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To the Editor: Worldwide, pre-eclampsia is a leading cause of maternal death, affecting 3% to 5% of all pregnancies.¹ Recently, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to pre-eclampsia and impaired endothelial function.^2-5

Methods
To assess plasma ADMA concentration in pregnant women living in a high-risk area for pre-eclampsia, we sequentially enrolled, from November 2000 until February 2002, 160 women (67 women with pre-eclampsia [49 moderate and 19 severe cases] and 93 healthy pregnant controls) (Table 1) presenting in 4 Colombian study centers in a case-control study. All women were primigravid and younger than 25 years. Inclusion criteria for the pre-eclampsia group were: more than 20 weeks of gestation, blood pressure of 140/90 mm Hg or higher in 2 separate measurements, and proteinuria (0.3 g in 24 hours or a urine dipstick reading of 2+ for protein with no evidence for urinary tract infection). Controls were clinically healthy women with onset of labor at 37 or more weeks of gestation. None of the controls had hypertension or proteinuria at the onset of labor. Ethnicity (as determined by a validated questionnaire⁶) and exclusion criteria for both groups (history of renal, cardiac, metabolic [diabetic], or autoimmune disease) were assessed by the enrolling physicians. The study was approved by the ethics committee of the Universidad Autónoma de Bucaramanga, Colombia, and all women enrolled provided written informed consent. Plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were measured blinded (within-assay and between-assay variations for ADMA, 1.7% and 2.5%, respectively; limit of detection, 0.004 µmol/L) by minor modifications of an established method.⁴ Our sample size had a greater than 93% power to detect a 40% difference in plasma ADMA concentrations, with P<.05 (2-sided) used to determine statistical significance.

View this table: [in this window] [in a new window] Table 1. Patient Characteristics

Results
We found no significant differences in plasma ADMA concentrations among Colombian women with pre-eclampsia (Table 2). Median (interquartile range) ADMA concentrations in the subgroup of white women (n = 12) with pre-eclampsia were not different from those of the rest of the case group (n = 55) (0.44 [0.28-0.55] µmol/L vs 0.43 [0.32-0.61] µmol/L; P = .83; 95% confidence interval for difference between the medians, -0.15 to 0.13). Within the subgroup of white women ADMA concentrations of pre-eclamptic women (n = 12) and healthy pregnant women (n = 19) were also not different (0.44 [0.28-0.55] µmol/L vs 0.39 [0.27-0.49] µmol/L; P = .59; 95% confidence interval for difference between the medians, -0.11 to 0.18).

View this table: [in this window] [in a new window] Table 2. Plasma Concentrations of ADMA, L-Arginine, and SDMA

Comment
Several possible explanations could be considered for this unexpected finding. It is unlikely that the study was underpowered, as it included the largest number of cases reported to our knowledge. Timing of blood sampling (third trimester at delivery), severity of pre-eclampsia, gestational age at delivery, and birth weight (Table 1) were comparable with those from previous studies from Western Europe.^2-3,5 In light of the lack of ethnicity-related differences in ADMA concentrations in our sample, ethnicity does not appear to explain our results.

Thus, our results support the hypothesis that pre-eclampsia in low- and high-risk populations may have distinct underlying causes.

Funding/Support: Financial support to the VILANO group and the Pregeno project was provided by COLCIENCIAS (Colombia).

Acknowledgment: We thank Mariola Kastner and Anna Steenpaß for excellent technical assistance, and the midwives and the pregnant women who participated in this study.

Renke Maas, MD
maas{at}uke.uni-hamburg.de

Rainer H. Böger, MD; Edzard Schwedhelm, PhD
AG Klinische Pharmakologie
Institut für Experimentelle und Klinische Pharmakologie
Universitätsklinikum Hamburg Eppendorf
Hamburg, Germany

Juan P. Casas, MD; Patricio López-Jaramillo, MD, PhD
Instituto Colombiano de Investigaciones Biomédicas
Bucaramanga
Colombia

Norma Serrano, MD, MSc; Luis A. Díaz, MD
Universidad Autónoma de Bucaramanga
Bucaramanga

1. Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001;357:53-56. FULL TEXT | ISI | PUBMED 2. Fickling SA, Williams D, Vallance P, Nussey SS, Whitley GS. Plasma concentrations of endogenous inhibitor of nitric oxide synthesis in normal pregnancy and pre-eclampsia. Lancet. 1993;342:242-243. ISI | PUBMED 3. Holden DP, Fickling SA, Whitley GS, Nussey SS. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998;178:551-556. FULL TEXT | ISI | PUBMED 4. Savvidou MD, Hingorani AD, Tsikas D, Frölich JC, Vallance P, Nicolaides KH. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet. 2003;361:1511-1517. FULL TEXT | ISI | PUBMED 5. Ellis J, Wennerholm UB, Bengtsson A, et al. Levels of dimethylarginines and cytokines in mild and severe preeclampsia. Acta Obstet Gynecol Scand. 2001;80:602-608. FULL TEXT | ISI | PUBMED 6. Herrera JA, Salmeron B, Hurtado H. Prenatal biopsychosocial risk assessment and low birth weight. Soc Sci Med. 1997;44:1107-1114. PUBMED

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2004;291:823-824.