Nutraceutical Citrulline in Pregnancy

The pregnancy-specific syndrome preeclampsia is a leading cause of maternal and fetal
morbidity and mortality. The underlying cause of preeclampsia is unknown, however several
pre-existing maternal conditions are associated with an increased risk of preeclampsia
including: diabetes, hypertension, renal dysfunction, obesity and history of preeclampsia.
Specifically, the risk of preeclampsia is five times greater in women with diabetes.

Several lines of evidence indicate that endothelial dysfunction is a central feature of the
pathophysiology of preeclampsia. Asymmetric dimethylarginine (ADMA) is a methylated
metabolite of the amino acid L-arginine and an endogenous inhibitor of nitric oxide synthase
(NOS). High concentrations of ADMA contribute to endothelial dysfunction and ADMA inhibits
angiogenesis and arteriogenesis, activities important in pregnancy and deficient in
preeclampsia. ADMA concentrations are higher early in pregnancy among women who later develop
preeclampsia. This protocol describes a randomized placebo-controlled trial of L-citrulline
in 40 pregnant women with type 2 diabetes from approximately sixteen to nineteen weeks
gestation, to determine whether L-citrulline supplementation increases the plasma
L-arginine/ADMA ratio, lowers maternal blood pressure and increases a circulating marker of
placental function (placental growth factor PLGF).

Inclusion Criteria:

- Singleton pregnancy

- Type 2 diabetes with hemoglobin A1c <8

- Gestational age at randomization between 14 and 16 weeks based on clinical information

- Maternal age between 14 and 40 years

Exclusion Criteria:

- Chronic hypertension

- Major fetal anomaly

- Fetal demise

- Planned termination of the pregnancy

- Collagen vascular disease (autoimmune disease) on medication

- Renal disease

- Epilepsy or other seizure disorder

- Active or chronic liver disease

- Heart disease, known illicit drug or alcohol abuse during current pregnancy

- Already taking L-citrulline as a supplement (1gram/day or more)