**1. Introduction**

Preeclampsia complicates 3%–5% of all pregnancies and remains one of the leading causes of maternal and perinatal morbidity and mortality [1]. In particular, pregnancies complicated by early onset preeclampsia (prior to 34 weeks gestation) are associated with a 20-fold increase in maternal death [2] and considerably increased rates of maternal and perinatal morbidities [3]. As such,

the managemen<sup>t</sup> of early onset preeclampsia continues to pose significant challenges to obstetricians attempting to balance maternal risks with fetal benefits of prolonging pregnancy.

Although not fully understood, the pathophysiology of preeclampsia is generally agreed to originate with poor placentation [4]. Inadequate trophoblast invasion and failure of maternal spiral arterial remodeling leads to impaired placental development, including exposure to chronic progressive ischaemia–reperfusion injury characterized by evidence of excessive oxidative stress. In turn, this induces excessive placental release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), coupled with inflammatory cytokines including tumour necrosis factor-α (TNF-α) and activin A [5–8]. These various factors target the maternal vasculature and contribute significantly to the widespread maternal vascular dysfunction, which is often associated with oxidative injury [9–12]. Dysfunctional cells of the vasculature are characterized by increased endothelial cell permeability, altered distribution of endothelial junctional proteins, and reduced endothelium-dependent relaxation [13,14].

Antimalarials, such as hydroxychloroquine, were first formally used as a treatment for cutaneous lupus in 1894. Following the observation in the 1940s that they had improved rheumatoid arthritis, they became a popular therapy in rheumatic diseases [15]. However, research has only recently unraveled some of the mechanisms of hydroxychloroquine's therapeutic effect, as observed by Wallace et al. 2012 [16]. Hydroxychloroquine is classified as C under the U.S. Food and Drug Administration pregnancy category because it crosses the placenta but has not been reported to cause any teratogenic effects to the fetus [17,18]. It has both anti-inflammatory and immunomodulatory properties [19–21], and is widely used in autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome. The exact mechanisms by which hydroxychloroquine improves the activity of these disorders are still not fully understood. However, in women with SLE, it has been shown to decrease circulating levels of pro-inflammatory cytokines IL-6, IL-8, and TNF-α [22], as well as IL-17 and IL-22, which are cytokines produced by helper T cells [23]. Recently, in a female mouse model of SLE, it was reported that hydroxychloroquine decreased endothelial oxidative stress by reducing Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase activity, which led to improved endothelial function, lower blood pressure, and a reduction in proteinuria [24].

In preeclampsia, NADPH oxidase-dependent oxidative stress is one of the pathways underlying the maternal endothelial dysfunction [12]. Accordingly, we hypothesize that hydroxychloroquine may confer beneficial effects in women diagnosed with preeclampsia by reducing placental production of potentially deleterious mediators, thus improving the overall maternal endothelial homeostasis.
