{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T12:24:34Z","timestamp":1789302274540,"version":"build-2803163510"},"reference-count":88,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2015,6,8]],"date-time":"2015-06-08T00:00:00Z","timestamp":1433721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Complications of pregnancy represent a significant disease burden, with both immediate and lasting consequences for mother and baby. Two key pregnancy complications, fetal growth restriction (FGR) and preeclampsia (PE), together affect around 10%\u201315% of all pregnancies worldwide. Despite this high incidence, there are currently no therapies available to treat these pregnancy disorders. Early delivery remains the only intervention to reduce the risk of severe maternal complications and\/or stillbirth of the baby; however early delivery itself is associated with increased risk of neonatal mortality and morbidity. As such, there is a pressing need to develop new and effective treatments that can prevent or treat FGR and PE. Animal models have been essential in identifying and screening potential new therapies in this field. In this review, we address recent progress that has been made in developing therapeutic strategies for pregnancy disorders, some of which are now entering clinical trials.<\/jats:p>","DOI":"10.3390\/ijms160612907","type":"journal-article","created":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T14:05:45Z","timestamp":1433945145000},"page":"12907-12924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["From Pre-Clinical Studies to Clinical Trials: Generation of Novel Therapies for Pregnancy Complications"],"prefix":"10.3390","volume":"16","author":[{"given":"Elizabeth","family":"Cottrell","sequence":"first","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Institute of Human Development,  University of Manchester, Manchester M13 9WL, UK"},{"name":"Maternal and Fetal Health Research Centre, St. Mary\u2019s Hospital,  Central Manchester University Hospitals NHS Foundation Trust,  Manchester Academic Health Science Centre, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Sibley","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Institute of Human Development,  University of Manchester, Manchester M13 9WL, UK"},{"name":"Maternal and Fetal Health Research Centre, St. Mary\u2019s Hospital,  Central Manchester University Hospitals NHS Foundation Trust,  Manchester Academic Health Science Centre, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bamfo, J.E., and Odibo, A.O. (2011). Diagnosis and management of fetal growth restriction. J. Pregnancy, 2011.","DOI":"10.1155\/2011\/640715"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gardosi, J., Madurasinghe, V., Williams, M., Malik, A., and Francis, A. (2013). Maternal and fetal risk factors for stillbirth: Population based study. BMJ, 346.","DOI":"10.1136\/bmj.f108"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1056\/NEJM199904223401603","article-title":"Birth weight in relation to morbidity and mortality among newborn infants","volume":"340","author":"McIntire","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.physbeh.2007.11.017","article-title":"Early life programming of obesity and metabolic disease","volume":"94","author":"Cottrell","year":"2008","journal-title":"Physiol. Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0140-6736(05)17987-2","article-title":"Pre-eclampsia","volume":"365","author":"Sibai","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1152\/physiol.00033.2008","article-title":"Maternal uterine vascular remodeling during pregnancy","volume":"24","author":"Osol","year":"2009","journal-title":"Physiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.siny.2004.03.006","article-title":"Developmental biology of the placenta and the origins of placental insufficiency","volume":"9","author":"Chaddha","year":"2004","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1203\/01.PDR.0000181381.82856.23","article-title":"Placental phenotypes of intrauterine growth","volume":"58","author":"Sibley","year":"2005","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1016\/j.placenta.2012.10.011","article-title":"Review: Transport across the placenta of mice and women","volume":"34","author":"Dilworth","year":"2013","journal-title":"Placenta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.placenta.2015.03.003","article-title":"Animal models of fetal growth restriction: Considerations for translational medicine","volume":"36","author":"Swanson","year":"2015","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/apha.12160","article-title":"Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting","volume":"210","author":"Charalambous","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/nature00819","article-title":"Placental-specific IGF-II is a major modulator of placental and fetal growth","volume":"417","author":"Constancia","year":"2002","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1161\/01.HYP.0000218440.71846.db","article-title":"Cardiovascular function in mice during normal pregnancy and in the absence of endothelial no synthase","volume":"47","author":"Kulandavelu","year":"2006","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1161\/HYPERTENSIONAHA.112.201996","article-title":"Endothelial no synthase augments fetoplacental blood flow, placental vascularization, and fetal growth in mice","volume":"61","author":"Kulandavelu","year":"2013","journal-title":"Hypertension"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1161\/HYPERTENSIONAHA.111.187559","article-title":"Endothelial nitric oxide synthase deficiency reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant mice","volume":"60","author":"Kulandavelu","year":"2012","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R86","DOI":"10.1152\/ajpregu.00600.2011","article-title":"Enos knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype","volume":"303","author":"Kusinski","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1095\/biolreprod.111.096198","article-title":"Effect of the anti-oxidant tempol on fetal growth in a mouse model of fetal growth restriction","volume":"87","author":"Stanley","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.placenta.2011.03.010","article-title":"Animal models of preeclampsia; uses and limitations","volume":"32","author":"McCarthy","year":"2011","journal-title":"Placenta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1161\/HYPERTENSIONAHA.107.096594","article-title":"Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression","volume":"50","author":"Gilbert","year":"2007","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1161\/01.HYP.26.6.1019","article-title":"Effects of long-term nitric oxide synthesis inhibition on plasma volume expansion and fetal growth in the pregnant rat","volume":"26","author":"Salas","year":"1995","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/S0002-9378(13)90488-9","article-title":"Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation","volume":"170","author":"Molnar","year":"1994","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/0002-9378(93)90299-X","article-title":"Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia","volume":"169","author":"Yallampalli","year":"1993","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R259","DOI":"10.1152\/ajpregu.00319.2011","article-title":"l-arginine supplementation abolishes the blood pressure and endothelin response to chronic increases in plasma sFlt-1 in pregnant rats","volume":"302","author":"Murphy","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1161\/HYPERTENSIONAHA.109.141473","article-title":"Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats","volume":"55","author":"Murphy","year":"2010","journal-title":"Hypertension"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia","volume":"111","author":"Maynard","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1073\/pnas.1011293108","article-title":"Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model","volume":"108","author":"Kumasawa","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature10897","article-title":"Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy","volume":"484","author":"Cui","year":"2012","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/nature06951","article-title":"Deficiency in catechol-o-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia","volume":"453","author":"Kanasaki","year":"2008","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1161\/HYPERTENSIONAHA.111.202994","article-title":"Preeclampsia-like symptoms induced in mice by fetoplacental expression of stox1 are reversed by aspirin treatment","volume":"61","author":"Doridot","year":"2013","journal-title":"Hypertension"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1161\/hy02t2.102904","article-title":"Discovery of a spontaneous genetic mouse model of preeclampsia","volume":"39","author":"Davisson","year":"2002","journal-title":"Hypertension"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1095\/biolreprod.106.053603","article-title":"Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia","volume":"75","author":"Dokras","year":"2006","journal-title":"Biol. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/S0002-9378(97)70048-6","article-title":"Role of nitric oxide in the regulation of vascular tone in pressurized and perfused resistance myometrial arteries from term pregnant women","volume":"177","author":"Kublickiene","year":"1997","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0163-7258(94)00064-A","article-title":"Control of vascular resistance in the maternal and feto-placental arterial beds","volume":"65","author":"Poston","year":"1995","journal-title":"Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s00404-006-0149-8","article-title":"Plasma- and urine concentrations of nitrite\/nitrate and cyclic guanosinemonophosphate in intrauterine growth restricted and preeclamptic pregnancies","volume":"274","author":"Schiessl","year":"2006","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.placenta.2012.09.015","article-title":"Endothelial enos\/arginase imbalance contributes to vascular dysfunction in iugr umbilical and placental vessels","volume":"34","author":"Krause","year":"2013","journal-title":"Placenta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.3945\/jn.110.125658","article-title":"Parenteral administration of l-arginine prevents fetal growth restriction in undernourished ewes","volume":"140","author":"Lassala","year":"2010","journal-title":"J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0002-9378(98)80007-0","article-title":"Dietary l-arginine prevents fetal growth restriction in rats","volume":"178","author":"Vosatka","year":"1998","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00726-011-1168-8","article-title":"Arginine nutrition and fetal brown adipose tissue development in nutrient-restricted sheep","volume":"45","author":"Satterfield","year":"2013","journal-title":"Amino Acids"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1365-2362.2005.01445.x","article-title":"Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia","volume":"35","author":"Rytlewski","year":"2005","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/14767050410001725280","article-title":"Ultrasound evaluation of intrauterine growth restriction therapy by a nitric oxide donor (l-arginine)","volume":"15","author":"Sieroszewski","year":"2004","journal-title":"J. Matern. Fetal Neona"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijgo.2004.09.017","article-title":"l-arginine treatment for asymmetric fetal growth restriction","volume":"88","author":"Xiao","year":"2005","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_42","first-page":"202","article-title":"l-arginine infusion reduces blood pressure in preeclamptic women through nitric oxide release","volume":"6","author":"Facchinetti","year":"1999","journal-title":"J. Soc. Gynecol. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/14767050701419458","article-title":"Clinical use of nitric oxide donors and l-arginine in obstetrics","volume":"20","author":"Chiossi","year":"2007","journal-title":"J. Matern. Fetal Neona"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1080\/01443610701194978","article-title":"A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour","volume":"27","author":"Necoechea","year":"2007","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1210\/jc.2004-1831","article-title":"Sildenafil citrate (viagra) enhances vasodilatation in fetal growth restriction","volume":"90","author":"Wareing","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/HYPERTENSIONAHA.111.186270","article-title":"Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model","volume":"59","author":"Stanley","year":"2012","journal-title":"Hypertension"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e77748","DOI":"10.1371\/journal.pone.0077748","article-title":"Sildenafil citrate increases fetal weight in a mouse model of fetal growth restriction with a normal vascular phenotype","volume":"8","author":"Dilworth","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ejogrb.2011.03.005","article-title":"Sildenafil citrate decreases sFlt-1 and seng in pregnant l-name treated sprague-dawley rats","volume":"157","author":"Ramesar","year":"2011","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1111\/j.1471-0528.2012.03430.x","article-title":"Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats","volume":"119","author":"Herraiz","year":"2012","journal-title":"BJOG"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1097\/01.AOG.0000125148.82698.65","article-title":"Management of eisenmenger syndrome in pregnancy with sildenafil and l-arginine","volume":"103","author":"Lacassie","year":"2004","journal-title":"Obstet. Gynecol."},{"key":"ref_51","first-page":"87","article-title":"Eisenmenger\u2019s syndrome in a 27 week pregnancy\u2014management with bosentan and sildenafil","volume":"98","author":"Molelekwa","year":"2005","journal-title":"Ir. Med. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3109\/10641950802601278","article-title":"A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia","volume":"28","author":"Samangaya","year":"2009","journal-title":"Hypertens. Pregnancy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/j.1471-0528.2010.02879.x","article-title":"Sildenafil citrate therapy for severe early-onset intrauterine growth restriction","volume":"118","author":"Dwinnell","year":"2011","journal-title":"BJOG"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ganzevoort, W., Alfirevic, Z., von Dadelszen, P., Kenny, L., Papageorghiou, A., Gluud, C., van Wassenaer-Leemhuis, A., Mol, B.W., and Baker, P.N. (2014). Strider: Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction\u2014A protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst. Rev., 3.","DOI":"10.1186\/2046-4053-3-23"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1113\/jphysiol.2006.104968","article-title":"Placental adaptive responses and fetal programming","volume":"572","author":"Myatt","year":"2006","journal-title":"J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/HYPERTENSIONAHA.107.107219","article-title":"Chronic tempol prevents hypertension, proteinuria, and poor feto-placental outcomes in bph\/5 mouse model of preeclampsia","volume":"51","author":"Hoffmann","year":"2008","journal-title":"Hypertension"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e64401","DOI":"10.1371\/journal.pone.0064401","article-title":"Effects of resveratrol in pregnancy using murine models with reduced blood supply to the uterus","volume":"8","author":"Poudel","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1096\/fj.13-245472","article-title":"Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates","volume":"28","author":"Roberts","year":"2014","journal-title":"FASEB J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1600-079X.2010.00813.x","article-title":"Melatonin and vitamin c increase umbilical blood flow via nitric oxide-dependent mechanisms","volume":"49","author":"Thakor","year":"2010","journal-title":"J. Pineal Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5083","DOI":"10.1113\/jphysiol.2013.258210","article-title":"Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy","volume":"591","author":"Niu","year":"2013","journal-title":"J. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/S0140-6736(99)80010-5","article-title":"Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: A randomised trial","volume":"354","author":"Chappell","year":"1999","journal-title":"Lancet"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1067\/mob.2002.125735","article-title":"Vitamin c and e supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function","volume":"187","author":"Chappell","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0140-6736(06)68433-X","article-title":"Vitamin c and vitamin e in pregnant women at risk for pre-eclampsia (vip trial): Randomised placebo-controlled trial","volume":"367","author":"Poston","year":"2006","journal-title":"Lancet"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0008-6363(02)00827-1","article-title":"Melatonin: A novel protective agent against oxidative injury of the ischemic\/reperfused heart","volume":"58","author":"Reiter","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/jpi.12121","article-title":"Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction","volume":"56","author":"Miller","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1600-079X.2009.00671.x","article-title":"Melatonin improves placental efficiency and birth weight and increases the placental expression of antioxidant enzymes in undernourished pregnancy","volume":"46","author":"Richter","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Hobson, S.R., Lim, R., Gardiner, E.E., Alers, N.O., and Wallace, E.M. (2013). Phase i pilot clinical trial of antenatal maternally administered melatonin to decrease the level of oxidative stress in human pregnancies affected by pre-eclampsia (pampr): Study protocol. BMJ Open, 3.","DOI":"10.1136\/bmjopen-2013-003788"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Alers, N.O., Jenkin, G., Miller, S.L., and Wallace, E.M. (2013). Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction\u2014A phase i pilot clinical trial: Study protocol. BMJ Open, 3.","DOI":"10.1136\/bmjopen-2013-004141"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1159\/000358338","article-title":"Vitamin d and pre-eclampsia: Original data, systematic review and meta-analysis","volume":"63","author":"Hypponen","year":"2013","journal-title":"Ann. Nutr. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1210\/jc.2014-4407","article-title":"Maternal vitamin d deficiency during pregnancy elevates the risks of small for gestational age and low birth weight infants in chinese population","volume":"100","author":"Chen","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta18450","article-title":"Vitamin d supplementation in pregnancy: A systematic review","volume":"18","author":"Harvey","year":"2014","journal-title":"Health Technol. Assess."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Henderson, J.T., Whitlock, E.P., O\u2019Conner, E., Senger, C.A., Thompson, J.H., and Rowland, M.G. (2014). Low-Dose Aspirin for the Prevention of Morbidity and Mortality from Preeclampsia: A Systematic Evidence Review for the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality (US).","DOI":"10.7326\/M13-2844"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pharmthera.2009.01.002","article-title":"Statins and cardioprotection\u2014More than just lipid lowering?","volume":"122","author":"Ludman","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/AOG.0b013e3181e10ebd","article-title":"Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia","volume":"116","author":"Costantine","year":"2010","journal-title":"Obstet. Gynecol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1177\/1933719113492207","article-title":"Effects of pravastatin on angiogenic and placental hypoxic imbalance in a mouse model of preeclampsia","volume":"21","author":"Saad","year":"2014","journal-title":"Reprod. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1161\/HYPERTENSIONAHA.111.00226","article-title":"Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension","volume":"61","author":"Bauer","year":"2013","journal-title":"Hypertension"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1111\/j.1582-4934.2008.00466.x","article-title":"Statins are detrimental to human placental development and function; use of statins during early pregnancy is inadvisable","volume":"12","author":"Forbes","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/molehr\/gau093","article-title":"Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation","volume":"21","author":"Forbes","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.niox.2014.03.162","article-title":"Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health","volume":"38","author":"Kapil","year":"2014","journal-title":"Nitric Oxide"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"A21","DOI":"10.1016\/j.placenta.2014.06.071","article-title":"Supplementation with inorganic nitrate during pregnancy improves maternal uterine artery function and placental efficiency in mice","volume":"35","author":"Cottrell","year":"2014","journal-title":"Placenta"},{"key":"ref_81","first-page":"182A","article-title":"Maternal supplementation with dietary inorganic nitrate improves uteroplacental vascular function in enos(\u2212\/\u2212) mice","volume":"22","author":"Cottrell","year":"2015","journal-title":"Reprod. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Matsui, D. (2012). Adherence with drug therapy in pregnancy. Obstet. Gynecol. Int., 2012.","DOI":"10.1155\/2012\/796590"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1038\/gt.2008.102","article-title":"Local delivery of vegf adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep","volume":"15","author":"David","year":"2008","journal-title":"Gene Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e100021","DOI":"10.1371\/journal.pone.0100021","article-title":"Local over-expression of VEGF-ddeltandeltac in the uterine arteries of pregnant sheep results in long-term changes in uterine artery contractility and angiogenesis","volume":"9","author":"Mehta","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1089\/hum.2013.214","article-title":"Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies","volume":"25","author":"Carr","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_86","first-page":"A44","article-title":"Identification of novel placental homing peptides","volume":"33","author":"Harris","year":"2012","journal-title":"Placenta"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"A9","DOI":"10.1016\/j.placenta.2014.06.032","article-title":"Targeted delivery of insulin-like growth factor-II to the placenta using homing peptide-decorated liposomes increases placental weight","volume":"35","author":"King","year":"2014","journal-title":"Placenta"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"A37","DOI":"10.1016\/j.placenta.2013.06.111","article-title":"Homing peptide-mediated targeting of liposomes to term villous explants: Novel nanocarriers for targeted drug delivery","volume":"34","author":"Cureton","year":"2013","journal-title":"Placenta"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/6\/12907\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:47:34Z","timestamp":1760215654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/6\/12907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,8]]},"references-count":88,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,6]]}},"alternative-id":["ijms160612907"],"URL":"https:\/\/doi.org\/10.3390\/ijms160612907","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,8]]}}}