Abstract
Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for ⍺-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule ( 14C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. Results: RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (⍺-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both 14C-sucrose and ⍺-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Conclusion: Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.
Highlights
Paracetamol is commonly taken, either by prescription or self-medication, for the relief of pain and fever
In a recent study we have found that paracetamol, when administered to a pregnant dam at doses within the clinical range used in patients, transfers across the placenta to reach the fetus at about 40% of the levels of the drug in the maternal circulation (Koehn et al, 2019b)
This RNA sequencing (RNA-Seq) study yielded the unexpected outcome of widespread up-regulation of inflammatory and immune-related genes in the placenta of the dam exposed to paracetamol over a prolonged period, with a much less pronounced effect on inflammatory-related genes following a single dose; many other genes showed a regulatory response following a single dose of paracetamol
Summary
Paracetamol (acetaminophen) is commonly taken, either by prescription or self-medication, for the relief of pain and fever In pregnancy it is the most widely consumed drug, with estimates of expectant mothers talking this medication ranging from 56% in Australia and the Americas (Wyszynski & Shields, 2016) to 76% in Europe (Dreyer et al, 2015). In a recent study we have found that paracetamol, when administered to a pregnant dam at doses within the clinical range used in patients, transfers across the placenta to reach the fetus at about 40% of the levels of the drug in the maternal circulation (Koehn et al, 2019b). We have carried out an RNA sequencing (RNA-Seq) study of E19 placentas and brains from control (un-treated) rats and from rats treated with a single (acute) or multiple (chronic) doses of paracetamol. Increased placental permeability appeared to be only from fetus to mother for both 14C-sucrose and -fetoprotein, but not in the reverse direction
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