Oral L-Citrulline and ADMA 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, and obesity. Among these conditions,
obesity has been increasing in the population, such that 30% of the adult population in the
US is now considered obese, and because of this obesity has the largest attributable risk
for preeclampsia, accounting for 15 to 32% of the population attributable risk for
preeclampsia. There is abundant evidence that pre-pregnancy obesity increases the risk of
preeclampsia. However, it is unknown how pre-pregnancy obesity increases the risk of
preeclampsia, how obesity-mediated metabolic aberrations interact with current hypotheses of
the pathogenesis of preeclampsia, and why only a subset of obese women (~6-8%) develops
preeclampsia. Several lines of evidence indicate that endothelial dysfunction is a central
feature of the pathophysiology of preeclampsia, and endothelial dysfunction is a common
endpoint of obesity. 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 is
higher in obesity and ADMA concentrations are higher early in pregnancy among women who
later develop preeclampsia. This protocol describes a randomized placebo-controlled trial of
L-citrulline vs. placebo in 80 obese pregnant women from twelve to twenty weeks gestation,
to determine whether L-citrulline supplementation decreases the plasma ADMA/L-arginine
ratio, lowers maternal blood pressure, improves endothelial-dependent vascular function and
peripheral vascular stiffness, and improvement in uterine artery Doppler resistance and
flow. We will compare the data obtained from these obese pregnant women to the same measures
obtained from 40 untreated lean pregnant women.

Inclusion Criteria:

- Pre-pregnancy body mass index greater than or equal to 30kg/m2

- Primiparity

- Singleton pregnancy

- Gestational age at randomization between 10 and 14 weeks based on clinical
information and evaluation of earliest ultrasound

- Maternal age between 14 and 40 years

Exclusion Criteria:

- chronic hypertension

- pregestational diabetes on medication (insulin, glyburide)

- major fetal anomaly or 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

- cigarette smoker

- known illicit drug or alcohol abuse during current pregnancy

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