FDA warns of possible fetal risk linked to NSAIDs
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The FDA announced that manufacturers of nonsteroidal anti-inflammatory drugs will be required to update their boxed warning to list potential fetal risk in women using the medications 20 weeks or later in their pregnancies.
The agency notified health care professionals of reports of rare, but serious, kidney problems and low amniotic fluid levels in the fetuses of women using NSAIDs in the second half of their pregnancies, which could increase the likelihood of pregnancy-related complications.
“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of the FDA's Center for Drug Evaluation and Research, said in the press release. “To this end, the agency is using its regulatory authority to inform women and their health care providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”
The label change applies to both prescription and over-the-counter NSAIDs, such as ibuprofen, naproxen, diclofenac and celecoxib, which are intended to reduce pain, decrease fever, prevent blood clots and decrease inflammation. Low-dose aspirin, however, is exempt from the required label change, the FDA noted.
According to the agency, oligohydramnios — low levels of amniotic fluid — can be detected days or weeks after starting these medications, but it could be detected as early as two days after initiating regular NSAID use. The FDA noted that this condition typically resolves itself if the woman discontinues the medication.
“For prescription NSAIDs, the FDA is requiring changes to the prescribing information to describe the risk of kidney problems in unborn babies that result in low amniotic fluid and to recommend that NSAID use be limited between about 20 weeks to 30 weeks of pregnancy because of this risk,” the FDA said in the release. “Warnings to avoid taking NSAIDs after about 30 weeks of pregnancy are already included in the prescribing information because taking these medications during this time may lead to heart issues in the unborn baby.”
However, the agency said if a health care provider deems NSAID use necessary between 20 weeks to 30 weeks of pregnancy, its use should be restricted to the lowest effective dose and shortest duration. Likewise, the manufacturers of OTC NSAIDs for adult use will implement similar updates to their Drug Facts labels.
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This FDA news highlights the importance of several things. The first is the necessity for ongoing vigilance, even with medications that have been around for years and been proven to be effective for many people. The second is that even over-the-counter medications need ongoing vigilance and capturing of long-term data. The third is that sometimes it becomes important to relay information that may be known to some medical providers but may not be known in a more broad medical community, or to the general public, in a more visible format.
For many years, it has been known that NSAIDs are contraindicated towards the end of pregnancy due to the risk of premature closure of the ductus arteriosus. The association between the use of NSAIDs during the end of the second trimester and beginning of the third trimester and oligohydramnios is less well known. Oligohydramnios can lead to small for gestation babies, cord accidents and fetal death, and poor maturation of lungs, along with other complications.
NSAIDs are often used in rheumatology as a first line of treatment or in conjunction with other treatments. Many of our patients are in their childbearing years. We cannot assume that our pregnant patients are hearing precautions about the medications we use commonly from other sources. It is not only important for us to be educating our patients on the use of NSAIDs during mid-pregnancy but also to caution them to read the labels of all over-the-counter medications they may be used to taking.
Pregnancy changes many things about how we treat our patients because now we are having to consider the anatomy and physiology of two human bodies, one of them in a rapid state of development with lifetime implications.
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Ellen M. Field, MD
While NSAIDs have been used as tocolytic agents to suppress premature labor, and delay delivery for at least 48 hours and up to 7-10 days, caution should be taken in its overall use in pregnancy due to potential deleterious outcomes.
NSAIDs cross the placenta and may cause embryo, fetal and neonatal adverse events, dependent on dose, duration of treatment and the specific time period during pregnancy. Inhibition of prostanoid activity may increase risk of miscarriage in early pregnancy. Later exposure, after 30 weeks gestation, is associated with increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Prenatal exposure to NSAIDs can potentially affect fetal and neonatal brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular systems.
Most recently, the FDA issued a warning to avoid NSAIDs in pregnancy at 20 weeks gestation or later due to potential for low amniotic fluid and pregnancy complications. The current labeling is for use after 30 weeks gestation, but it will now include warning against use starting at 20 weeks gestation. Low amniotic fluid, or oligohydramnios, can be found after taking NSAIDs for days or weeks, but can be seen even after only two days use, which can lead to kidney compromise. Most often, this condition may resolve with abrupt discontinuation of the NSAIDs.
While acetylsalicylic acid is considered an NSAID, low dose acetylsalicylic acid, 81 mg, is an exception, as it is utilized as a treatment for pregnant women, particularly to prevent significant adverse outcomes in antiphospholipid antibody syndrome. The FDA is encouraging health care providers — if they deem necessary the use of NSAIDs between 20- and 30-weeks gestation — to use the lowest dose for the shortest period of time possible.
This warning is incredibly prudent for patients with rheumatic conditions who utilize NSAIDs to treat pain or inflammation, and the rheumatology community will need to caution our patients about potential adverse outcomes with NSAIDs in all three trimesters of pregnancy, and consider other alternatives such as acetaminophen for short-term usage. While the normal dose of acetaminophen during pregnancy has not been associated with increased risk of miscarriage or still birth, increases in fetal death or spontaneous abortion may be seen with maternal overdose if treatment is delayed. Ongoing data will be needed to provide clinicians with additional information to guide therapeutic decisions.
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David A. McLain, MD, FACP, FACR
In rheumatology, we use NSAIDs on a daily basis. In pregnant females, I usually defer to the obstetrician regarding continuing medications I have prescribed — with the exception of hydroxychloroquine, prednisone and certolizumab.
This warning from the FDA on the development of oligohydramnios in pregnancy with the use of NSAIDs after 20 weeks of gestation was new to many of us, despite being first reported in 1980. Most of the amniotic fluid is produced by the fetus’ kidneys after 20 weeks and NSAIDs can suppress fetal kidney function, just as in adults. The resultant drop in amniotic fluid causes oligohydramnios and can lead to fetal deformation, umbilical cord compression and pulmonary hypoplasia.
NSAID use in early pregnancy increases the risk of miscarriage and malformations. Fetal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been reported after prenatal exposure to NSAIDs. Exposure to NSAIDs after 30 weeks’ gestation is also associated with an increased risk of premature closure of the fetal ductus arteriosus. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for the shortest duration possible.
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