Table 1.

Summary of substances tested as potential treatments for placental dysfunction in pre-clinical studies.

Treatment	Putative mode of action	Test system (s)	Dosing regime	Main outcomes of treatment (compared to appropriate control)	Reference
Sildenafil citrate	Improved uteroplacental blood flow	See text	See text	See text	See text
Adenovirus vector with VEGF	Improved uteroplacental blood flow	See text	See text	See text	See text
Pomegranate juice (PJ)	Antioxidant	Women having normal pregnancy/placental explants and primary cytotrophoblast cells (cytos)	Women drank 8 oz/day PJ from 35 to 38 weeks gestational age (ga) to term. Explants 1% PJ in medium	Decreased placental oxidative stress in vivo and in vitro/decreased apoptosis/punicalagin key component of PJ	Chen et al. (2012, 2013)
Tempol (superoxide dismutase mimetic)	Antioxidant	BPH/5 mouse model of pre-eclampsia	1 mmol/L from 2 days before until end pregnancy	ROS levels reduced/reduced blood pressure/reduced proteinuria/fetal and placental weights restored towards normal	Hoffmann et al. (2008)
		eNOS−/− mouse model of FGR	1 mmol/L 12.5–18.5 days ga	Fetal weight increased towards normal/no effect on placental weight/UtA end diastolic velocity restored to normal	Stanley et al. (2012a)
Resveratrol	Antioxidant/enhanced NO bioavailability	COMT−/− and eNOS−/− mouse models of FGR	4 g/kg in diet 0.5–15.5 days ga	Fetal weight increased towards normal in COMT−/− mouse only/no effect on placental weight/UtA minimum and maximum velocity improved towards normal in COMT mouse only/no effects on UmA velocity	Poudel et al. (2013)
Melatonin	Antioxidant/melatonin receptor	Lipopolysaccharide induced fetal death and FGR in mice	4 mg/kg orally in diet throughout pregnancy	Reduced fetal deaths and increased fetal weight towards normal/oxidative stress reduced	Chen et al. (2006)
		Ischaemia/reperfusion damage to placenta in rats	20 µg/mL orally over course of I/R experiment only	Fetal weight restored towards normal/no effect on the reduced placental weight/improved placental mitochondrial respiratory control index/decreased placental oxidative stress	Nagai et al. (2008)
		Undernutrition induced FGR in rats	5 µg/mL in drinking water 15–20 days ga	No effect on fetal weight but placental weight reduced so that fetal:placental weight ratio restored towards control values/restored birth weight towards control following normal delivery/upregulation of placental antioxidant enzymes	Richter et al. (2009)
		Nutrient restriction induced FGR in sheep	5 mg supplement daily in diet 50 days – end of experiment	Data not easy to interpret: UmA blood flow increased irrespective of nutrient intake/no effect on UtA blood flow/fetal weight only increased when nutrition adequate	Lemley et al. (2012)
		Nutrient restriction induced FGR in sheep	As above	Increased fetal uptake of branch chained amino acids in maternal nutrient restriction	Lemley et al. (2013)
		Hypobaric hypoxia (high altitude) induced FGR in sheep	10 mg/kg/day orally 100–150 days ga	Fetal weight and size further reduced/gestation increased/maternal antioxidant capacity increased	González-Candia et al. (2016)
Sofalcone	Hemoxygenase-1 (HO-1) induction; antioxidant enzyme	In vitro study: Cytos and human umbilical vein endothelial cells (HUVECs)	10, 20, 50 µmol/L in culture medium	HO-1 induced in cytos and HUVECs/decreased sFlt-1 production from cytos/suppressed endothelial dysfunction in HUVECs	Onda et al. (2015)
Proton pump inhibitors	HO-1 induction/anti-oxidant/anti-inflammatory/vasodilation	In vitro study: cytos, HUVECS and placental explants from women with severe early-onset pre-eclampsia. In vivo studies: sFLT-1 overexpressing and eNOS−/− mouse models of pre-eclampsia/hypertension	In vitro: 5–100 µmol/L lansoprazole, rabeprazole, esomerprazole in culture medium over 24 h. In vivo: 150 µg esomeprazole sodium i.p. daily	sFLT-1 and sENG secretion from cytos, explants and HUVECs reduced/endothelial dysfunction reversed/vasodilated maternal blood vessels and decreased BP in mouse models/increased antioxidant protein expression/decreased secretion of cytokines	Onda et al. (2017)
Statins	Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) cholesterol synthesis pathway	Placental explants from early pregnancy	Cerivastatin 50 nmol/L, pravastatin 250 nmol/L in culture medium over 24 h	Proliferative effect of IGF-I and IGF-II on cytos prevented by both statins	Forbes et al. (2008, 2015)
		Mouse model of pre-eclampsia generated by lentivral vector-mediated overexpression of sFLT-1 in placenta	Pravastatin 5 µg/day i.p. from 7.5 day ga onwards	Blood pressure lowered/proteinuria ameliorated/sFLT-1 decreased/placental growth factor (PLGF) increased	Kumasawa et al. (2011)
		Mouse model of pre-eclampsia generated by injection of adenovirus carrying sFLT-1 (not placenta specific)	Pravastatin 5 mg/kg/day from 9 day ga	Placental PLGF and VEGF upregulated/markers of hypoxia downregulated	Saad et al. (2014)
		In vitro study: cytos, HUVECS and placental explants from women with severe early-onset pre-eclampsia. Clinical study: 4 women with pre-eclampsia at 23–30 weeks ga	In vitro study: pravastatin in 20, 200, 2000 µmol/L culture medium. Clinical study: women received 40 mg pravastatin daily	sFLT-1 secretion from all in vitro tissues reduced/increased sENG production from HUVECs/effect on sFLT-1 mediated via HMG-CoA pathway/clinical study showed data consistent with disease stabilization	Brownfoot et al. (2015a)
		In vitro study similar to Brownfoot et al. above	In vitro study: comparison of simvastatin, rosuvastatin and pravastatin at 0–2000 µmol/L in culture medium	Simvastatin most potent inhibitor of sFLT-1 from all cells/all increased sENG secretion/only simvastatin upregulated HO-1 expression by placental explants from pre-eclampsia	Brownfoot et al. (2016b)
		Perfused placental cotyledons and explants (21% and 1% O2) in vitro	0.2 µmol/L pravastatin (twice the serum concentration of a 40 mg daily dose’)	No effects on sFLT-1 or PIGF secretion, or fetal perfusion pressure in perfused cotyledons/increased sFLT-1 secretion by explants under hypoxic conditions	Balan et al. (2017)
		11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) knockout mouse model of FGR	20 µg/kg pravastatin i.p. daily from 6 day ga onwards	Fetal weight and placental weight increased/UmV blood velocity measurements normalized	Wyrwoll et al. (2016)
C-1	Nitric oxide induction, guanylyl cyclase activation/HIF1α inhibition	In vitro study: cytos, HUVECS and placental explants from women with severe early-onset pre-eclampsia	0–100 µmol/L in culture medium 24–72 h	sFLT-1 and sENG secretion from cytos, explants and HUVECs reduced/endothelial dysfunction reversed/HIF1α expression by explants reduced	Brownfoot et al. (2015b)
Metformin	HIF1α inhibition via blocking of mitochondrial electron transport chain inhibition	In vitro study: cytos, HUVECS and placental explants from women with severe early-onset pre-eclampsia	0–1 mmol/L in culture medium 24–72 h	Similar results to YC-1: sFLT-1 and sENG secretion from cytos, explants & HUVECs reduced/endothelial dysfunction reversed/HIF1α expression by explants reduced. Evidence that effect via mitochondrial electron transport chain complex 1	Brownfoot et al. (2016a)
[Leu27] insulin-like growth factor-II (IGF-II)	IGF-II receptor antagonist – increasing IGF-II bioavailability	eNOS−/− mouse model of FGR	1 mg/kg/day sc 12.5–18.5 day ga	Reduction in number of FGR (<5th centile) pups	Charnock et al. (2016)