Health Canada is investigating the use of nonsteroidal anti-inflammatory drugs – used to treat fever, pain and inflammation – at 20 weeks or later of pregnancy on the heels of a U.S. Food and Drug Administration (FDA) warning that the drugs may cause rare but serious harm to unborn babies.
The FDA updated its warning on the drugs, commonly known as NSAIDs, on Oct. 15, stating they should be avoided by pregnant women after 20 weeks, rather than the 30 weeks previously considered safe. More than 20 different NSAIDs – including naproxen (Aleve), ibuprofen (Advil) and aspirin – are in use. Some can be bought over the counter; others require a prescription.
While its investigation is under way, Health Canada is advising pregnant women not to use NSAIDs after 19 weeks unless advised to do so by their healthcare professional.
Consistent with the FDA, Health Canada is also recommending that, if deemed necessary by a healthcare professional, the use of NSAIDs from 20 to 30 weeks of pregnancy be limited to the lowest effective dose for the shortest duration possible and that healthcare professionals consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours.
Unborn babies’ kidneys produce most of the amniotic fluid in the uterus that the baby floats in during pregnancy. This fluid serves as a protective cushion for the fetus and is important in the development of its lungs, digestive system and muscles. NSAIDs taken after 20 weeks can decrease the amount of fluid made, causing harm to the unborn baby.
A spokesperson for the FDA says its decision is based on a review of the medical literature and cases reported through the FDA Adverse Event Reporting System (FAERS) on low amniotic fluid levels or kidney problems in unborn babies associated with NSAID use during pregnancy.
Christopher M. Zahn, vice-president of Practice Activities for the American College of Obstetricians and Gynecologists, says “the risks associated with taking NSAIDs are widely known to obstetrician-gynecologists and, therefore, are generally not recommended to women as the pain relievers of choice during pregnancy and should largely be avoided.”
Douglas Wilson, an obstetrician and gynecologist in Calgary who has dedicated part of his career to pre-pregnancy counselling, acknowledges that the issue is well-known to doctors. He even recalls that “in my days of fetal surgery and fetal therapy, in situations with severe polyhydramnios (excess amniotic fluid) we would actually use (NSAIDs) for a number of days after an amnioreduction to minimize the fetal urine output.” Amnioreduction is done to reduce the amount of excess amniotic fluid.
Carl Laskin, an internationally recognized expert in the specialized field of Reproductive Immunology and Autoimmune disease in pregnancy, says he “was very surprised by the recommendations.”
“I have yet to find a patient who I see in follow-up, as I do with all women that I manage in pregnancy, where there is a renal problem in the neonate,” he says.
Before the FDA’s new concerns, it was already understood that NSAIDs taken after 30 weeks in pregnancy could lead to premature closing of an unborn baby’s fetal ductus arteriosus, a shunt that runs from the fetal pulmonary artery to the aorta. Unborn babies don’t rely on their lungs for oxygen until birth; until then, they receive oxygen from the placenta. The fetal ductus arteriosus helps bypass the lungs. The premature closing of this blood vessel can cause high blood pressure in the lungs of the developing baby.
The FDA identified multiple reports of low amniotic fluid levels around 20 weeks gestation. In most cases, this was reversed after pregnant women stopped taking an NSAID and recurred if the NSAID was restarted.
The FDA reviewed 20 reports describing kidney failure in newborns whose mothers took NSAIDs. Eleven of the babies died; of those, eight were a direct consequence of kidney failure. The exposure to NSAIDs ranged from two days to 11 weeks.
A search through the FAERs database identified 35 cases of low amniotic fluid or renal dysfunction associated with NSAIDs in pregnancy. All cases had a serious outcome; five resulted in death of the newborn.
Wilson says he believes that this “may just be a new review with a number of more adverse events and the FDA is being more cautious.”
Though the FDA’s literature search included mainly case studies and case reports, Wilson says he thinks “there is validity in small case series or case reports … sometimes putting together those case reports of small cohorts can add additional knowledge.”
“Clinicians need to watch for these things,” he says. “When something doesn’t seem right, think a little bit harder … Sometimes these case reports or observations can be very important.”
Laskin plans to review the data before giving credence to the FDA warning. He says his “suspicion is that where this occurs, the woman is given a higher dose of NSAID and the amniotic fluid volume is not assessed earlier on in the pregnancy.”
“Before Health Canada issues its warning as a recommendation, a small committee of MDs and experts familiar with the drugs and their use in pregnancy need to review the data,” Laskin adds.
Zahn notes that the recommendations do not apply to the use of low-dose aspirin. “It is important for patients to understand that daily low-dose aspirin prescribed by a healthcare professional is considered safe – and, for some patients, beneficial – during pregnancy,” he says.
Laskin has recommended low-dose aspirin in pregnancy as a treatment for recurrent miscarriage and as a means of minimizing the risk of high blood pressure in late pregnancy. When ASA is used, it can be continued up to 35 weeks gestation. “There is no risk of fetal cardiac side effects and the use of ASA is not associated with a decrease in amniotic fluid volume, which is the issue highlighted in the FDA and Health Canada documents,” he says.
The American College of Obstetricians and Gynecologists recommends that for general pain relief, pregnant women should consider alternative methods such as warm baths and massages or, in consultation with their doctor, take over-the-counter acetaminophen medications (such as Tylenol) “that have long been considered safe to use at any stage of pregnancy.”
Adds Wilson: “Medications in pregnancy need to be re-evaluated because things do change, manufactures change and I think patients become complacent and they think over-the-counter and health-food store medications are safe.”
Laskin echoes those sentiments. “Whenever a side effect is found regarding a drug, both patients and healthcare workers need to be informed. In this way, appropriate management can be undertaken,” he says.
“This is especially the case when dealing with a drug that is so readily available over the counter. In such cases, if the patients are unaware of the issue, they may neglect informing their doctor that they are using the drug.”