Use of Ibuprofen, Other NSAIDs During Pregnancy Could Increase Risk of Childhood CKD

Gestational exposure to certain nonsteroidal anti-inflammatory drugs (NSAIDs) during different stages of pregnancy could increase the risk of childhood chronic kidney disease (CKD) in offspring, according to findings from a recent study.1

Results suggest the need for caution when using NSAIDs during pregnancy due to their potential nephrotoxic effects. Specifically, the study warns against using indomethacin and ketorolac in the first trimester, mefenamic acid and diclofenac in the second trimester, and ibuprofen in the third trimester.1

According to the US Centers for Disease Control and Prevention, about 35.5 million US adults are estimated to have CKD, as many as 9 in 10 of whom do not know they have it. Exposure to an adverse maternal environment with nephrotoxic medications during fetal development may increase the risk of CKD later in life. Accordingly, the US Food and Drug Administration has warned that the use of NSAIDs around 20 weeks or later in pregnancy may cause rare but serious kidney problems in unborn children, prompting further evaluation of long-term kidney outcomes in children exposed to NSAIDs during pregnancy.2,3

“To our knowledge, this is the first population-based cohort study in 15 years to investigate the association of gestational exposure to NSAIDs and childhood CKD,” You-Lin Tain, MD, PhD, director of the department of pediatrics at Kaohsiung Chang Gung Memorial Hospital and a professor of pediatrics at Chang Gung University College of Medicine in Taiwan, and colleagues wrote.1

Their national population-based cohort study used data from the Taiwan National Maternal and Child Health Database and Birth Reporting Database to assess 1,025,255 children born in Taiwan from January 1, 2007, to December 31, 2017. Follow-up was conducted until December 31, 2021, using medical records obtained from the Taiwan National Health Insurance Research Database and death certificate database.1

Investigators examined maternal exposure to NSAIDs, including aspirin and nonaspirin NSAIDs, from the last menstrual period to birth based on prescription records of the medication name, date, number of pills, and duration of use throughout the pregnancy. Based on this information regarding NSAID exposure, live newborns were categorized into 2 groups: nonexposure (n = 793,464) and gestational exposure (n = 231,791).1

The study’s primary outcome was a childhood CKD diagnosis, including congenital anomalies of the kidney and urinary tract and other kidney diseases.1

The final analytic cohort comprised 1,025,255 children, including singleton-born (n = 680,696) and discordant sibling-matched children (n = 344,559). Of the singleton-born children analyzed, 163,516 (24%) had mothers who had ≥ 1 dispensing of an NSAID during pregnancy. Specifically, 99,846 (61.1%), 54,034 (33.0%), and 43,447 (26.6%) of these participants used NSAIDs in the first, second, and third trimesters, respectively.1

Among 157,025 nonaspirin NSAID users, most received diclofenac (42.9%), primarily during their first and second trimesters, followed by mefenamic acid (35.6%) and ibuprofen (20.4%). Among all NSAID users, aspirin was used during pregnancy by 5.5% of participants and indomethacin was used by 4.5%, mainly during the second and third trimesters.1

During a median follow-up of 9.75 (range, 0-15) years, a total of 10,547 (1.6%) children in the singleton-born cohort had CKD, including 7144 (1.0%) with non-CAKUT CKD and 273 (0.04%) requiring kidney replacement therapy.1

Upon analysis, gestational NSAID exposure was significantly associated with a higher risk of childhood CKD (weighted hazard ratio [wHR], 1.10; 95% CI, 1.05-1.15). Additionally, investigators observed an increased risk of all-cause mortality with gestational NSAID exposure after adjustment for fetal characteristics (wHR, 1.12; 95% CI, 1.03-1.23).1

Of note, significantly greater risk estimates were discovered during the second (wHR, 1.19; 95% CI, 1.11-1.28) and third trimesters (wHR, 1.12; 95% CI, 1.03-1.22) in singleton-born children. Investigators also pointed out the risk of CKD significantly increased with gestational exposure to ibuprofen (wHR, 1.11; 95% CI, 1.01-1.22), diclofenac (wHR, 1.14; 95% CI, 1.06-1.22), and ketorolac (wHR, 1.21; 95% CI, 1.01-1.46).1

Use of specific NSAIDs during different trimesters also increased risk estimates, including indomethacin (wHR, 1.69; 95% CI, 1.10-2.60) and ketorolac (wHR, 1.28; 95% CI, 1.01-1.62) in the first trimester; mefenamic acid (wHR, 1.29; 95% CI, 1.15-1.46) and diclofenac (wHR, 1.27; 95% CI, 1.13-1.42) in the second trimester; and ibuprofen (wHR, 1.34; 95% CI, 1.07-1.68) in the third trimester.1

After adjusting for fetal characteristics, sibling-matched analyses revealed no statistical association (wHR, 1.05; 95% CI, 0.97-1.13) between gestational NSAID use and childhood CKD.1

Investigators acknowledged multiple limitations to these findings, including the potential for exposure misclassification due to use of prescription records to determine NSAID use; residual confounding of maternal factors; the lack of generalizability to populations with health insurance systems; and the use of diagnostic codes to ascertain CKD status rather than laboratory measurements of glomerular filtration rate.1

“Findings suggest that caution should be taken when using indomethacin and ketorolac in the first trimester, mefenamic acid and diclofenac in the second trimester, and ibuprofen in the third trimester to ensure the safety of the child’s kidneys. These NSAIDs should be prescribed only after a thorough assessment of benefits and risks for both mother and child,” investigators concluded.1 “Future research should investigate the specific roles of genetic and environmental factors in kidney development across different stages of pregnancy.”

References

1. Tain YL, Li LC, Kuo HC, et al. Gestational Exposure to Nonsteroidal Anti-Inflammatory Drugs and Risk of Chronic Kidney Disease in Childhood. JAMA Pediatr. doi:10.1001/jamapediatrics.2024.4409
2. US Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. May 15, 2024. Accessed December 23, 2024. https://www.cdc.gov/kidney-disease/php/data-research/index.html
3. US Food and Drug Administration. FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. October 15, 2020. Accessed December 23, 2024. https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic