Discussion
AIDS, RECRUITMENT, HYPERTENSION, RECRUITMENT
To our knowledge, this is the first randomised controlled trial (RCT) to investigate the effects of L-citrulline supplementation in a population of pregnant women with chronic hypertension. In this feasibility study, we have confirmed acceptability of the intervention and the study protocol, but we also highlighted significant issues with compliance and the timing of study visits which have complicated the interpretation of the clinical findings. We did not demonstrate a difference in diastolic BP following 8 weeks’ treatment (primary clinical outcome), nor a consistent effect of L-citrulline supplementation on maternal cardiovascular function.Recruitment rate was high within our single centre (5.1 women/month) and the majority of women reported that “taking the allocated treatment” was “easy”. These data confirm the acceptability of the intervention to this group of women and support the feasibility of recruiting to a larger study. However, despite high acceptability, only 65.6% self-reported good compliance with the intervention (missing 1–2 doses/month or fewer), and this correlated well with biochemical measurements. Whilst qualitative measures of compliance were planned, these could not be completed due to inadequate return of treatment/placebo bottles. Further studies of this L-citrulline intervention must (i) seek to improve compliance through participant education or use of adherence aids, (ii) attempt to enforce more robust assessments of compliance and (iii) anticipate reduced compliance when calculating sample size.Supplementation with 3g of L-citrulline twice daily was associated with a significant increase in plasma arginine, particularly in women who reported good compliance with the intervention. Accordingly, the AAR was increased at 4 weeks. This relationship did not persist at the final study visit, perhaps because the timing of the third visit in relation to completion of the intervention was inconsistent and some women had completed their treatment several days prior to their final visit. Alternatively, it is possible that compliance reduced over time. In studies outside of pregnancy, supplementation with the same dose of L-citrulline increased the plasma AAR and also resulted in elevated urinary nitrate and increased cGMP excretion [There could be several explanations for the negative effect on primary outcome reported in this study. Firstly, that there is no effect of L-citrulline treatment on BP in pregnant women with chronic hypertension, despite encouraging preliminary data [The failure to perform appropriate early-phase experimental studies in pregnant women is often driven by a failure to recognise the impact of pregnancy physiology in pharmacokinetics or a desire to reduce intervention studies in pregnant women. However, this compromises the quality and reliability of clinical trials, paradoxically exposing an additional number of women to ineffective therapies and delaying or preventing effective new therapies from reaching clinical use. The role of this study was to test the feasibility of recruitment and intervention in preparation for a definitive RCT. The findings of this study do not support the continuation of a large-scale RCT using this experimental protocol. Rather, a robust assessment of the pharmacokinetics of L-citrulline treatment in pregnant women is indicated prior to further investigation in randomised trials.