Hydroxychloroquine can reduce fetal growth restriction in a dexamethasone-induced rat model

Fetal growth restriction (FGR) is a major cause of neonatal mortality, but no therapeutic options are available for the intrauterine period. Hydroxychloroquine (HCQ), a drug used to treat malaria and autoimmune diseases, reportedly has beneficial effects on pregnancy outcomes in women with lupus or antiphospholipid antibody syndrome, which is often associated with FGR. We investigated the effect of HCQ on fetal growth using a dexamethasone (DEX)-induced FGR rat model. Pregnant Sprague-Dawley rats were divided into three groups (n = 10 for each group): control, DEX (using an osmotic pump), and DEX plus HCQ (administered on gestational days 13-19). All animals were sacrificed on gestational day 20. The weight of each pup was recorded. Maternal serum and placental proteins in each group were compared using an Olink proteomics tool. Administration of DEX induced the FGR (<10th percentile; P < 0.001) , which was marginally recovered by HCQ (P = 0.087). However, systolic blood pressure, serum soluble fms-like kinase-1 levels, and placental thickness were not affected by DEX or the addition of HCQ. Olink proteomic analysis revealed that multiple maternal serum proteins involved in embryonic and placental development were significantly decreased in the DEX-induced FGR rat model but restored by HCQ. Our data showed that HCQ partially restored decreased fetal weight in DEX-induced FGR rats, and these changes involved embryonic and placental development-related signaling pathways during pregnancy. Collectively, these results suggest that HCQ can serve a therapeutic drug to mitigate intrauterine FGR.