Elsevier

Clinica Chimica Acta

Volume 475, December 2017, Pages 70-77
Clinica Chimica Acta

Association of serum asymmetric dimethylarginine, homocysteine, and l-arginine concentrations during early pregnancy with hypertensive disorders of pregnancy

https://doi.org/10.1016/j.cca.2017.10.007Get rights and content

Highlights

  • •

    Maternal Hcy concentration at early gestation was significantly higher in the HDP group compared to that in the normal group.

  • •

    A higher maternal Hcy level (> 7.2 μM) at early gestation was associated with the development of HDP.

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    A combination of higher Hcy and lower l-arginine levels in early gestation might be a predictor of HDP.

Abstract

Background

Our previous study suggested that a lower l-arginine level (< 70 μM) at early gestation is associated with pregnancy-induced hypertension. The maternal asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) concentrations also have been reported to be increased in hypertensive disorders of pregnancy (HDP). These molecules have a key role in metabolism of nitric oxide. The aim of this study is to determine the most useful predictor of HDP at early gestation.

Methods

The concentrations of ADMA and Hcy at each of three periods in normal pregnancy were determined, and the values compared between the normal pregnancy and HDP groups. Moreover, the possible risk factors for the development of HDP also were evaluated using a multivariate logistic regression model and propensity score (PS).

Results

The maternal ADMA concentration was significantly elevated with advance of gestational age, while Hcy concentration was decreased from early to mid-gestation and increased from mid- to late-gestation in normal pregnancy. The maternal Hcy concentration at early gestation was significantly higher in the HDP group compared to that in the normal group. A higher maternal Hcy level (> 7.2 μM) in early pregnancy was independently associated with the development of HDP (PS-adjusted odds ratio = 4.47, 95% confidence interval = 1.51–12.82), as well as pre-pregnancy overweight [body mass index (BMI) > 25 kg/m2], primipara status, and a lower maternal l-arginine level (< 70 μM).

Conclusions

The risk factors, such as overweight (BMI > 25 kg/m2) before pregnancy, primipara status, higher Hcy (> 7.2 μM), and lower l-arginine (< 70 μM) concentration in early pregnancy, for development of HDP were detected.

Introduction

Hypertensive disorders of pregnancy (HDP), including chronic hypertension, gestational hypertension, preeclampsia and superimposed preeclampsia [1], lead to maternal and neonatal mortalities and morbidities. Effective therapy after the onset of HDP remains unknown, and treatment delivery is occasionally required to protect maternal health. However, the prognosis in the premature neonate is poor due to complications of fetal growth restriction or prematurity. Thus, prediction and prevention of the disease are important for improvement of the neonatal prognosis in a mother at risk of HDP.

Nitric oxide (NO) is well-known to be a vasodilator that relaxes vascular smooth muscle [2] via the cyclic guanosine monophosphate-dependent pathway [3]. NO also has a physiologic role in the regulation of placental blood flow, trophoblast invasion, and placental development during normal pregnancy [4]. Disruption of the NO pathway causes placental insufficiency-related diseases, such as HDP [3]. NO is produced from its precursor, l-arginine, by endothelial NO synthase (eNOS) in intact endothelium. In a previous cohort case-control study, we reported that a lower concentration of l-arginine (< 70 μM) was associated with a higher risk of pregnancy-induced hypertension, as the previous definition [adjusted odds ratio (OR) = 4.26; 95% confidence interval (CI), 1.29–14.50] [5]. The homocysteine (Hcy)–asymmetric dimethylarginine (ADMA)–NO pathway also is important in the NO metabolism pathway. ADMA is an endogenous inhibitor of eNOS, which reduces NO release from the endothelium, and causes endothelial dysfunction. Hcy increases ADMA level by inhibiting dimethylaminohydrolase (DDAH), which hydrolyzes and degrades ADMA [6], [7], [8], [9], [10]. In addition, elevated serum levels of ADMA and Hcy were reported among women with HDP [7], [10].

These findings inspired us to evaluate the values of ADMA and Hcy during early pregnancy as a predictor of HDP. We investigated the alterations of ADMA and Hcy concentrations in maternal serum at different gestation periods in Japanese women with HDP, and compared their values to those of normal controls. We also evaluated whether these biomarkers might be useful as a predictor of HDP.

Section snippets

Study participants

The study was approved by the ethics committee of Nagoya University Graduate School of Medicine (approval number, 648). A written informed consent was obtained from all study participants. Recruitment of participants and collection of clinical information and blood samples in our study have been previously described in detail [5]. However, two patients with HDP were added to the study because their outcome had been newly confirmed. In brief, all subjects (n = 223) were recruited from a single

Levels of ADMA and Hcy in maternal serum with the advance of gestation and their relationship with the levels in cord blood

The level of ADMA gradually increased with the advance of gestation (P < 0.0001) in the normal control group, from early to mid (0.33 ± 0.07 vs. 0.37 ± 0.07 μM; P = 0.002) and from mid to late (0.37 ± 0.07 vs. 0.39 ± 0.06 μM; P = 0.008) gestation (Fig. 1A). The Hcy concentration significantly decreased from early to mid-gestation (5.7 ± 1.5 vs. 4.8 ± 1.4 μM; P < 0.0001) and then elevated remarkably from mid- to late-gestation (4.8 ± 1.4 vs. 6.2 ± 1.5 μM; P < 0.0001; Fig. 1B). Maternal level of Hcy in mid (cor = 0.37; P = 0.003)

Discussion

Previously, we demonstrated that a lower maternal l-arginine (< 70 μM) concentration at early gestation, overweight before pregnancy (BMI > 25 kg/m2), and primipara status could predict the development of pregnancy-induced hypertension [5]. The current study demonstrated that a higher Hcy (> 7.2 μM) concentration at early gestation also was related to HDP. In addition, a combined evaluation of lower l-arginine and higher Hcy concentrations showed a higher OR for HDP compared with that from evaluation

Conclusions

In our study, an l-arginine concentration < 70 μM and an Hcy concentration > 7.2 μM in early pregnancy was associated with the development of HDP, independent of other risk factors, such as advanced age (> 35 years), overweight (BMI > 25 kg/m2), and primipara status. Thus, it would be useful to evaluate the l-arginine and Hcy levels in early pregnancy and detect a deficit of l-arginine and higher levels of Hcy for the supplementation of l-arginine and folic acid, respectively. However, a cutoff value of

Acknowledgments

We gratefully acknowledge midwives and nurses at Royal Bell Clinic for valuable support. This study was supported by the fund of Ogya (2016-2017). The authors would like to thank Enago (www.enago.jp) for the English language review.

Conflict of interest

The authors declare no conflicts of interest in association with this study.

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    E.M. and J.W. contributed equally to this work.

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