Table 4.

Studies associating preeclampsia and its outcomes with levels of inflammatory markers in humans and animals.

Study	Population	Inclusion/exclusion criteria	Inflammation biomarkers	Outcomes
Cackovic et al. (2008) [58]	Humans: CG (n = 45) PE (n = 45)	Inclusion criteria: CG matched one to one for maternal and gestational age at enrollment and had a pregnancy course uncomplicated by PE. Exclusion criteria: preexisting proteinuria and/or SAH, active labor, clinical symptoms suggestive of viral or bacterial infection, known or suspected congenital malformation, and isolated IUGR.	Serum and urinary TNF-α	A ↑ serum concentration was observed in PE vs. CG as well as sFlt-1. On the other hand, urinary levels of TNF-α were ↓ in PE and did not correlate with the degree of proteinuria, when compared to CG. In addition, in PE, the fractionated excretion of TNF-α was significantly ↓ despite the existence of proteinuria. Thus, the ↓ renal excretion of TNF-α may contribute to the exacerbated inflammatory response, observed in the pathophysiology of the disease, considering that there is an accumulation of this biomarker in the body.
Sandrim et al. (2008) [59]	Humans: CG (n = 58) GDH (n = 56) PE (n = 45)	Inclusion criteria: women without preexisting SAH. Exclusion criteria: twin or multiple pregnancies or any evidence of previous medical illness.	Nitrite-serum	Serum levels of nitrite were ↓ in GDH and PE women vs. CG (-36% and -58%, respectively, both p < 0.05). Even ↓ serum concentrations of sEndoglin and sFlt-1 were observed in PE women vs. GDH and CG. Thus, impairment in the formation of NO• in PE was suggested.
LaMarca et al. (2011) [62]	Experimental: Rats CG (n = 6) IG (n = 6)	—	IL-6	The results indicated a ↑ mean arterial pressure and AT1-AA in animals receiving chronic infusion of IL-6, which was abolished in those treated previously with the antihypertensive agent (losartan: angiotensin receptor antagonists). Thus, these data showed that IL-6 stimulates AT1-AA and that activation of AT1R mediates IL-6-induced hypertension during pregnancy.
Lai et al. (2011) [63]	Experimental: Rats CG (n = 6) IG (n = 6)	—	IL-10	Animals exposed to hypoxia tended to develop the characteristic symptoms of PE, such as placental injury, proteinuria, hypertension, and systemic symptoms. In addition, there was an ↑ in the expression of antiangiogenic factors, such as sFlt-1. However, after IL-10 administration, the protective role of this cytokine was observed, in relation to the development of symptoms and disease progression, indicating an IL-10 protective role in PE.
Dhillion et al. (2012) [40]	Experimental: Rats NP (n = 20) NP+IL-17 (n = 12) NP+tempol (n = 7) NP+IL-17+tempol (n = 11)	—	IL-17	IL-17 causes placental oxidative stress, which serves as stimulus modulating AT1-AAs that may play an important role in mediating IL-17-induced hypertension during pregnancy.
LaMarca et al. (2005) [64]	Experimental: Rats NP (n = 16) NP+ETa (n = 15) VR+TNF-α (n = 12) CG (n = 11)	—	TNF-α	Chronic infusion of TNF-α had no significant effect on arterial pressure or renal preproendothelin levels in virgin rats. These results suggest an important role for endothelin in mediating TNF-α-induced hypertension in pregnant rats.
Sahin et al. (2015) [123]	Humans: PE (n = 41) CG (n = 80)	Inclusion criteria: CG had all women in the 3rd trimester of pregnancy and none of them developed PE or other pregnancy complications. Exclusion criteria: women in labour, multiple pregnancies, ruptured membranes, or medical history of SAH and DM.	IL-8	An enhanced inflammatory response was observed in severe PE women demonstrated by ↑ levels of IL-8 and decreased levels of IL-10. However, the intensity of platelet activation did not correlate directly with the change in plasma levels of IL-8 and IL-10 in PE women.
Silva et al. (2013) [65]	Humans: PE (n = 50) CG (n = 50)	Inclusion criteria: pregnant women in the 3rd trimester with PE or with an uncomplicated pregnancy. Exclusion criteria: smokers and had systemic diseases and/or associated genital tract diseases (DM, SAH, RD, TD, LE, UI, and cervical or vaginal inflammation).	IL-6, IL-10, TNF-α, and IL-6/IL-10 ratio	The study reinforces the hypothesis that there is an immune dysfunction in PE, with an ↑ in the production of proinflammatory cytokines IL-6 and TNF-α, and a compensatory increase in IL-10.
Molvarec et al. (2015) [124]	Humans: PE (n = 59) CG (n = 60)	Inclusion criteria: all women were Caucasian and lived in the same geographic area. CG was in the early follicular phase of their menstrual cycle, and none of them received hormonal contraception. Exclusion criteria: multifetal gestation, SAH, DM, AID, angiopathy, RD, maternal or fetal infection, and fetal congenital anomaly. None of them was in active labor, and none had rupture of the amniotic membranes. Pregnant women with eclampsia or HELLP syndrome.	IL-17	The serum IL-17 levels are ↑ in PE, which may contribute to the development of the excessive systemic inflammatory response characteristic of the maternal syndrome of the disease.
Sun et al. (2016) [125]	Humans: PE (n = 160) CG (n = 140)	All women in the 3rd trimester of pregnancy. Single pregnancy; cesarean section; same types of anesthesia; no previous medical history of SAH, CD, RD, DM, hyperthyroidism, or other complications that may lead to vascular disorders and hypoxic changes; and no infectious diseases.	IL-8	The IL-8 expression had positive association with the severity of PE. Results from enzyme-linked immunosorbent assay showed that the concentration of serum IL-8 in PE patients (180.27 ± 5.81 ng/L) was significantly higher than that in healthy controls (41.57 ± 5.67 ng/L). Patients with severe PE had even higher serum IL-8 levels.
Ribeiro et al. (2017) [126]	Humans: Early PE (n = 20) Late PE (n = 20) CG (n = 20)	Inclusion criteria: primiparous women without previous history of SAH or obstetric and medical complications. In CG, women with an uncomplicated pregnancy and matched for gestational age with the PE group. Exclusion criteria: multiple gestation, prior PE, illicit drug use, and medical conditions such as DM, cancer, SAH, acute infectious diseases, CD, AID, RD, and LD.	IL 4, IL-6, IL-17,IL-22, and TNF-α	Endogenous plasma levels of IL-6, IL-17, and TNF-α were significantly ↑ in the early-onset PE group than in the late-onset PE and normotensive groups, whereas IL-4 (Th2 profile) and IL-22 (Th17 profile) were not significantly different between the studied groups.
Aggarwal et al. (2019) [127]	Humans: PE+CG (n = 194) Mixed groups: I (n = 55) 28-36 weeks II (n = 139) 37 weeks onwards	PE diagnosis and CG not having any history of pregnancy-related complications, DM or any other chronic medical illness, vaginal bleeding throughout pregnancy, along with no evidence of congenital abnormalities, tuberculosis, and not having habits like tobacco, alcohol, and smoking.	TNF-α, IL-6, IL-4, and IL-10	The levels of TNF-α and IL-6 were significantly ↑ in PE cases, while the IL-4 and IL-10 were downregulated in comparison to control. In addition, a negative correlation was also observed between the two in PE (p = 0.0001).
Peixoto et al. (2016) [128]	Humans: CG (n = 30) PE (n = 16)	Inclusion criteria: women with PE, eclampsia, and HELLP syndrome, irrespective of gestational age and indication for delivery. The CG included pregnant women without complications, according to clinical and laboratory parameters. Exclusion criteria: pregnant women with gestational SAH, chronic SAH, PE superimposed on SAH, and patients who have had spontaneous premature delivery and PPRM.	IL-4, IL-10, IL-13, TNF-α, and IFN-γ	Patients with PE presented significantly ↓ placental levels of IL-10 and IL-13 than the CG. IL-4, TNF-α, and IFN-γ levels were similar on the two groups. ↑ inflammatory balance was observed in patients with PE vs. normal.
Kalantar et al. (2013) [129]	Humans: CG (n = 40) PE (n = 44)	Inclusion criteria: CG consisted of healthy women with uncomplicated pregnancy. They did not receive any special drug during the pregnancy except routine supplements. Exclusion criteria: pregnant women with pregestational DM and SAH.	TNF-α, IL-15, and IL-10	For PE women, significantly ↑ serum levels of TNF-α and IL-15, in comparison with CG. Conversely, the serum levels of IL-10 in CG were significantly ↑ vs. PE.
Kalinderis et al. (2011) [130]	Humans: CG (n = 30) PE (n = 30)	Inclusion criteria: PE developed during the 3rd trimester of pregnancy. CG with no evidence of SAH or proteinuria during the current pregnancy and had no sign of gestational complication or fetal distress. Similar maternal age, gestational age and BMI to PE women. Exclusion criteria: women with multiple gestation, DM, SAH, infectious diseases in pregnancy, PPRM, active labour, polyhydramnios, and signs of other concurrent medical complications.	IL-1β, IL-6	Serum IL-6 and IL-1β levels were significantly ↑ in women with PE vs. CG.
El-Kabarity and Naquib (2011) [131]	Humans: CG (n = 60) PE (n = 120)	All pregnant women were in their 3rd trimester, and CG were demographically matched to the PE women.	IL-12, IL-18	IL-18 was significantly ↑ in women with PE than in CG. IL-12 was not significantly ↑ in mild PE but significantly ↑ in severe cases.
Sharma et al. (2011) [132]	Humans: CG (n = 200) PE (n = 300)	Inclusion criteria: women in both the groups were primiparous, and the gestational age was between 25 and 36 weeks. All the selected women were nonsmokers and did not suffer from any active infectious process. Exclusion criteria: women associated with multiple pregnancies, DM, Rh-incompatibility, bleeding disorders, systemic LE, hydramnios, and pregnancies complicated by fetal abnormalities; pregnant women on any medication or chronic disorders, and metabolic disorders.	ET1, IL-2, TNF-α, and IFN-γ	↑ ET1, IL-2, TNF-α, and IFN-γ in the PE group vs. CG.

Legend: AID: autoimmune disease; AT1: autoantibody receptor against Ang II type 1; AT1-AA: angiotensin II receptor type 1; BMI: body mass index; CD: cardiovascular disease; CG: control group; DM: diabetes mellitus; ET1: endothelin-1; Eta: endothelin receptor antagonist; GDH: pregnant woman with hypertensive disorder; IFN: interferon; IG: intervention group; IL: interleukin; IUGR: intrauterine growth restriction; LD: liver disease; LE: lupus erythematosus; NP: normal pregnant; NT: normotensive; PE: preeclampsia; PPRM: preterm premature rupture of membranes; RD: renal disease; SAH: systemic arterial hypertension; tempol: 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl; TD: thyroid disorders; TNF-α: tumor necrosis factor alpha; UI: urinary infection; VR: virgin rats; vit. E: vitamin E; sFlt-1: soluble Fms-like receptor tyrosine kinase; ↑: higher; ↓: lower.