A Common Medicine, A Critical Window
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Introduction
Acetaminophen (Tylenol)—known in other countries, such as the Philippines, as paracetamol—is one of the most widely used medicines worldwide. It is available without a prescription; it treats mild pain and fever and is generally considered the safest pain reliever during pregnancy. More than half of pregnant women report using it at some point before giving birth. Because it crosses the placenta freely, any paracetamol a mother takes reaches her developing fetus.
For years, the main concern about paracetamol in pregnancy was that it was safer than the alternatives. But a growing body of animal research has raised a different question: could this common medicine affect the developing reproductive system of a female fetus?
A new study from Denmark, called the COPANA study, is the first human study designed specifically to investigate that question. Published in Human Reproduction Open, it followed hundreds of pregnant women and their infant daughters, measuring paracetamol exposure carefully and then examining the girls’ ovaries, uterus, and reproductive hormones during a brief but important window of early life.
The findings suggest that even mild to moderate paracetamol exposure during fetal life is associated with measurable differences in how the female reproductive system develops.
Why the Female Reproductive System Is Vulnerable Before Birth
To understand why this matters, it helps to understand how a girl’s reproductive system is built.
A female is born with all the eggs she will ever have. Unlike men, who produce sperm continuously throughout life, women are born with a finite supply of immature eggs, each contained within a tiny structure called a follicle. This reserve of follicles is established before birth during fetal development and gradually depletes over a woman’s lifetime until menopause.
The most critical period for building this reserve occurs early in pregnancy. Between roughly 10 and 17 weeks of gestation, the fetal ovaries undergo intense activity. Germ cells—the precursors of eggs—multiply rapidly through a process called mitosis.
Then, around the same time, these cells begin to enter meiosis, a special type of cell division that prepares them for eventual fertilization. This transition from multiplication to maturation is delicate, and anything that interferes with it could potentially reduce the number of eggs a girl is born with.
Later in pregnancy, from about 17 weeks onward, the pattern shifts. Cell multiplication slows, more germ cells enter meiosis, and follicles begin to form and mature. This is also a sensitive period, but for different reasons.
Because these developmental windows are so distinct, the COPANA researchers decided to study whether the timing of paracetamol exposure mattered. Did exposure early in pregnancy have different effects than exposure later on?
How the Study Was Designed
The COPANA study—short for Copenhagen Analgesic Study—was a prospective, observational cohort study conducted at a single university hospital in Denmark between March 2020 and November 2022. Researchers invited over 3,400 healthy pregnant women to participate and ultimately enrolled 685 women in their first trimester. Of these, 302 infant daughters returned for detailed examinations.
The study excluded women with diabetes, thyroid disease, multiple pregnancies, or deliveries that were significantly premature or post-term. They also excluded infants with serious illnesses. The goal was to create a homogeneous group so that any differences observed could be more confidently attributed to paracetamol exposure rather than other factors.
What made this study unusually rigorous was how carefully it measured exposure. Rather than relying on a single question about medication use, the researchers asked women to complete detailed questionnaires every two weeks throughout pregnancy.
These questionnaires asked about medicine consumption, including drug names, doses, and reasons for use. In addition, all women provided urine samples during the first trimester, which were analyzed for paracetamol concentrations using highly sensitive laboratory methods.
This combination of self-reported data and objective biomarkers gave researchers a much more complete picture of paracetamol exposure than most previous studies.
The girls were then grouped based on when their mothers first used paracetamol:
- Early fetal exposure: Paracetamol use before 17 weeks of gestation (92 girls)
- Mid-to-late fetal exposure: Paracetamol use at or after 17 weeks (67 girls)
- Unexposed controls: No paracetamol use during pregnancy (143 girls)
A smaller subgroup of 22 girls was exposed exclusively during early fetal life, which allowed researchers to isolate the effects of that specific window.
What the Researchers Measured
When the infant girls were about three months old—during a period called “minipuberty”—they underwent a series of examinations.
Minipuberty is a fascinating but little-known phenomenon. In the first few months after birth, the infant’s reproductive system temporarily activates. The ovaries produce hormones, follicles begin to grow, and the uterus and breasts respond to estrogen. This window offers a unique opportunity to observe how the reproductive system is functioning early in life.
The researchers performed transabdominal ultrasound scans to measure:
- Ovarian volume – the size of the ovaries
- Antral follicle count – the number of small, fluid-filled follicles visible on ultrasound
- Uterine volume – the size of the uterus
- Breast tissue diameter – a marker of estrogen activity
They also collected blood samples from 269 of the 302 girls to measure reproductive hormones, including:
- Anti-Müllerian hormone (AMH) – produced by small follicles in the ovaries and considered a marker of ovarian reserve
- Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) – hormones that regulate ovarian activity
- Inhibin B – another hormone produced by ovarian follicles
- Estradiol – the primary form of estrogen
To ensure accuracy, all ultrasound examinations were performed by a single experienced clinician who did not know which girls had been exposed to paracetamol and which had not.
What the Study Found
The results were striking and consistent across multiple measures.
Early Exposure and Ovarian Volume
Girls exposed to paracetamol before 17 weeks of gestation had significantly smaller ovaries compared to unexposed girls. The average reduction was 0.11 cubic centimeters, which represented about a 41% difference in size. This association remained statistically significant even after adjusting for factors like maternal age, body mass index, smoking, alcohol use, and other medication use.
Early Exposure and Uterine Volume
The same group of girls also had reduced uterine volume—about 0.18 cubic centimeters smaller, or roughly a 13% reduction. The uterus is highly responsive to estrogen, so a smaller uterus may reflect lower estrogen activity during this critical developmental window.
Early Exposure and AMH
Girls exposed exclusively during early fetal life had lower levels of AMH. Specifically, their AMH levels were 0.45 standard deviations lower than those of unexposed girls. Since AMH is produced by small ovarian follicles and is considered a marker of ovarian reserve, this finding suggests that early paracetamol exposure may reduce the number of healthy follicles in the ovaries.
Mid-to-Late Exposure and Follicle Count
Girls first exposed to paracetamol at or after 17 weeks of gestation had fewer ovarian follicles—about one fewer follicle on average, representing a 23% reduction. This association was specific to the timing of exposure: early exposure did not affect follicle count, and late exposure did not affect ovarian volume.
Dose-Response Relationships
Perhaps most importantly, the researchers found evidence of a dose-response relationship. Using both self-reported doses and urinary paracetamol concentrations, they found that higher exposure was associated with greater reductions in ovarian and uterine volume, as well as breast tissue diameter.
In other words, the more paracetamol a mother took, the more pronounced the differences in her daughter’s reproductive development.
This dose-response pattern strengthens the case that the associations are real and not simply due to chance or confounding factors.
Replication in an Independent Cohort
A key strength of this study was that the researchers attempted to replicate their findings in a completely separate group of girls—the Copenhagen Mother-Child Cohort, which included 1,210 girls born between 1997 and 2002 and followed from infancy through adolescence.
In this confirmatory cohort, paracetamol exposure was assessed differently: mothers were asked once, during the third trimester, whether they had used any medication during pregnancy, with paracetamol specifically listed as an example. This method was less detailed than the biweekly questionnaires used in COPANA, and exposure was likely underreported. Nevertheless, the researchers found similar patterns.
At puberty, girls exposed to paracetamol or non-steroidal anti-inflammatory drugs during pregnancy had reduced uterine volume—about 4.11 cubic centimeters smaller. They also had lower levels of inhibin B, a hormone produced by ovarian follicles.
During adolescence, exposed girls still had reduced ovarian volume—about 2.76 cubic centimeters smaller—than unexposed girls.
These findings suggest that the differences observed in infancy may persist into later childhood and adolescence, though the replication was not uniform across all outcomes.
What About Other Factors?
The researchers took great care to rule out alternative explanations.
They adjusted their analyses for a wide range of potential confounders, including:
- Maternal use of aspirin or other anti-inflammatory drugs
- Infant treatment with paracetamol after birth
- Maternal polycystic ovary syndrome
- Alcohol consumption during pregnancy
- Smoking or nicotine use
- Conception through in vitro fertilization
- Maternal age and body mass index
They also conducted sensitivity analyses excluding women who reported fever as the reason for paracetamol use. This was important because fever itself could affect fetal development, and if paracetamol were merely a marker of fever, the associations might not be due to the drug itself. However, excluding fever-related use did not change the findings.
The results were robust across these analyses, strengthening the conclusion that the associations are specifically linked to paracetamol exposure.
How Does This Compare to Animal Research?
The findings align closely with a substantial body of animal research. Multiple independent studies in rodents have shown that fetal exposure to paracetamol reduces the number of ovarian follicles in female offspring by up to 40%. These studies have also found impaired fertility and shortened reproductive lifespans in exposed animals.
Several biological mechanisms have been proposed to explain these effects. Paracetamol may:
- Inhibit the rapid multiplication of germ cells, reducing the number of eggs that enter meiosis
- Interfere with prostaglandin synthesis, which is important for normal ovarian development
- Delay the transition from mitosis to meiosis, leading to increased germ cell death
While animal studies cannot be directly translated to humans, the consistency of findings across species—and the biological plausibility of the mechanisms—lends support to the human observations.
What the Study Does Not Prove
It is important to be clear about what this study can and cannot tell us.
This was an observational study, not a randomized controlled trial. That means the researchers observed associations between paracetamol exposure and reproductive outcomes, but they cannot definitively prove that paracetamol caused the differences. It is possible that some other factor—related to why women took paracetamol, or something else entirely—explains the findings.
The researchers acknowledge that residual confounding by indication cannot be completely excluded. In other words, the underlying condition for which paracetamol was taken—such as pain, infection, or inflammation—could itself influence fetal development.
However, most women in the study reported using paracetamol for headaches or migraines, not for systemic illness, and sensitivity analyses did not change the results.
Another limitation is that the study population was predominantly Caucasian and term-born, so the findings may not generalize to all populations. Additionally, ovarian volume and follicle counts could be obtained for only about two-thirds of the infants, reflecting the technical challenges of imaging very small ovaries.
The researchers also performed many statistical analyses, which increases the risk of finding associations by chance. However, the analyses were predefined and hypothesis-driven, based on prior animal evidence, and related outcomes tended to move in the same direction, making chance findings less likely.
What Does This Mean for Pregnant Women?
This is the question many readers will be asking. The study does not provide a simple answer.
Acetaminophen is widely used during pregnancy, and in some situations—such as severe fever—it is clearly necessary. Untreated fever during pregnancy can be dangerous for both mother and fetus. Current guidelines from the European Medicines Agency recommend using the lowest effective dose for the shortest possible time.
The exposure levels in this study fall within the recommended ranges. The median total dose reported by mothers was about 3 grams over the entire pregnancy—roughly equivalent to six standard 500-milligram tablets. Yet even at these low levels, associations with ovarian and uterine development were observed.
This raises a concern that current guidance may not be sufficiently protective. The researchers suggest that non-pharmacological alternatives and enhanced education for pregnant women may help reduce unnecessary exposure. However, they also emphasize that pregnant women should not avoid treating serious conditions like high fever without consulting a healthcare provider.
What Comes Next?
The study authors call for larger prospective studies with repeated biomarker-based assessments of paracetamol exposure throughout pregnancy and long-term follow-up into adolescence and adulthood. Future research should also focus on clinically meaningful outcomes—such as fertility and reproductive lifespan—to determine whether the early differences observed in this study translate into real-world health effects.
For now, the findings add to a growing body of evidence suggesting that paracetamol is not entirely without risk when used during pregnancy. While the clinical implications remain uncertain, the consistency of the findings across multiple outcomes, the dose-response relationships, and the alignment with animal research all point in the same direction: fetal exposure to paracetamol is associated with measurable differences in the development of the female reproductive system.
Conclusion: Key Takeaways
- Paracetamol is the most commonly used pain reliever during pregnancy, and it crosses the placenta freely.
- In this Danish cohort study of 302 infant girls, prenatal paracetamol exposure was associated with smaller ovaries, fewer ovarian follicles, lower AMH levels, and reduced uterine volume during minipuberty.
- The timing of exposure mattered: early exposure (before 17 weeks) was associated with reduced ovarian and uterine volumes, whereas later exposure (after 17 weeks) was associated with fewer follicles.
- Higher doses and higher urinary paracetamol concentrations were associated with greater reductions in ovarian and uterine size, suggesting a dose-response relationship.
- Similar associations with reduced ovarian and uterine size were observed in an independent cohort of girls followed into adolescence.
- The findings are consistent with animal studies showing that fetal paracetamol exposure impairs ovarian development and reduces fertility.
- The study cannot prove causation, but the associations were robust after adjusting for many potential confounding factors, including fever and other medication use.
- Current guidelines recommend using the lowest effective dose for the shortest duration; this study suggests that even low-dose exposure may be associated with measurable differences.
- Pregnant women should not avoid treating serious conditions like high fever, but unnecessary paracetamol use may be worth discussing with a healthcare provider.
- Further research with long-term follow-up is needed to determine whether these early differences affect fertility and reproductive lifespan later in life.
If you’re pregnant and looking for ways to manage fever or pain without relying on medication, our companion article covers evidence-based non-drug strategies—from physical cooling and targeted exercise to heat therapy, massage, and acupuncture. It also explains when self-care is enough and when it’s time to call your doctor.
Read next: Non-Drug Alternatives for Managing Fever and Pain During Pregnancy: What Works, What’s Safe, and When to Call Your Doctor
Don’t Get Sick!
About Dr. Jesse Santiano, MD
Dr. Santiano is a retired internist and emergency physician with extensive clinical experience in metabolic health, cardiovascular prevention, and lifestyle medicine. He reviews all medical content on this site to ensure accuracy, clarity, and safe application for readers. This article is for educational purposes and is not a substitute for personal medical care.
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Disclaimer:
This article is for educational purposes and is not a substitute for professional medical advice, diagnosis, or treatment. Always consult your physician before making health decisions based on the TyG Index or other biomarkers.
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