Ibuprofen Use in Pregnancy: Less Dangerous Than Thought?

Ibuprofen prematurely closes the heart’s ductus arteriosus, increases reactive oxygen species, and inhibits placenta vascularization. Ibuprofen use late in pregnancy can reduce the production of the prostaglandins responsible for maintaining a patent ductus arteriosus. Pregnancy is an energy-intensive process spurring mitochondrial production of large amounts of reactive oxygen species. These free radicals reduce the vascularization of the intervillous space and limit the supply of nutrients to the developing embryo.¹

The ductus arteriosus typically closes at or within days after birth once the newborn’s pulmonary circuit begins use. A patent ductus arteriosus allows small clots to bypass the lungs and cause a stroke. In contrast, premature ductus arteriosus closure is clinically insignificant for most births because the blood is no longer bypassing the lungs in the airless environment of the womb. However certain diseases require a patent ductus arteriosus at birth for patient survival. For example, infants with dextro-transposition of the great arteries need the right-left shunting through the ductus arteriosus to circulate blood to the systematic circulation. Dextro-transposition of the great arteries is a rare disease (1 in 3300 births) often identified in prenatal screening.²

Ibuprofen’s vascularization inhibition may predispose newborns to low birth weight and its complications. Recent findings contradict the belief that NSAIDs increase the risk of miscarriage (and by extension pre-term birth). The failure to treat ongoing severe pain adequately during pregnancy can cause pregnancy-endangering high blood pressure, depression, and anxiety. The Food and Drug Administration has maintained their recommendation to women to consult with their gynecological provider before using NSAIDs during pregnancy.³

A team of researchers from Norway have found second and third trimester ibuprofen exposure has no effect on birth weight or pre-term birth in a new study published on December 9, 2016 by PLOS ONE.¹

The authors used data on 28597 siblings from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway. A slim fraction (1080) of siblings had ibuprofen exposure and the remainder had no NSAID exposure. The authors excluded siblings from multiple pregnancies, with missing information, or exposed to a non-ibuprofen NSAID.

The first trimester was the most common time of ibuprofen exposure. Some mothers may have been unaware of their pregnancy at the time of exposure. One in three newborns had multiple trimester exposure. Ibuprofen-using mothers were less likely to have tertiary education or used folic acid supplements. These mothers were more likely to consume alcohol or smoke during pregnancy than non-ibuprofen using women.

Ibuprofen exposure had no effect on gestational age at delivery and little effect on birth weight. Ibuprofen-exposed newborns were at slightly increased risk of delivery before 37 weeks or a birth weight less than 2500 grams. Mean birth weight was less among newborns exposed during first or second trimester. However, the birth weight reduction was statistically significant but clinically insignificant among term infants. A 79 gram difference in mean birth weight between exposed and unexposed newborns does not suggest any impact on infant development or health outcomes. Exposure duration had no effect on birth weight.

Potential confounders included newborn sex, birth order, maternal age, parity, pre-pregnancy maternal BMI, education, smoking status, and alcohol intake during pregnancy. The sibling design minimizes genetic and environmental confounders. This study was able to control for smoking history and alcohol intake that are well-known strong factors on birth weight. Confounding by indication is unavoidable but the authors adjusted for the most common indications for NSAID therapy. The authors could not evaluate for a dose-response relationship because the Norwegian databases lack dosage information.

Prenatal ibuprofen exposure has little effect on birth weight and no effect on gestational age at delivery. Uncontrolled study factors or selection bias may have caused the small change in mean weight. Pregnant women should consult their gynecological provider, and weigh the risks and benefits, before using any NSAID therapy.

Works Cited

• NezvalovaÂ-Henriksen K, Wood M, Spigset O, Nordeng H. Association of prenatal ibuprofen exposure with birth weight and gestational age: a population-based sibling study. PLoS One. 2016; 11(12): e0166971. doi:10.1371/journal.pone.0166971.
• Facts about dextro-Transposition of the Great Arteries (d-TGA). Centers for Disease Control and Prevention Website. https://www.cdc.gov/ncbddd/heartdefects/d-tga.html. Updated November 14, 2016. Accessed December 14, 2016.
• FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. US FDA Web site. http://www.fda.gov/Drugs/DrugSafety/ucm429117.htm. Published January 9, 2015. Accessed December 14, 2016.