In vitro studies of ferric carboxymaltose on placental permeability using the dual perfusion model of human placenta

Abstract

An in vitro perfusion model of human placenta was used to study the transplacental passage of iron applied in the form of the drug compound ferric carboxymaltose (FCM) which had been radio-labelled with 59Fe. In four placental perfusion experiments, two simulated circuits for the maternal and fetal sides of the placenta were set up with two experimental phases each lasting 3 h. FCM was added to the maternal circuit at the beginning of each phase to a final iron concentration of 11 mM, which is at least 10 times higher than the maximal predicted level in blood after an administration of 200 mg iron as FCM. The effects of adding transferrin at a physiological concentration of 1.67 mg/ ml were also tested. The concentration profiles of 59Fe showed a 10% decrease within the first 30 min of perfusion on the maternal side. Thereafter the radioactivity levels remained unchanged. The addition of transferrin had no effect on the tissue uptake of 59Fe-FCM. No transferred iron radioactivity could be detected in the fetal circuit. Despite a loss of approximately 10% of the radio-labelled iron observed on the maternal side, only 0.5-2% of the radioactivity was detected in the placental tissue after perfusion. No free iron could be detected at the end of perfusion on the maternal side using ultrafiltration or acid precipitation methods. In addition, the production of transferrin receptor remained unchanged, with similar concentrations in placental tissue before and after perfusion. No effects of FCM on placental viability were observed in terms of energy metabolism (glucose consumption and lactate production), hormone release or placental permeability (assessed by the transfer rates of creatinine and antipyrine). However, two additional observations were made: firstly, a significant reduction in the rate of cell death compared to control conditions was observed in the presence of FCM; secondly, the integrity of the fetal capillary system was improved on the fetal side of the perfusion system. It is concluded that the iron compound FCM does not cross the placenta and may increase the integrity of placental tissue (at least under in vitro conditions), but this latter observation needs further investigation.

Intravenous iron treatment in pregnancy: comparison of high-dose ferric carboxymaltose vs. iron sucrose

“…Previously, an in vitro study using a dual-placenta perfusion model has shown that ferric carboxymaltose does not cross the placental barrier to the fetal side [15] . Though there is no previous published clinical data available on the use of ferric carboxymaltose in pregnancy and its effects on the fetus, ferric carboxymaltose is approved for use in the second and third trimesters of pregnancy.…”

“…This iron preparation can be used intravenously in high doses with up to 1000 mg infused in 15 min and low risk of side effects. We have previously shown that ferric carboxymaltose does not cross the placental barrier in an in vitro dual perfusion model (15), and its use is approved in the second and third trimesters of pregnancy. However, no published data are available concerning the clinical use of ferric carboxymaltose use in pregnant women.…”

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose

“…The transferof iron across the placentain pregnant animalsfollowing FCM administration hasbeen assessed in studiesw ith 59 Fe-labelled FCM.Seven days afteradministration of 5mgi ron asFCM top regnant rats on Day12of gestation,3.1 %o fthe iron dosewas found in the placentaa nd 9.2%i nthe fetuses [9].Fetal concentrationsw erel owert hanp lacentalconcentrations,suggesting thatt he placentaa cts asapartialbarriertothe transferof iron. Moreover,no iron crossed the placentalbarrierin an in vitro studyw ithh umanp lacentas,whichm ayindicatethatt he FCM complexcannotcross the placenta [ 10].Thisobservation together withthe kineticsof iron transferintof oetusesin the in vivo study[9]suggest thatt he placentaltransferisessentiallydependenton the metabolismo fthe FCM complex.…”

Management of Restless Legs Syndrome in Pregnancy and Lactation

“…34 Ferric carboxymaltose is not known to cross the placenta; however, based on current evidence, the risk to the fetus is unknown and cannot be fully ruled out. 37 Last, there are multiple studies on iron sucrose in pregnancy and no adverse effects to the mother or fetus have been described. 27,38 In 2 pregnant patients, iron sucrose given in 4 doses of 100 mg each 1 to 2 weeks apart successfully treated RLS symptoms.…”