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FDA Warnings Regarding Use of General Anesthetics and Sedation Drugs in Young Children and Pregnant Women

  • Practice Advisory PA
  • December 2016

(Reaffirmed March 2020)

This is an area of evolving care and practice. Fellows should check periodically for revisions and updates. ACOG will communicate important changes and updates to these guidelines.

On December 14, 2016, the U.S. Food and Drug Administration (FDA) published a Drug Safety Communications entitled "FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women" 1 2. In this announcement, the FDA announced that it will require warnings to be added to the labels of general anesthetic and sedation drugs. The FDA warns that "repeated or lengthy use of general anesthetic or sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains."

The American College of Obstetricians and Gynecologists (ACOG) has significant concerns related to the FDA’s warning about the use of general anesthetics and sedation drugs in pregnant women. Some important limitations to this announcement are: 1) The SmartTots (Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots) program is a pediatric study only; pregnant women were not included in the SmartTots study; 2) The clinical significance of these findings are not known and ACOG is concerned that this warning could inappropriately dissuade providers from providing medically indicated care during pregnancy, and 3) 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. Based on current evidence, ACOG continues to recommend that women in any trimester of pregnancy should be counseled regarding evidence-based benefits and risks of any proposed interventions which may involve the use of general anesthetic or sedative agents, and no woman should be denied a medically indicated surgery or procedure which may involve the use of these agents 3.

Data Limitations

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. Later in the announcement, the “Data Summary” section details the studies apparently leading to this conclusion. In non-clinical studies of pregnant primates, in the third trimester, exposure to 24 hours of ketamine, or exposure to 5 hours of isoflurane plus nitrous oxide or propofol, resulted in neuronal cell loss. In the "clinical studies" section of this summary, there are no data regarding pregnant women; there is only data on young children who were exposed to anesthetic agents. ACOG is unaware of data on pregnant women that support the FDA’s claims. Therefore, there are significant data limitations related to this warning.

Clinical Application: Limitations and Concerns

The broader clinical significance of these findings is not known. Pregnant women may undergo general anesthesia for a nonobstetric surgical procedure or, in some instances, for delivery. When a nonobstetric surgery is performed during pregnancy, it is because it is medically indicated. When analgesia is needed for delivery (included cesarean delivery), it is usually regional analgesia that is used and not general anesthesia. In both circumstances, the likelihood that a pregnant woman, and thus an exposed fetus, would be vulnerable to a general anesthetic or sedative agent for an extended period would be extremely low. In instances when general anesthesia is used for delivery instead of regional anesthesia and prolonged exposure may occur due to complications, the fetus would be delivered long before the potentially harmful range of anesthetic exposure would be reached. Related to sedation exposure, pregnant women could theoretically be treated for nonobstetric indications (such as trauma or pain), or potentially during labor if regional analgesia/anesthesia is not used. In this situation, however, it is also unlikely that the period of fetal exposure would reach the hypothetically harmful ranges that are described.

The FDA states that health care professionals should “balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risk, especially for procedures that may last longer than 3 hours”. ACOG agrees with and supports this approach, as for any intervention during pregnancy. ACOG supports appropriately informing patients regarding any potential risks. However, by requiring that warnings be added to labels, particularly with the limited evidence regarding potential effects and the extremely low likelihood that the threshold of fetal exposure would be reached, these warnings may cause patients and providers to inappropriately reject the use of these medically indicated drugs. The risks associated with inappropriately withholding these medications include delaying the performance of medically indicated procedures, withholding a medically indicated procedure or substituting it with a less-appropriate procedure, and the potential for unnecessary discomfort or pain. In addition, this announcement is in direct contradiction to longstanding experience, clinical guidance, and the current standard of care 3.

ACOG and Obstetrician--Gynecologist Involvement

The Safety Announcement states that the FDA investigated the potential adverse effects of general anesthetic and sedation drugs via several advisory committee meetings, as well as through research endeavors such as the SmartTots program. The FDA did not seek input from ACOG, obstetrician-gynecologists, and other obstetric providers; such input would have been valuable in the development of this published safety announcement.

In Summary

  • This warning is based on animal studies and pediatric studies; there are no data regarding pregnant women cited in this warning.
  • The clinical significance of these findings is not known. Additionally, the likelihood that a pregnant woman and her fetus would be vulnerable to a general anesthetic or sedative agent for the time periods suggested in this warning is extremely low.
  • Input from ACOG and obstetrician-gynecologists was not requested and would have been valuable in the development of this published safety announcement.
  • ACOG is concerned that this warning could potentially dissuade providers from providing medically indicated care during pregnancy.
  • Obstetrician-gynecologists and other obstetric providers should continue to follow ACOG’s clinical guidance as outlined in Committee Opinion 474, Nonobstetric Surgery During Pregnancy.
  • It is important to involve ACOG, obstetrician-gynecologists and other obstetric providers in the development of safety announcements that affect obstetric care.

References

  1. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Silver Spring (MD): FDA; 2016. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Retrieved December 16, 2016.
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  2. U.S. Food and Drug Administration. FDA statement from Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, on new safety information on anesthesia use in young children and pregnant women. Silver Spring (MD): FDA; 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm533346.htm. Retrieved December 16, 2016.
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  3. Nonobstetric surgery during pregnancy. Committee Opinion No. 474. American College of Obstetricians and Gynecologists. Obstet Gynecol 2011;117:420-1.
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This Practice Advisory was developed by the American College of Obstetricians and Gynecologists in collaboration with Christopher M. Zahn, MD; Yasser Y. El-Sayed, MD; Marc Jackson, MD, MBA; Mark A. Turrentine, MD; and Joseph R. Wax, MD.

A Practice Advisory is issued when information on an emergent clinical issue (e.g. clinical study, scientific report, draft regulation) is released that requires an immediate or rapid response, particularly if it is anticipated that it will generate a multitude of inquiries. A Practice Advisory is a brief, focused statement issued within 24-48 hours of the release of this evolving information and constitutes ACOG clinical guidance. A Practice Advisory is issued only on-line for Fellows but may also be used by patients and the media. Practice Advisories are reviewed periodically for reaffirmation, revision, withdrawal or incorporation into other ACOG guidelines.

This document reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed.

The American College of Obstetricians and Gynecologists (ACOG), is the nation's leading group of physicians providing health care for women. As a private, voluntary, nonprofit membership organization of more than 58,000 members, ACOG strongly advocates for quality health care for women, maintains the highest standards of clinical practice and continuing education of its members, promotes patient education, and increases awareness among its members and the public of the changing issues facing women's health care. www.acog.org

Publications of the American College of Obstetrician and Gynecologists are protected by copyright and all rights are reserved. The College's publications may not be reproduced in any form or by any means without written permission from the copyright owner.

Topics
Advisory committees Counseling Elective surgical procedures General anesthesia Gynecologic surgical procedures Obstetric surgical procedures Policy making Practice guideline Pregnant women