New research from Ben-Gurion University of the Negev (BGU) is offering much-needed clarity to pregnant women worldwide regarding the safety of common painkillers.
A large-scale data analysis of over 264,000 pregnancies led to two studies conducted by BGU’s Dr. Sharon Daniel. The research found that taking paracetamol (Acamol/Tylenol) or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen (Advil/Nurofen) does not increase the risk of birth defects.
These findings, published in PLOS Medicine and Human Reproduction Open, are based on 20 years of comprehensive clinical data. The research was conducted through the siPREG (Southern Israeli Pregnancy Registry), a high-fidelity data initiative that tracks maternal and fetal health outcomes to answer critical questions for global medicine.
This research uses advanced statistical modeling to distinguish between the effect of a drug and the reason it was taken.
“At first glance, raw data might suggest a slight increase in birth defects among women who took these medications," explained Dr. Daniel, a senior pediatrician at BGU and Director of Innovation at Clalit Health Services. “However, our analysis revealed that the risk was actually tied to the mother’s underlying condition - such as a high fever, infection, or chronic illness - rather than the painkillers themselves."
Key insights from the siPREG analysis include:
- NSAIDs are safe in early pregnancy: The research shows no link between first-trimester NSAID use and malformations in any major organ system, including the heart and central nervous system.
- Paracetamol safety confirmed: One of the most common medications used globally, paracetamol, was found to have no independent association with birth defects, stillbirth, or low birth weight.
- No late-pregnancy complications: Third-trimester use of paracetamol showed no increased risk of newborn renal failure or heart-related complications (premature closure of the ductus arteriosus).
Study 1: NSAIDs During the First Trimester
The first study led by Dr. Daniel comprehensively examined the relationship between NSAID exposure during the first trimester and the risk of birth defects.
Researchers analyzed all pregnancies documented at Soroka University Medical Center between 1998 and 2018 that ended either in birth or pregnancy termination due to suspected fetal abnormalities. In total, 264,858 pregnancies were included, more than 20,000 of which involved NSAID exposure.
The study found no association between NSAID use and birth defects.
Although the raw rate of birth defects was slightly higher among exposed pregnancies (8.2% vs. 7.0%), after adjusting for factors such as fever, inflammatory diseases, pain, maternal background characteristics, and chronic illnesses, the apparent association disappeared. Researchers concluded that the increased risk was mainly explained by the underlying conditions requiring treatment rather than by the medications themselves.
No increased risk was found for specific categories of defects, including in the cardiovascular system, musculoskeletal system, central nervous system, digestive system, and urinary system abnormalities.
Even when each medication was analyzed separately, no increased risk was detected.
“The results showed that NSAID medications are safe to use during the first trimester and are not associated with the development of congenital malformations," Dr. Daniel stated.
Study 2: Acetaminophen (Paracetamol)
The second study focused on acetaminophen, the most commonly used medication worldwide for pain and fever reduction.
Recent concerns suggested that acetaminophen use during pregnancy might be linked to adverse pregnancy outcomes.
Researchers examined whether use throughout pregnancy was associated with congenital malformations, stillbirth, low birth weight, low Apgar scores, newborn kidney failure, or premature closure of the ductus arteriosus (an important fetal blood vessel).
Acetaminophen exposure occurred in 15.5% of pregnancies during the first trimester, and 14.1% during the third trimester, according to the study.
Again, although the raw rate of birth defects appeared slightly higher among exposed pregnancies (7.9% vs. 6.9%), after statistical adjustment for pregnancy characteristics and medical conditions, researchers found no independent association between acetaminophen exposure and birth defects.
Empowering Mothers and Clinicians
To ensure the findings were robust, the team developed a “sensitivity analysis" to account for the reality of unreported over-the-counter drug use.
“We had to ensure that ‘real-world’ habits didn’t skew our results," said Dr. Ariel Hassidim, co-author of the research. “We demonstrated that the volume of unreported use would have to be impossibly high."
By debunking long-standing myths with large-scale evidence, BGU researchers are empowering clinicians to manage maternal pain and fever more effectively. This research follows a similar recent study by the team that confirmed the safety of the antibiotic doxycycline during the first trimester.
“Our goal with the siPREG registry is to replace uncertainty with evidence," concluded Dr. Daniel. “These findings allow for the responsible, research-based management of pain and fever, ensuring better health outcomes for both mother and child."
The multidisciplinary research group led by BGU included experts from Soroka University Medical Center, Schneider Children’s Medical Center, and Ariel University.
PHOTO: Dr. Sharon Daniel of Ben-Gurion University of the Negev (BGU). Credit: BGU.