A large study from southern Israel has found reassuring news for pregnant women managing pain in early pregnancy: common painkillers like ibuprofen and naproxen show no link to major birth defects. The research, led by Dr. Sharon Daniel of Ben-Gurion University of the Negev and published in PLOS Medicine, analyzed nearly 265,000 pregnancies over two decades and offers clarity on a question that has long left doctors and expectant mothers uncertain.
Pain and fever are facts of early pregnancy, yet the options for safe relief have felt increasingly limited. Safety concerns about acetaminophen have circulated for years, while nonsteroidal anti-inflammatory drugs—NSAIDs—have remained clouded in inconclusive data. This research cuts through that ambiguity with concrete findings from the Southern Israeli Pregnancy Registry (SiPREG), which tracks medication use and birth outcomes with unusual precision, following pregnancies not just through delivery but through the first year of life.
The study examined 264,858 singleton pregnancies between 1998 and 2018. Of these, 20,202 pregnancies—7.6% of the total—involved exposure to NSAIDs during the first trimester, predominantly ibuprofen at 5.1%, diclofenac at 1.6%, and naproxen at 1.2%. The researchers identified major congenital malformations using linked clinical, hospitalization, and termination records, then adjusted their analysis for maternal age, ethnicity, diabetes, obesity, folic acid use, and the reason the medication was taken. That careful accounting matters: it means the researchers weren't comparing apples to oranges, but rather controlling for factors that might independently affect birth defect risk.
The results were clear. NSAID exposure was not associated with major birth defects overall—8.2% in exposed pregnancies versus 7.0% in unexposed ones, with a matched adjusted relative risk of 0.99. The researchers found no increased risk for malformations in specific organ systems either: the cardiovascular, musculoskeletal, central nervous system, gastrointestinal, and genitourinary systems all showed no link to NSAID use. Individual drugs showed no association, and dose-response analyses found no significant connection between cumulative NSAID exposure and birth defect risk.
Dr. Ariel Hasidim, speaking to the rigor of the work, noted an often-overlooked challenge: real-world data gaps. Some pregnant women may have used over-the-counter ibuprofen without it being recorded, a fact that could theoretically skew results. Rather than ignore this limitation, the team used sophisticated statistical methods to test whether and how missing data might have influenced their findings—and found the conclusions held.
"Our results provide reassuring evidence that NSAID use in early pregnancy is not associated with major birth defects," the authors write. "These findings can help both pregnant women and physicians make informed decisions about managing pain and fever in early pregnancy." That clarity matters not just for individual choices, but for the conversations between doctors and patients, many of whom may have been suffering through preventable discomfort out of caution that turns out to have been unnecessary.