Paracetamol (N-acetyl-para-aminophenol), also known as acetaminophen, is one of the most widely used over-the-counter analgesics, often considered safe for use during pregnancy and medical procedures. However, its potential impact on the earliest stages of human development has been a subject of growing concern. The peri-implantation period is a critical window characterised by rapid cell division and differentiation, where the embryo is highly vulnerable to environmental exposures. Understanding how common medications like paracetamol interfere with reproductive processes is essential to provide evidence-based guidance to women attempting to conceive.
The recent study by Nielsen et al. provides crucial insights into this issue, investigating the hypothesis that paracetamol interferes with cell division and disrupts pre-implantation embryonic development (1). Using a comprehensive translational approach that included in vitro, ex vivo, and in vivo models, ranging from yeast to human embryos, the authors found that paracetamol exposure at clinically relevant concentrations inhibits cell cycle progression. This disruption, likely caused by the inhibition of ribonucleotide reductase with a subsequent reduction in DNA synthesis, led to decreased cell numbers in cleavage-stage embryos and, in some cases, embryonic death. These findings formed the basis of the ESHRE Journal Club’s discussion, which explored the study’s implications for embryo competence, endometrial receptivity, paternal effects, and clinical counselling.
One of the central topics of discussion was the stage-specific vulnerabilities of the embryo to paracetamol exposure. The study by Nielsen et al. revealed that paracetamol exposure delays cleavage-stage cell divisions. While some affected embryos were able to reach the blastocyst stage with a normal total cell count, they exhibited a reduced inner cell mass (ICM) and impaired DNA synthesis. This suggests that morphological assessment alone is insufficient to determine embryo viability. As highlighted in the discussion, the development to blastocyst stage does not necessarily equate to preserved developmental competence, as internal cellular deficits may undermine implantation potential (2). This stage-specific disruption could also affect endometrial synchrony if the embryo’s development is “off-tempo” further complicating implantation. The Journal Club noted that if these findings are clinically validated, they may encourage a refinement of embryo selection criteria, shifting the focus from traditional morphology toward functional markers of ICM integrity and molecular resilience.
The discussion also addressed the broader molecular and systemic effects of paracetamol. Nielsen et al. demonstrated that paracetamol reduces DNA synthesis in early embryogenesis, a finding consistent with previous work in animal models (3). However, the effects of paracetamol may not be limited to the embryo. Paracetamol is known to modulate the cyclooxygenase (COX) pathway, which plays a role in endometrial implantation and decidualization. Evidence from animal studies suggests that paracetamol could therefore affect endometrial tissue during the implantation window, and its effects might even extend to other reproductive tissues beyond the peri-implantation period (4). Journal Club participants agreed that prospective studies are urgently needed to clarify these systemic effects, with careful control of confounders such as the indication for analgesic use and precise tracking across stages of pregnancy and IVF treatment. However, interventional human trials at these early developmental windows remain ethically sensitive and difficult to justify.
Emerging evidence on sperm-borne epigenetic and RNA cargo effects on early development prompted a discussion on whether paternal paracetamol use around conception could affect embryo dynamics and implantation. Although direct evidence remains limited, the theoretical basis is strong. Sperm small RNAs, histone retention, and epigenetic marks are known to shape early embryonic development. The Journal Club considered feasible designs for future human and animal studies to investigate this question. A prospective IVF/ICSI cohort study, for example, could track peri-conception paracetamol use, changes in semen profiles and sperm small-RNA/methylation, and subsequent embryo development, with adjustment for confounding by indication, including documented fever, inflammatory symptoms, and intercurrent illness at the time of exposure. Mouse models, which show strong parallels with human embryos, were highlighted as a valuable tool for supporting the feasibility and translational relevance of such paternal-exposure epigenetic studies.
Finally, the Journal Club addressed the practical implications for clinical counselling. Given the findings from Nielsen et al., a key question is what constitutes a proportionate message for patients undergoing TTC/IVF. The consensus was that while prospective data are awaited, it is prudent to advise avoiding paracetamol around the time of the trigger shot and during the implantation window. When analgesia is clinically indicated, it should be used appropriately and not excessively. The discussion emphasised the importance of evidence-aware counselling, where clinicians help patients weigh the risks and benefits. This approach explores alternatives to reduce the need for analgesics, such as anti-inflammatory diets, exercise, and stress management. It was also noted that the American College of Obstetricians and Gynaecologists consensus on paracetamol use states that any medication during pregnancy should be used only as needed, in moderation, and after consultation with a doctor (5). Future research, including a retrospective clinical study during IVF/embryo transfer, appears feasible and necessary to provide more definitive guidance.
To summarise, the study by Nielsen et al. provides compelling evidence that paracetamol can interfere with critical cellular processes during early embryogenesis. The Journal Club discussion highlighted the multifaceted implications of these findings, from the molecular mechanisms affecting embryo competence and endometrial function to the potential for paternal epigenetic effects and the immediate need for revised clinical counselling. While many questions remain, this study serves as a critical call for caution regarding the use of one of the world’s most common drugs among women attempting to conceive. The research also underscores the need for further high-quality research to protect the earliest stages of human life.
Acknowledgements
The author would like to express his gratitude to all the members of the ESHRE Journal Club editors Juan J. Fraire-Zamora, Georgios Liperis, Sarah Ribeiro, Noemi Salmeri, Attilio Anastasi, and Dimitrios-Rafail Kalaitzopoulosand. Also, we would like to acknowledge David Møbjerg Kristensen (first author), Julia Uraji, and Thanos Papathanasiou as experts.
References
1.Nielsen BS, Petersen MR, Martin-Gonzalez J, et al. Paracetamol (N-acetyl-para-aminophenol) disrupts early embryogenesis by cell cycle inhibition. Hum Reprod. 2025;40(10):1860-1876.
2.Fragouli E, Alfarawati S, Spath K, et al. The cytogenetic constitution of human blastocysts: insights from comprehensive chromosome screening strategies. Hum Reprod Update. 2019;25(1):15-33.
3.Lauschke VM, Vorrink SU, Moro SM, et al. Massive rearrangements of cellular microarchitecture in primary human hepatocytes in response to paracetamol. Sci Rep. 2020;10(1):21565.
4.Holm JB, Mazaud-Guittot S, Danneskiold-Samsøe NB, et al. Intrauterine exposure to paracetamol and aniline impairs female reproductive development by reducing the primordial follicle pool in female goat offspring. Toxicol Sci. 2016;150(1):178-89.
5.Committee on Obstetric Practice. Committee Opinion No. 743: Analgesia and Anesthesia for the Pregnant Patient. Obstet Gynecol. 2018;132(3):e100-e115.
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