Oral citrulline supplementation in pregnancies with preeclampsia: a multicenter, randomized, double-blind clinical trial

IF 6.5 1区医学 Q1 NUTRITION & DIETETICS American Journal of Clinical Nutrition Pub Date : 2025-02-01 DOI:10.1016/j.ajcnut.2024.12.001

Norbert Winer , Emilie Misbert , Damien Masson , Aude Girault , Marie-Cecile Alexandre-Gouabau , Guillaume Ducarme , Vincent Dochez , Thibault Thubert , Marion Boivin , Véronique Ferchaud-Roucher , Morgane Péré , Dominique Darmaun

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Abstract

Background

Preeclampsia (PE) contributes to maternal and fetal mortality and morbidity. Supplementation with L-arginine, the precursor of nitric oxide, has not proven effective, possibly due to extensive arginine catabolism in the splanchnic bed. Citrulline is converted by the kidney to L-arginine. Citrulline, therefore, could be a more effective nitric oxide donor in the treatment of PE.

Objectives

The study aimed to determine whether oral L-citrulline supplementation would prolong the delay between diagnosis and delivery in preeclamptic females.

Methods

A total of 115 females with monofetal preeclamptic pregnancy were enrolled before 36 weeks of gestation in a multicenter randomized, double-blind trial: 58 received oral L-citrulline supplementation, and 57 received placebo. The duration of pregnancy, neonatal and maternal outcomes, and soluble fms-like tyrosine kinase 1/placental growth factor ratio, an index of placental dysfunction, were monitored.

Results

Gestational age at inclusion was similar in both groups. The duration of pregnancy between inclusion and delivery was unaltered (hazard ratio: 0.90; 95% confidence interval: 0.62, 1.31). Neither neonatal weight nor pregnancy outcome differed between groups. Liver enzymes were higher on the day of delivery in the treated, compared to the placebo group (65.1 compared with 33.2 UI and 70.4 compared with 33.7 UI for alanine aminotransferase and aspartate aminotransferase, respectively, (estimate: 5.92; 95% confidence interval: 1.09, 10.74). Systolic blood pressure (BP) was higher at delivery in the citrulline group compared with the control group (P = 0.015), whereas the diastolic BP showed no difference. We did not find any difference in neonatal outcomes nor soluble fms-like tyrosine kinase 1/placental growth factor ratio.

Conclusions

The current trial found no benefit of oral L-citrulline supplementation to females with PE regarding either the duration of pregnancy, fetal growth, or maternal and neonatal outcomes. Systolic BP and liver enzymes levels were found to increase at delivery in the treated group. L-citrulline oral supplementation does not seem to be a promising candidate as a therapeutic intervention in pregnancies with PE.

This trial was registered at CITRUPE as NCT02801695.

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妊娠子痫前期口服瓜氨酸补充：一项多中心、随机、双盲临床试验

背景：先兆子痫会增加产妇和胎儿的死亡率和发病率。补充l -精氨酸，一氧化氮（NO）的前体，尚未被证明有效，可能是由于广泛的精氨酸在内脏床分解代谢。瓜氨酸通过肾脏转化为l -精氨酸。因此，瓜氨酸可能是治疗子痫前期更有效的NO供体。目的：本研究的目的是确定口服l -瓜氨酸补充剂是否会延长子痫前期妇女诊断和分娩之间的延迟。患者和方法：在一项多中心随机双盲试验中，共有115名单胎子痫前期妊娠妇女在妊娠36周前入组：58名接受口服l -瓜氨酸补充，57名接受安慰剂。监测妊娠持续时间、新生儿和产妇结局，以及胎盘功能障碍指标可溶性类纤维样酪氨酸激酶1/胎盘生长因子（sFlt1/PLGF）比值。结果：两组患者入组时胎龄相近。从纳入到分娩的妊娠持续时间没有改变(HR 0.90, 95% CI [0.62；1.31])。两组新生儿体重和妊娠结局均无差异。与安慰剂组相比，治疗组的肝酶在分娩当天更高(ALAT和ASAT分别为65.1 vs 33.2 UI和70.4 vs 33.7 UI,(估计5.92,95%CI [1.09；10.74])。瓜氨酸组分娩时收缩压高于对照组（p = 0.015），而舒张压无差异。我们没有发现新生儿结局和sFlt-1/ PlGF比值有任何差异。结论：目前的试验发现口服l -瓜氨酸补充剂对先兆子痫妇女在妊娠期、胎儿生长或孕产妇和新生儿结局方面没有益处。治疗组分娩时收缩压和肝酶升高。l -瓜氨酸口服补充似乎不是一个有希望的候选人作为治疗干预妊娠先兆子痫。临床试验注册CITRUPE)临床试验。网址：NCT02801695。

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来源期刊

American Journal of Clinical Nutrition 医学-营养学

CiteScore

12.40

自引率

4.20%

发文量

332

审稿时长

38 days

期刊介绍： American Journal of Clinical Nutrition is recognized as the most highly rated peer-reviewed, primary research journal in nutrition and dietetics.It focuses on publishing the latest research on various topics in nutrition, including but not limited to obesity, vitamins and minerals, nutrition and disease, and energy metabolism. Purpose: The purpose of AJCN is to: Publish original research studies relevant to human and clinical nutrition. Consider well-controlled clinical studies describing scientific mechanisms, efficacy, and safety of dietary interventions in the context of disease prevention or health benefits. Encourage public health and epidemiologic studies relevant to human nutrition. Promote innovative investigations of nutritional questions employing epigenetic, genomic, proteomic, and metabolomic approaches. Include solicited editorials, book reviews, solicited or unsolicited review articles, invited controversy position papers, and letters to the Editor related to prior AJCN articles. Peer Review Process: All submitted material with scientific content undergoes peer review by the Editors or their designees before acceptance for publication.