Acetaminophen Use in Pregnant Women and Their Neonates: Safe or Unsafe till Proven Otherwise?

Anker, John N. van den; Allegaert, Karel

doi:10.1159/000506837

Cited by 7 publications

(8 citation statements)

References 17 publications

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“…Despite being widely considered as 'safe' for use even in pregnancy [4] numerous studies have suggested that fetal exposure to paracetamol could have long-term neurological implications, although recent reviews have drawn attention to signi cant methodological limitations in these studies e.g. [5] [6] [7].…”

Section: Introductionmentioning

confidence: 99%

Efflux Transporters in Rat Placenta and Developing Brain: Transcriptomic and Functional Response to Paracetamol

Koehn

Huang

Habgood

et al. 2021

Preprint

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Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. RNAseq analysis identified transcripts for ABC transporters and enzymes in rat E19, P5 and adult brain and choroid plexus and E19 placenta. Their functional capacity to efflux small molecules was studied by quantitative analysis of paracetamol (acetaminophen) and its metabolites using liquid scintillation counting, autoradiography and ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Animals were treated acutely (30min) and chronically (5 days, twice daily) with paracetamol (15mg/kg) to investigate ability of brain and placenta barriers to regulate ABC transport functionality during extended treatment. Results indicated that transcripts of many efflux-associated ABC transporters were higher in adult brain and choroid plexus than at earlier ages. Chronic treatment upregulated certain transcripts only in adult brain and altered concentrations of paracetamol metabolites in circulation of pregnant dams. Combination of changes to metabolites and transport system transcripts may explain observed changes in paracetamol entry into adult and fetal brains. Analysis of lower paracetamol dosing (3.75mg/kg) indicated dose-dependent changes in paracetamol metabolism. Transcripts of ABC transporters and enzymes at key barriers responsible for molecular transport into the developing brain showed alterations in paracetamol pharmacokinetics in pregnancy following different treatment regimens.

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Section: Introductionmentioning

confidence: 99%

Efflux Transporters in Rat Placenta and Developing Brain: Transcriptomic and Functional Response to Paracetamol

Koehn

Huang

Habgood

et al. 2021

Preprint

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“…In the event of transient placental acetaminophen accumulation, it is likely that this will affect prostaglandin synthesis, and subsequent fetal exposure. This may provide additional insight in the side effects associated with maternal acetaminophen (neurodevelopmental, fetal patent ductus constriction, atopy, fertility) intake during pregnancy, in addition or besides the subsequent fetal acetaminophen exposure (43)(44)(45)(46). Finally, the concept of accumulation in placental tissue as observed for different compounds, and integrated in the current PBPK model should stimulate researchers to also consider conducting ex vivo cotyledon perfusion studies in both naïve as well as in placentas already exposed to a given compound before delivery.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

et al. 2021

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Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

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“…Further to this, there is emerging evidence that antenatal paracetamol exposure may be associated with attention deficit hyperactivity disorder and autistic spectrum disorder [14]. Less is known about the long-term effects of paracetamol administered in the early neonatal period [15, 16].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants

et al. 2021

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Introduction: This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. Methods: This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at <29-week gestation with a ductus arteriosus >0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. Results: Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [p = 0.003]; relative risk reduction 0.35 [95% CI 0.16–0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [p = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; p = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. Discussion/Conclusion: Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.

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Acetaminophen Use in Pregnant Women and Their Neonates: Safe or Unsafe till Proven Otherwise?

Cited by 7 publications

References 17 publications

Efflux Transporters in Rat Placenta and Developing Brain: Transcriptomic and Functional Response to Paracetamol

Efflux Transporters in Rat Placenta and Developing Brain: Transcriptomic and Functional Response to Paracetamol

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants

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