Extended Acetaminophen Use During Pregnancy May Pose Risk

Lara C. Pullen, PhD

May 20, 2015

A study in mice and rats reveals that as little as 1 week of prenatal exposure to acetaminophen (paracetamol) can suppress fetal testosterone production. In contrast, a single day of acetaminophen use does not result in long-lasting suppression of testosterone production.

The results suggest a mechanistic explanation for the previously reported association between protracted acetaminophen use in human pregnancy and increased occurrence of cryptorchidism.

However, in a related statement released to the media, the Royal College of Obstetricians and Gynaecologists cautions that further studies are needed to understand how these animal data apply to human fetal development. In the meantime, the college recommends clinicians continue to follow current guidelines on acetaminophen use for their pregnant patients.

Sander van den Driesche, PhD, from the University of Edinburgh in the United Kingdom, and colleagues published data from their validated xenograft model online May 20 in Science Translational Medicine. The investigators xenografted fragments of human fetal testes to mice in a way that was engineered to simulate the normal endocrine environment of the fetal testis.

The researchers found that following a therapeutically relevant acetaminophen regimen for 7 days resulted in a 45% reduction in testosterone production by human fetal testis xenografts. A high dose of 350 mg/kg once daily for 7 days resulted in a weight reduction of the androgen-dependent seminal vesicles in host mice.

"To confirm the potential human health relevance of our findings, we measured plasma acetaminophen concentrations in host mice, and found concentrations of 0.74 to 0.94 μg/ml at 1 hour after a dose (therapeutic regimen). This is well below the concentrations reported in adult humans (6 μg/ml) at the same time point (1 hour) after the equivalent oral dose.... In addition, a study that investigated pregnant and nonpregnant women demonstrated a maximum serum concentration at 0.8 hour after a dose of 20.8 μg/ml during pregnancy and 23.7 μg/ml in the nonpregnant state," the authors write.

The investigators acknowledge that the xenograft model may not accurately reflect in utero human exposure. They thus sought to reinforce their results with data from pregnant rats.

"To provide mechanistic support for our findings in an in utero model, we exposed pregnant rats to acetaminophen using two different regimens. We demonstrated that once daily exposure to acetaminophen from [embryonic day 13.5] resulted in a reduction in [intratesticular testosterone] 24 hours after the final dose at [embryonic day 17.5]," they explain.

The authors have disclosed no relevant financial relationships.

Sci Transl Med. Published online May 20, 2015.

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