A review of experimental studies in rodent models suggests that taking paracetamol (acetaminophen, or N-acetyl-para-aminophenol [APAP]) during pregnancy may be harmful to the future fertility of female pups. Dr. David Kristensen and colleagues at Copenhagen University Hospital say their analysis of three published experimental studies in mice and rats indicates that the female offspring of rodents who were given paracetamol during pregnancy had fewer primordial follicles than control offspring, demonstrated irregular cycling, and had reduced fertility. “All three published rodent studies suggest a direct link between prenatal APAP exposure and disruption of female reproductive development,” the researchers write in their published paper in Endocrine Connections (“EDC IMPACT: Is Exposure during Pregnancy to Acetaminophen/Paracetamol Disrupting Female Reproductive Development?”).

The observed changes to female reproductive system development collectively resemble a condition in humans that is linked with premature menopause. “This could be problematic in the Western world where the age of childbirth is continuously being delayed and acetaminophen is recommended during pregnancy for pain and fever,” the authors comment. The overall data suggested that the reproductive systems of developing female offspring are particularly sensitive to maternal exposure to acetaminophen during a timeframe that is comparable with the last weeks of the first trimester of human pregnancy.

It is already known that exposure to some chemicals during pregnancy can cause developmental effects that may not be evident until later in life.  One group of drugs of particular concern are over-the-counter (OTC) pain-relief medicines, such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used during pregnancy. This is “problematic”, Dr. Kristensen’s team notes, because the drugs can cross the placenta, yet women may be taking this type of analgesic before they are aware that they are pregnant. They may also continue to use pain-relief medicines throughout their pregnancy simply because they “may not always identify analgesics as drugs.”

In fact, figures cited by the Copenhagen researchers indicate that up to 90% of mothers may use analgesics during pregnancy. Acetaminophen tops the list of preferred pain-relief drugs among pregnant women, “likely due to the fact that it is regarded as safe during pregnancy and hence is recommended by both doctors and pharmacists,” the researchers suggest.

A number of studies have investigated whether taking mild analgesics during pregnancy might affect the developing male reproductive system, but there is less research on whether fetal exposure to pain-relief medications may also impact the reproductive health of female offspring. The reproductive systems of female rat and mice embryos and fetuses develop through a set of stages and processes that are similar to those in humans.

The published rodent studies reviewed by the Copenhagen University Hospital researchers looked at the effects of maternal analgesic exposure during pregnancy on development of their female offsprings’ reproductive systems and fertility in adulthood. All three suggested a direct link between prenatal exposure to paracetamol taken by their mothers and disruption of female reproductive system development—in particular, reduced numbers of primordial follicles. One of the studies found that female offspring of acetaminophen-exposed mothers had 50% fewer primordial follicles than control animals.

Given that rodents and human females are born with a finite number of follicles available for reproduction in adulthood, this reduction in follicle numbers could feasibly reduce fertility, the researchers suggest. “These data have created concern, as it is generally accepted that the mammalian females are born with a defined set number of follicles that depletes throughout their reproductive lifespan, inevitably leading to menopause and infertility,” they write. “Disturbed establishment of the follicle pool during fetal development may therefore be damaging to fertility in the adult female.”

Dr. Kristensen acknowledges that this reduction in follicle numbers may not represent a “severe impairment to fertility.” Nevertheless, he states, “it is still of real concern since data from three different labs all independently found that paracetamol may disrupt female reproductive development in this way, which indicates further investigation is needed to establish how this affects human fertility.”

One of the reviewed studies in addition found that the female offspring of acetaminophen-exposed mothers had fewer pups when they reached adulthood than control offspring. Subsequent experiments by the same researchers suggested that prenatal exposure to acetaminophen may not reduce female fertility only in the first generation, but also that the effect may be transferable to subsequent generations.

Experimental data also indicated that the ovaries of female pups born to mothers given acetaminophen during pregnancy weighed less at maturity than those of control animals, while additional changes in their ovaries, including increased numbers of follicular cysts and cyst-like structures suggested that “the exposure had accelerated the rate of age-related changes of the female offspring,” Kristensen et al. note.

“The reduction in primordial follicles, as well as irregular cycling and premature absence of CL (corpus luteum) resemble premature ovarian insufficiency syndrome in humans, a disorder usually leading to premature menopause.”  And while the exact cause of premature ovarian insufficiency isn’t understood, exposure to chemicals has been suggested as a factor. “This has raised the concern that prenatal exposure to chemicals may compromise the reproductive life span of women,” the researchers comment.

They state that epidemiological studies assessing the possible link between prenatal exposure to acetaminophen and reduced fertility are now “crucially needed,” although they note that it won’t be easy to demonstrate a causal link between maternal paracetamol use during pregnancy and fertility problems in their daughters. Dr. Kristensen recommends that an interdisciplinary approach should be taken: “…by combining epidemiological data from human studies with more experimental research on models, such as rodents, it may be possible to firmly establish this link and determine how it happens, so that pregnant women in pain can be successfully treated, without risk to their unborn children.”

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