The Impact of Immunosuppressive Drugs on Human Placental Explants

Abstract

The use of immunosuppressive drugs guarantees the vitality of the graft and allows gestation in spite of intercurrences such as prematurity and intrauterine growth restriction. However, little is known about the direct effects of immunosuppressive drugs on placental cells. We investigated the effects of immunosuppressive drugs in the chorionic villous explants from human term placentas of healthy gestations. Human placental explants from term gestations (37-39 week gestational age, n = 12) were exposed to cyclosporine A (CSA, 0, 62.5, 125, 1250 ng/mL) or azathioprine (AZA, 0, 5, 10, 100 ng/mL) separately or, in combination for up to 48 hours. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed a significant decrease in the explant metabolic activity between AZA and the control group (24 hours, 100 ng/mL, 48 hours, all concentrations, P < .005). Cyclosporin A (CsA) reduced cell activity when associated with AZA (48 hours, P < .005). Fibrinoid deposits increased in AZA-treated explants alone (5 ng/mL, 48 hours; 10 ng/mL, 24-48 hours; P < .005) or when associated with CsA (10 AZA/125 CsA, P < .05), whereas in CsA treatment alone, there was an augment in syncytial knots (24-48 hours, P < .005). The sFLT1 gene (24 hours, P < .05) and protein ( P < .005) expression increased in AZA and CsA-treatments separately or in combination ( P < .05). Placental growth factor increased in AZA (24 hours, 10 ng/mL) and CsA (125 ng/mL; P < .05). In conclusion, our data indicate that AZA primarily acts on the villous metabolism, perturbing placental homeostasis. Since these drugs may alter the balance of angiogenic factors in its selection for clinical application, their impact on the behavior of placental villous should be considered.

Soluble Flt‐1, Placental Growth Factor, and Vascular Endothelial Growth Factor Serum Levels to Differentiate Between Active Lupus Nephritis During Pregnancy and Preeclampsia

“…A protective effect on endothelial function has been described, but there was no influence on sFlt-1 and soluble endoglin release (19). In a similar study, azathioprine significantly increased sFlt-1 and PlGF expressions on term placenta explants after 24 hours of incubation when compared to controls (20). However, there are no studies evaluating whether these drugs affect angiogenic and antiangiogenic levels in pregnant women.…”

Comparative study of pregnancy outcomes in women with inflammatory bowel disease treated with thiopurines and/or anti‐TNF: a French nationwide study 2010–2018

“…A large first trimester placenta is associated with macrosomia and large for gestational age 29 . A study performed in term placental explants of healthy gestations has shown that thiopurines perturbs placental homeostasis and more specifically villous metabolism 30 . Further studies are needed to assess whether, and how thiopurines interfere with placental development.…”

Pregnancy-Related Attack in Neuromyelitis Optica Spectrum Disorder With AQP4-IgG: A Single-Center Study and Meta-Analysis

“…Therefore, the literature to date indicates that the dosage of prednisone should be upregulated during single drug maintenance; more studies are needed to identify the specific dose. Although AZA may be a safe therapy for patients with NMOSD occurring during pregnancy ( 39 ), many patients in our cohort refused to use AZA during pregnancy because of concerns about the adverse effects of this drug. In relation to this, monoclonal antibodies are increasingly used in pregnancy ( 40 , 41 ).…”