On December 14, 2016, the FDA released a new “Drug Safety Communication” about the use of general anesthetics and sedation drugs in young children and pregnant women. The warning affects all of the most common anesthesia drugs, including Suprane, Amidate, halothane, Forane, ketamine, Ketalar, Ativan, Brevital, midazolam injection, pentobarbital, Nembutal, propofol, Diprivan, Ultane, and Sojourn.
Based on FDA’s understanding of brain development, and a review of the latest scientific studies conducted in pregnant animals and young animals, the data suggests that the fetuses of women in their third trimester of pregnancy and children younger than 3 years are most likely vulnerable to this effect. For example, this 2014 study in the Journal of Neurosurgical Anesthesiology found that “early studies identified anesthetic-induced neuronal apoptosis as a possible mechanism of injury, and more recent work suggests that anesthetics may interfere with several critical processes in brain development.” Most anesthetic drugs have been shown to cause these negative effects on brain development in different species of animals, and no specific medications have been proven to be safer than any other. Nonetheless, the FDA says “Recent studies in children suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning.” That seems consistent with the most rigorous studies, like this 2011 study in Pediatrics that said “Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing [learning disabilities] (hazard ratio: 2.12 [95% confidence interval: 1.26–3.54]), even when accounting for health status.” A hazard ratio of 2.12 means a child is 2.12 times as likely to develop learning disabilities if they were exposed to anesthesia before the age of 2.
The American College of Obstetricians and Gynecologists was quick to criticize the FDA’s announcement, mostly by whining that they weren’t included in the process: “The FDA did not seek input from ACOG prior to publishing the safety announcement and neither ACOG nor other obstetrician-gynecologists participated in the development of this announcement.” ACOG admits that, in animal studies of pregnant primates, in the third trimester, exposure to 24 hours of ketamine, or contact with 5 hours of isoflurane plus nitrous oxide or propofol, led to neuronal cell loss. But, ACOG complains, there are no data regarding pregnant women; there is only data on young children who were exposed to anesthetic agents, and so the broader clinical significance of these findings is not known, and that, when analgesia is needed for delivery (included cesarean delivery), it is usually regional analgesia that is used and not general anesthesia. Moreover, although pregnant women could theoretically be treated for nonobstetric indications (such as trauma or pain), or possibly during labor if local analgesia/anesthesia is not used, it is also unlikely that the period of fetal publicity would reach the “hypothetically” dangerous ranges.
I’ve criticized the FDA repeatedly in my work on dangerous medications and medical devices, including their foot-dragging on transvaginal mesh and their failure to act on the link between incretin mimetics and pancreatic cancer. I’ve also had plenty of differences with ACOG in the past, like with my criticism of ACOG’s “Neonatal Encephalopathy and Cerebral Palsy: Defining the Pathogenesis.” Here, the FDA has it right, and ACOG’s criticism is pure hypocrisy. Their own guidance on “Nonobstetric Surgery During Pregnancy,” Number 474, February 2011, reaffirmed again in 2015, admits “that the issue of nonobstetric surgery during pregnancy is an important concern for physicians who care for women,” and that,”[b]ecause of the difficulty of conducting large-scale randomized clinical trials in this population, there are no data to allow for specific recommendations.” Exactly: there is no ethical way for the FDA to do randomized clinical trials on pregnant women, because to do so would be to intentionally subject fetuses, infants, and children to a risk of brain injury. It’s more than a little hypocritical for ACOG to now claim that, without more data on pregnant women, the FDA can’t reach a conclusion about this important issue.
ACOG implicitly admits that the data from animal studies and children shows that anesthesia and sedation drugs can have a major impact on developing brains. They say “The FDA reported that published studies in pregnant or juvenile animals and studies in human children have reported that the use of general anesthetic and sedation drugs for more than 3 hours resulted in widespread loss of nerve cells in the brain,” then never challenge it. In fact, the FDA’s announcement cited twenty different studies “showing that early exposure to anesthetic drugs can produce adverse neurotoxic effects in different species, including simple nematodes, rats, and nonhuman primates.” The FDA also cited eleven studies showing a relationship between young children being exposed to anesthesia and suffering harmful neurodevelopmental outcomes, and five studies raising “concerns that longer or repeated exposures may contribute to various cognitive and behavioral problems, including neurodevelopmental delay-related diagnoses, learning disabilities, and attention deficit hyperactivity disorder.” It’s simply ridiculous to think that, with this wealth of data on animals and young children, there isn’t any effect on fetuses.
Dr. Jen Gunter raises another issue, pointing out that, “As a woman who had some of these drugs in my late second trimester, as a parent of a child who needed anesthesia three times before the age of three, and as an OB/GYN who has cared for pregnant women who needed prolonged anesthesia because of horrific circumstances I say to the FDA hey thanks for making a difficult situation worse.” As Dr. Gunter says, anesthesiologists and obstetricians already use the least amount of anesthesia and sedation necessary for the case, and it’s not clear that over-use of anesthesia is causing a problem, and so all this does it complicate the relationship between doctors and patients by adding an unnecessary concern that patients are hardly equipped to handle. I’d agree if we lived in a perfect world in which OBGYNs were always up to date on the latest scientific information and where they always treated women with a careful balancing of risks and benefits. But that’s not always the case. For example, several months ago the FDA specifically stated that fluoroquinolone antibiotics (like Cipro and Levaquin) shouldn’t be used for uncomplicated urinary tract infections — something that has been clear in the scientific data for years — and yet many OBGYNs still hand out these drugs like candy.
All in all, I’m glad to see the FDA stepping in to keep the public and doctors informed of the latest evidence of potential permanent complications arising from drugs that are regularly used. That’s exactly what the FDA is supposed to be doing. If a doctor can’t explain to their patient why the prolonged or repeated use of anesthesia or sedatives is necessary, then maybe they should reconsider using it at all.