Table 1.
Therapeutic strategies targeting aberrant innate immune system mechanisms implicated in preeclampsia.
| Innate immunity target | Treatment | Mechanism | Safety in pregnancy | References |
|---|---|---|---|---|
| Macrophages | Salidroside (SLDS) is a phenylpropanoid glycoside extracted from the root of Rhodiola rosea L | Reduction in M1 macrophage/microglia polarization and an increase in M2 macrophage/microglia polarization in mice | Unknown | (73, 181) |
| Macrophages | Macrophages transplantation | Increase in M2-polarized macrophages | Risk for fetal and maternal micro-chimerism | (182) |
| Neutrophils | Maternal corticosteroid administration- Betamethasone | Reversal of delayed neutrophil apoptosis (returning the normal rate of spontaneous neutrophil apoptosis) | Betamethasone acetate Category C (TGA) Betamethasone dipropionate Category B1 (TGA) |
(90) |
| STBM | Neprilysin (NEP) inhibitors Racecadotril (Hidrasec®) |
Inhibition of STBM released, promoting vasodilatation, and natriuresis | Category B1 (FASS) | (183, 184) |
| Maternal microbiome | Probiotic-rich food Milk-based probiotics e.g., Lactobacillus acidophilus and Lactobacillus rhamnosus |
Consumption of probiotic-rich food during pregnancy has been associated with lower rates of preterm birth and preeclampsia Probiotics have been implicated in the modification of placental trophoblast inflammation, systemic inflammation, and blood pressure, all features of preeclampsia Lactobacillus could be associated with lower risk of preeclampsia in primiparous women Overstimulation of the innate immune system due to dysbiosis of the maternal microbiome has been linked to preeclampsia |
Generally recognized as safe (GRAS) by FDA | (185–188) |
| IL-10 | Recombinant Human Interleukin-10 | Increased anti-inflammatory capacity | Recombinant IL-10 reverses hypoxia-induced effects in pregnant mice No significant effect on fetal development in mice |
(189–191) |
| TNFα | Infliximab | TNFα antagonist Anti-inflammatory effects |
Category B (FDA) No increases in miscarriage, structural neonatal malformations or prematurity were observed compared with non-exposed pregnancies |
(85, 192) |
| Complement system | Ravulizumab (Ultomiris®) |
Inhibit cleavage of C5 into C5a and C5b | Category B2 (FASS) | (193) |
| TLR9 | TLR9 antagonist Low-dose naltrexone (LDN) | Reduced inflammatory activity (studied in Crohn's disease) | Category B3 (FASS) | (194–196) |
| TLR2 & TLR4 | Sparstolonin B (SsnB) derived from the Chinese herb Spaganium stoloniferum | Blocks TLR2- and TLR4-mediated NFκB activation in mouse macrophages induced by LPS and Pam3CSK4 | Anti-angiogenic and anti-estrogen toxicity effects in pregnant rodents | (197) |
| TLR4 | Ibudilast | Upregulation of anti-inflammatory cytokines (IL-10, IL-4) Antagonism of TLR4 |
Not tested in pregnant women | (198) www.clinicaltrials.gov (NCT01389193) |
| TLR9 | TLR9 inhibitory oligodinucleotide (ODN2088) | Antagonism of TLR9 associated with reduction in systolic blood pressure | No adverse effects were observed in mice receiving this treatment in a model of type 1 diabetes mellitus ODN2088-treated mice gave birth to healthy pups |
(199–201) |
| TLR4 | Berberine- isoquinoline alkaloid mainly extracted from Rhizoma Coptidis | LPS antagonist Inhibition of LPS/TLR4 signaling |
Berberine can cause or worsen jaundice in newborn infants and could lead to kernicterus | (202–206) |
| TLR4/NF-κB pathway | Parthenolide- Feverfew (Tanacetum parthenium L.) | Inhibition of the TLR4/NF-κB pathway | Not safe in pregnancy Feverfew (Tanacetum parthenium L.) shows potential emmenagogue activity and induces abortion |
(202, 207, 208) |
| IL-1 beta | Canakinumab | Antibody targeting IL-1β Suppression of the innate immune response and systemic anti-inflammatory effects |
Category B1 (FASS) | (209) |
| MSC | MSC-derived EVs | MSC-derived EVs containing molecular cargo and functional mitochondria metabolically reprogram macrophages M1 pro-inflammatory phenotype toward M2 anti-inflammatory phenotype | Unknown/no major adverse effects were reported in preclinical studies with pregnant rodents | (210) (Reviewed in (70) |
| MSC | PLacental eXpanded (PLX-PAD) cells | Suppress TLR-induced inflammation. Release anti-inflammatory cytokines (IL-15 & GM-CSF) and growth factors (EGF & VEGF-A) |
No detrimental effects on fetal development of mice pups | (162) |
The Swedish classification system (Farmaceutiska Specialiteter i Sverige (FASS), American Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) were used to determine the safety profile of drugs used during pregnancy. FASS reports on medications on the European market and reflects international text book recommendations (211).
Category A—safe in pregnancy; Category B1, B2, B3—unknown risk in pregnancy or based on animal studies/Categories B (C and D)—unsafe in pregnancy; Category C—possible harmful effects on the human fetus or neonate without causing malformations. The “probably safe” group include FASS and Australian categories A, B1, and B2 and FDA categories A and B; the “potentially risky” group include FASS and Australian categories B3, C, and D, Australian category X, and FDA categories C, D, and X.