inpatient until induction and delivery at week 38. She delivered a healthy baby (F.4411).

A 34-year-old primigravida woman with adult-onset VLCAD developed malnutrition early in pregnancy due to hyperemesis gravidarum. She experienced a severe decompensation at gestation week 14 with a CK of 21,530 U/L and myoglobinuria. Treatment was not detailed, but appetite recovered during weeks 15 to 30. Infant was delivered via C-section without complications at 37 weeks (F.3816).

Another case report described a woman diagnosed at age 20 years following a 14-month history of recurring episodes of muscle weakness, chronic myalgia, rhabdomyolysis, and elevated CK.  Her history revealed hypoketotic hypoglycemia in infancy and seizures that persisted throughout childhood and adolescence. Episodes of myalgia and muscle weakness decreased as pregnancy progressed.  Her laboratory values (acylcarnitine profile, liver enzymes, organic acids, CK) improved in the 2nd trimester and normalized in the 3rd trimester. She elected a vaginal delivery; the 3485 g infant had normal APGAR scores (9/9) and normal newborn screen (NBS) (F.3795).

Delphi 1

There was 100% consensus to treat pregnancy-related nausea and vomiting aggressively to avoid catabolism.

In the formal literature, 9 vaginal deliveries (F.3795,F.4411, F.617) and 3 Cesarean deliveries (F.617, F.3816) are reported. The goal for the intrapartum period includes provision of continuous energy sources to meet metabolic demands and prevent catabolism, rhabdomyolysis, and renal insufficiency.

Plans for a woman opting for a vaginal delivery included on-site availability of 10% IV dextrose and IV L-carnitine. Pain management included avoidance of inhaled anesthetics that might trigger rhabdomyolysis. Fruit juice and other light carbohydrate-rich snacks were provided. This report details monitoring renal function with blood pressure, urine output, blood chemistry and CK every 4 hours. Hepatic function was monitored with liver transaminases and glucose every 8 hours.  Monitoring for rhabdomyolysis included serum CK-muscle/brain (CK-MB) fractions, aldolase and urine myoglobin every 8 hours. Acylcarnitine profile, carnitine and urine organic acids were followed intrapartum and postpartum. The woman proceeded through delivery at 39 weeks without instability except a mild increase in CK of 437 U/L (F.3795).

After induction at 38 weeks, a 17-year-old delivered a healthy infant. She was allowed to consume "drinks and food" during her labor and delivery to provide about 1700 kcals/day with MCT formula contributing 360 kcals. A dextrose-containing IV (concentration or rate not provided) provided an additional 400 kcals and was administered daily for one-week postpartum while she was breastfeeding (F.4411).

A 34-year-old woman delivered a healthy infant by C-section at 37 weeks without complication until cardiomyopathy and acute heart failure developed 10-days postpartum (F.3816).

Delphi 1

There was 100% consensus that during labor and delivery a woman should receive an IV solution containing 10% glucose and appropriate electrolytes at a maintenance rate.

MD comments included: Provide fluids at "1.25-1.5 times maintenance" and  "Through delivery and in immediate postpartum I would caution against catabolism. If she is already hospitalized erring on the side of caution and giving glucose would be my preference".

Nominal Group

There was good consensus that IV dextrose at 1.5 times maintenance is needed during delivery and that deliveries should occur at a hospital in order to provide supportive care.

One case reported acute heart failure due to cardiomyopathy on postpartum day 10 following an uncomplicated C-section delivery of a healthy infant. The 34-year-old woman had an abnormal left ventricular ejection fraction of 30% on electrocardiogram (ECG). Biochemical tests indicated normal glucose, CK, lactate, pyruvate, and ammonia, as well as cardiac troponin T; however, her brain natriuretic peptide (BNP) was 3194.5 pg/mL. She was treated with furosemide, carperitide, losartan, and carvedilol. Sixty days after admission, cardiomyopathy was resolved. The authors commented that the C-section may have been the trigger for acute energy failure, and that VLCAD should be included in the differential diagnosis of acute postpartum cardiomyopathy. The authors hypothesize that the use of MCT as a major source of dietary fat may prevent this severe complication; however, this woman's postpartum nutrition prescription was not reported (F.3816).

Questions on this topic were not included in the Delphi surveys.

Two case studies reported the return of abnormal laboratory findings and clinical symptoms during the post-partum period (F.3795, F.4411). Hormonal changes during puerperium may represent a risk factor for exacerbation of the disease condition (F.4411).

One woman was discharged on post-partum day 4 and instructed to consume 800-1000 additional calories while breastfeeding (a specific macronutrient regimen was not described). The importance of adequate hydration was also emphasized. By 3 weeks post-partum, abnormal acylcarnitine concentrations, which normalized during the third trimester of pregnancy, were measured. At 8 weeks post-partum, myalgia and muscle weakness returned after the start of menses (F.3795).

Another woman experienced episodic myalgia and rhabdomyolysis by four weeks post-partum after discontinuing breastfeeding. The C14:1 concentration normalized during the third trimester of pregnancy but increased after delivery (F.4411).

In the retrospective review of five women with nine pregnancies, three experienced delayed myalgia in the post-partum period following delivery of their first child (F.617). CK was elevated with or without myoglobinuria, but renal function remained stable in all three cases. This review did not provide C14 acylcarnitine concentrations.

Delphi 1

There was 100% consensus that a woman should be counseled to ensure adequate energy intake for at least 6 weeks postpartum in order to prevent catabolism.

There was 100% consensus that a woman with VLCAD can breastfeed her infant, if she wishes to do so.

Comments included: "As long as the woman's nutritional intake is adjusted to support lactation" (per RD). "If the woman has severe VLCAD and dietary restrictions, I would monitor baby's fatty acids and supplement with essential fatty acids if necessary" (per MD).