Study Underscores Caution for NSAID Use in Pregnancy

Some gestational exposures to nonsteroidal anti-inflammatory drugs (NSAIDs) may carry more chronic kidney disease (CKD) risk for the child than others, a cohort study from Taiwan found.

Gestational NSAID exposure was significantly associated with a higher risk of childhood CKD overall (weighted HR 1.10, 95% CI 1.05-1.15) but lost significance when controlling for environmental and genetic factors by comparing siblings (wHR 1.05, 95% CI 0.97-1.13), reported Chien-Ning Hsu, PhD, of Kaohsiung Chang Gung Memorial Hospital in Taiwan, and colleagues.

Increased CKD risk was seen with specific NSAID exposures at different stages of pregnancy, they noted in JAMA Pediatrics:

• In the first trimester, risk was seen with indomethacin (wHR 1.69, 95% CI 1.10-2.60) and ketorolac (Toradol) (wHR 1.28, 95% CI 1.01-1.62)
• In the second trimester, with diclofenac (wHR 1.27, 95% CI 1.13-1.42) and mefenamic acid (Ponstel) (wHR 1.29, 95% CI 1.15-1.46)
• In the third trimester, with ibuprofen (wHR 1.34, 95% CI 1.07-1.68)

Although the risk wasn’t seen overall in the sibling comparison, “the findings underscore the need for caution when prescribing NSAIDs during pregnancy, particularly 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 offspring’s kidneys,” Hsu and colleagues wrote.

“These NSAIDs should be prescribed only after a thorough assessment of benefits and risks for both mother and child,” they recommended.

While NSAIDs cross the placenta and have known fetal nephrotoxicity prompting the FDA to caution against use after 20 weeks’ gestation, use for analgesia in pregnancy has steadily increased in Western countries, with approximately 84% of pregnant people reporting over-the-counter NSAID use during the first trimester in a prior study.

In Taiwan, most NSAIDs are available only by prescription, allowing the researchers to track exposure.

They analyzed a population-based cohort of mother-child dyads in the Taiwan National Maternal and Child Health Database and Birth Reporting Database among babies born from Jan. 1, 2007, through Dec. 31, 2017.

Overall, of 680,696 singleton-born children analyzed, 24% had mothers who had at least one dispensing of an NSAID during pregnancy without any prescription in the 6 months prior to pregnancy. Within this group, mean maternal age at delivery was 31.25 years. In the overall cohort, slightly more than half of children were male, 7.1% were born before 37 weeks of gestation, and 6.7% had low birth weight.

National healthcare records were used for follow-up of outcomes through Dec. 31, 2021. Pediatric CKD was identified by at least one inpatient diagnostic code or at least two outpatient codes at least 3 months apart within 1 year.

Elevated risks were observed for NSAID exposure overall during the second trimester (wHR 1.19, 95% CI 1.11-1.28) and the third trimester (wHR 1.12, 95% CI 1.03-1.22).

Among the 163,516 participants who used NSAIDs during pregnancy, 61.1%, 33%, and 26.6% used NSAIDs in the first, second, and third trimesters, respectively. Additionally, 76.2% used NSAIDs in early pregnancy, at or before 20 weeks of gestation.

The most commonly used NSAID among the 157,025 non-aspirin NSAID users was diclofenac (42.9%), primarily in the first and second trimesters, followed by mefenamic acid (35.6%) and ibuprofen (20.4%). Among all NSAID users, aspirin was used by 5.5% of participants and indomethacin by 4.5% of participants. Both of these drugs were primarily used during the second and third trimesters.

Limitations of the study included that exposure was based solely on prescription records, “potentially leaning to exposure misclassification if actual NSAID use differed,” Hsu and colleagues noted. Also, maternal factors like malnutrition and micronutrient deficiencies as well as behaviors like smoking and alcohol consumption that can influence kidney outcomes were not accounted for, they added.

Results also may not be generalizable to populations with different health insurance systems, they noted. And CKD was based on diagnostic codes instead of laboratory measurement of glomerular filtration rate, “possibly leading to incomplete or misclassified diagnoses of less severe CKD,” they continued.

“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,” Hsu and colleagues concluded. “These NSAIDs should be prescribed only after a thorough assessment of benefits and risks for both mother and child.”

“Future research should investigate the specific roles of genetic and environmental factors in kidney development across different stages of pregnancy,” they added.