Clinical Opinion ajog.org

OBSTETRICS

Drug labeling in the practice of obstetric anesthesiaBrendan Carvalho, MBBCh, FRCA; Cynthia A. Wong, MD

This commentary outlines the current drug labeling practices that potentially compromisethe clinical care of pregnant women and their children. We highlight the need for drugmanufacturers and lawmakers to change the status quo and consider practices andregulations that will provide much-needed guidance to clinicians on the safe adminis-tration of drugs to certain populations such as pregnant and nursing women. Currentpractices have de facto contributed to a situation in which evidence is inadequate forindividual physicians and patients to weigh the risks and benefits of drug administrationand make informed decisions for drug use during pregnancy and lactation.

Key words: clinical care, drug labeling practices, pregnant women and children

“I will prescribe regimens for thegood of my patients according tomy ability and my judgment andnever do harm to anyone”

The Hippocratic Oath translated by

Michael North, National Library of Medicine,

National Institutes of Health

e are 2 academic obstetric anes-

W thesiologists who practice, teach,and research obstetric anesthesiology.Our professional goals include deter-mining which labor analgesia and ce-sarean delivery anesthesia and analgesicregimens are for the good of our patients(which we define as regimens that areeffective and safe in our daily clinicalpractice) and teaching these regimens

From the Department of Anesthesia, StanfordUniversity School of Medicine, Stanford, CA (DrCarvalho), and Department of Anesthesiology,Northwestern University Feinberg School ofMedicine, Chicago, IL (Dr Wong).

Received Aug. 10, 2013; revised March 12,2014; accepted April 30, 2014.

C.A.W. is a member of the Food and DrugAdministration Anesthesia and Analgesia DrugProducts Advisory Committee.

The authors report no conflict of interest.

Reprints: Brendan Carvalho MBBCh, FRCA,Department of Anesthesia, H3580, StanfordUniversity School of Medicine, Stanford,CA 94305. bcarvalho@stanford.edu

0002-9378/$36.00ª 2015 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2014.04.040

24 American Journal of Obstetrics & Gynecology

(which include specific combinations oftechnique[s] and drug[s]) to trainees.Stated differently, our goal is to practicecutting-edge, evidenced-based obstetricanesthesia.Our general clinical practice involves

performing epidural or combined spinalepidural labor analgesia, administeringneuraxial or general anesthesia for ce-sarean delivery, and providing effectivepostecesarean delivery analgesia. Wealso routinely participate in the care ofhigh-risk obstetric patients or those withcomplications of labor and delivery (eg,postpartum hemorrhage).The anesthetic techniques and routine

clinical care of the parturient require theadministration of a number of drugs(Table 1). These drugs, approved for usein the United States by the Food andDrug Administration (FDA), have beenadministered to thousands of our pa-tients. If we speculate that most anes-thesiologists in the United States followsimilar anesthetic practices, then mil-lions of women and their fetuses/neo-nates have been exposed to these drugs.We routinely use these drugs in this pa-tient population because according to(our) judgment and (our) ability, we areprescribing them for the good of (our)patients.Most drugs used by anesthesiologists

in the obstetric setting are used off label.For some drugs, even the route ofadministration is off label (eg, fentanylis not approved by the FDA in any

JANUARY 2015

patient population for spinal or epiduraladministration). Anesthesiologists andother physicians would prefer to adhereto FDA package labeling to guide druguse and dosing.

The FDA has strict requirements forthe evaluation of drug efficacy and safety.Physicians can be reasonably certain thatusing a drug for its approved indication,administered via the approved route and inthe approved dose, will be safe and effica-cious for most patients, and the benefitswill outweigh the risks. Unfortunately,the term, most patients, does not includepregnant or nursing women. In fact,commonly, printed material included inthe drugs’ package inserts specificallystates that the indicated population ex-cludes pregnant or lactating women.

Table 2 shows a sample of frequentlyadministered drugs in an obstetricanesthesia setting and outlines what thepracticing anesthesiologist would find ifhe/she consulted the package labelbefore administering our everyday drugsto the parturient. Many drugs are notrecommended for use in pregnant orlactating women.

If we followed the recommendationsof the package inserts, we would likelynot be able to administer effective andsafe labor analgesia, perform cesareandelivery under general anesthesia, orprovide adequate postoperative pain re-lief while minimizing and treating sideeffects. Thus, FDA package labeling islargely ignored by clinicians practicingobstetric anesthesia.

The current drug-regulatory envi-ronment and pharmaceutical industrydrug development practices allow manyanesthetic and analgesic drugs to cometo market without adequate testingin pregnant and nursing women. As aconsequence, much of the responsibilityfor performing drug risk-benefit andsafety administration studies lies withclinical researchers, and efficacy andsafety decisions are currently left toindividual clinicians. Anesthesiologists

TABLE 1Drugs commonly utilized by anesthesia care providers in an obstetricsetting

DrugPregnancyuse Obstetric setting Indication for use

Propofol Category Ba Cesarean delivery Induction of general anesthesia

Etomidate Category Cb Cesarean delivery Induction of general anesthesia

Ketamine Category Ba Cesarean delivery Induction of general anesthesiaanalgesia

Midazolam Category Dc Peripartum Anxiolysis

Succinylcholine Category Cb Cesarean delivery Skeletal muscle relaxation

Rocuronium Category Cb Cesarean delivery Skeletal muscle relaxation

Ephedrine Category Cb Peripartum Treatment of hypotension

Phenylephrine Category Cb Peripartum Treatment of hypotension

Ondansetron Category Ba Peripartum Treatment of nausea and vomiting

Metoclopramide Category Ba Peripartum Treatment of nausea and vomiting

Ranitidine Category Ba Peripartum Decrease gastric volume and pH

Sodium citrate Category Cb Cesarean delivery Decrease gastric pH

Cefazolin Category Ba Cesarean delivery Antibiotic prophylaxis

Nitroglycerin Category Cb Peripartum Treatment of uterine tachysystole

Bupivacaine Category Cb Labor and cesareandelivery

Neuraxial (epidural and intrathecal)analgesia and/or anesthesia

Ropivacaine Category Ba Labor and cesareandelivery

Neuraxial analgesia and/oranesthesia

Lidocaine Category Ba Labor and cesareandelivery

Neuraxial analgesia and/oranesthesia

Fentanyl Category Cb Labor and cesareandelivery

Neuraxial and/or intravenousanalgesia

Sufentanil Category Cb Labor and cesareandelivery

Neuraxial and/or intravenousanalgesia

Remifentanil Category Cb Labor and cesareandelivery

Intravenous analgesia

Morphine Category Cb Cesarean delivery Neuraxial and/or intravenousanalgesia

Hydromorphone Category Cb Cesarean delivery Neuraxial and/or intravenousanalgesia

Oxycodone Category Ba Peripartum Analgesia

Acetaminophen Category Ba Peripartum Analgesia

Ibuprofen Category Cb Postpartum Analgesia

Ketorolac Category Cb Postpartum Analgesiaa Pregnancy category B: animal studies have revealed no evidence of impaired fertility or harm to the fetus; however, thereare no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not alwayspredictive of human responses, this drug should be used during pregnancy only if clearly needed; b Pregnancy category C:animal reproductive studies have not been conducted. It is also unknown whether the drug can cause fetal harm whenadministered to a pregnant woman or can affect reproduction capacity. The drug should be given to a pregnant woman onlyif clearly needed; c Pregnancy category D: an increased risk of congenital malformations associated with the use ofbenzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used duringpregnancy, the patient should be apprised of the potential hazard to the fetus.

Carvalho. Drug labeling for obstetric anesthesia. Am J Obstet Gynecol 2015.

ajog.org Obstetrics Clinical Opinion

receive minimal authoritative guid-ance on safe drug administration toparturients.

In most cases, manufacturers providevery limited data in the package inserton which to make clinical decisionsabout safe drug use for the pregnantpopulation. The current rating system(pregnancy categories A to D) is overlyconservative and not very helpful tothe clinician in evaluating the risksand benefits of drug use in pregnantwomen.

A case in point is the pregnancy cate-gory C warning (ie, unknown whetherdrug can cause fetal harm when admin-istered to a pregnant woman and shouldbe given to a pregnant woman onlyif clearly needed) on the sterile watersolution that is required to reconstitutethiopental sodium (Pentothal; Hospira,Inc, Lake Forest, IL).1 We suggest thatthe drug manufacturers could state thatsterile water is safe.

Another example is the label of “notfor spinal” administration on the vialof plain bupivacaine (Hospira, Inc).2

The FDA has approved 0.75% hyper-baric bupivacaine for spinal anesthesia,yet vials of plain (in normal saline),preservative-free, 0.5% bupivacainecontain this warning.

A third example is ketorolac. Thepackage insert contains a black boxwarning that states, “The use of ketor-olac tromethamine is contraindicatedin nursing mothers because of the po-tential adverse effects of prostaglandin-inhibiting drugs on neonates.”3 Yet, atleast one study demonstrated that verylittle ketorolac crosses into breast milk,4

and the American Academy of Pediat-rics and the Academy of BreastfeedingMedicine consider the drug safe for usein nursing mothers.5,6

Another disadvantage of the currentlabeling system is that these drug re-strictions impede our ability to obtainethics committee approval to conductdrug trials in an obstetric setting.

The problematic drug labeling forsafe administration of drugs to pregnantand nursing women are not unique tothe United States. A review of drug

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TABLE 2Package insert material of sample drugs used in pregnancy, labor, and lactationDrug name and manufacturer Package insert related to drug use in pregnancy, labor and delivery, and while nursing

Propofol injectable emulsion Pregnancy category Ba

Labor and delivery: not recommended for obstetrics, including cesarean section deliveries; crosses theplacenta, and as with other general anesthetic agents, the administration of propofol may be associated withneonatal depression.Nursing mothers: not recommended for use in nursing mothers because propofol has been reported to beexcreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Fentanyl citrateinjection

Pregnancy category Cb

Labor and delivery: there are insufficient data to support the use of fentanyl in labor and delivery. Therefore,such use is not recommended.Nursing mothers: it is not known whether this drug is excreted in human milk. Because many drugs areexcreted in human milk, caution should be exercised when fentanyl citrate is administered to a nursingwoman.

Midazolam hydrochloride injection Pregnancy category Dc

Labor and delivery: the use of injectable midazolam in obstetrics has not been evaluated in clinical studies.Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeksof pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use.Nursing mothers: midazolam is excreted in human milk. Caution should be exercised when midazolam isadministered to a nursing woman.

Oxycodone hydrochloride Pregnancy category Ba

Labor and delivery: opioids cross the placenta and may produce respiratory depression andpsychophysiological effects in neonates. Oxycodone is not recommended for use in women during orimmediately prior to labor.Nursing mothers: low levels of oxycodone have been detected in maternal milk. The amount of oxycodonedelivered to the infant depends on the plasma concentration of the mother, the amount of milk ingested by theinfant, and the extent of first-pass metabolism. There is potential for serious adverse reactions in nursinginfants from oxycodone that includes respiratory depression, sedation, and potentially withdrawal symptomswhen the mother stops taking oxycodone. As such, one should consider either discontinuing nursing ordiscontinuing the drug and taking into account the importance of the drug to the mother.

Ketorolac tromethamine injection Black box warning: the use of ketorolac tromethamine in labor and delivery is contraindicated because it mayadversely affect fetal circulation and the uterus. The use of ketorolac tromethamine is contraindicated innursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates.Pregnancy category Cb

Nonteratogenic effects: because of the known effects of prostaglandin-inhibiting drugs on the fetalcardiovascular system (closure of the ductus arteriosus), the use of ketorolac tromethamine during latepregnancy should be avoided.Labor and delivery: the use of ketorolac tromethamine is contraindicated in labor and delivery because,through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterinemusculature, thus increasing the risk of uterine hemorrhage.Lactation and nursing: after a single administration of a 10 mg ketorolac tromethamine tablet to humans, themaximummilk concentration observed was 7.3 ng/mL and themaximummilk to plasma ratio was 0.037. After1 day of dosing (4 times a day), the maximum milk concentration was 7.9 ng/mL and the maximum milk toplasma ratio was 0.025. Because of the possible adverse effects of prostaglandin-inhibiting drugs onneonates, use in nursing mothers is contraindicated.

a Pregnancy category B: animal studies have revealed no evidence of impaired fertility or harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women. Becauseanimal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if clearly needed; b Pregnancy category C: animal reproductivestudies have not been conducted. It is also unknown whether the drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The drug should be givento a pregnant woman only if clearly needed; c Pregnancy category D: an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordi-azepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Carvalho. Drug labeling for obstetric anesthesia. Am J Obstet Gynecol 2015.

Clinical Opinion Obstetrics ajog.org

packaging labels of several countriesexposes similar drug labelling issues.Examples include the warnings thatpropofol should not be used duringpregnancy (United Kingdom, Canada,

26 American Journal of Obstetrics & Gynecology

and Australia); propofol should not beused for obstetric anesthesia (Australia);stop nursing and discard breast milkfor 24 hours after you have receivedpropofol (United Kingdom); the safe

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use of fentanyl safe has not been es-tablished (Canada); and breast-feedingis not recommended for 24 hoursfollowing administration of fentanyl(Australia).

ajog.org Obstetrics Clinical Opinion

We believe that the current packagelabeling may have a negative impact onthe care patients receive. For example,some clinicians avoid ketorolac in nursingmothers, and others avoid spinal injec-tion of plain bupivacaine, even thoughthe clinical situation merits their use.The FDA has recognized the limitationsof the current labeling system. In 1997,the agency convened a hearing onthe pregnancy-labeling categories. Afterextensive discussion with clinicians, theFDA proposed a new rule for the contentand format of labeling for human pre-scription drug products in pregnancyand lactation in May 2008.7

The new rule proposes that both thepregnancy and lactation subsectionsof package labeling include narrativesections on risk summary, clinicalconsiderations, and a data section thatincludes more detailed information.The current pregnancy categories A, B,C, D, and X would be eliminated.8

Information on the FDA web site in-dicates that “as of February 2011,the Final Rule is in the writing andclearance process.” 8

A system similar to the one proposedby the FDA7 is used by the widely usedreference compendium book by Briggset al,9 which evaluates drug use duringpregnancy and lactation. It is generallyagreed that this type of information ismore useful to both clinicians andpatients. For example, the reference’sconclusion regarding propofol use inpregnancy is “limited human data;

animal data suggests low risk” and foruse in lactation is “limited human data,probably compatible.”We write this commentary as a plea

to drug manufacturers and lawmakersto change the status quo and considerpractices and regulations that will pro-videmuch-needed guidance to clinicianson the safe administration of drugs tocertain populations such as pregnantand nursing women. The FDA’s pro-posed new rule on drug labeling inpregnancy, when enacted, will con-tribute to better decision making in theclinical environment. However, the la-beling change will not create newknowledge about drug risks.Possible solutions include mandating

and supporting large-scale, post-marketing, observational studies orintroducing new regulations for phar-maceutical industry drug developmentto facilitate adequate testing of selectanesthetic or analgesic drugs in preg-nant and nursing women before thedrugs come to market. Drug manufac-turers not only have an obligation to becompliant with marketing of their drugsbut also should share a responsibilityto investigate their drugs in specialpopulations such as pregnant andnursing women.Currently, there is inadequate infor-

mation for individual physicians andpatients to make informed decisionsfor drug use during pregnancy andlactation. We believe that the drug la-beling and drug testing practices that

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potentially compromise clinical care ofparturients and their children need tobe addressed to optimize safe drugadministration. -

REFERENCES

1. Pentothal (thiopental sodium injection)[package insert]. Lake Forest, IL: Hospira, Inc;2004.2. Bupivacaine hydrochloride injection [packageinsert]. Lake Forest, IL: Hospira, Inc; 2010.3. Ketorolac tromethamine injection) [packageinsert]. Lake Forest, IL: Hospira, Inc; 2005.4. Wischnik A, Manth SM, Lloyd J,Bullingham R, Thompson JS. The excretion ofketorolac tromethamine into breast milk aftermultiple oral dosing. Eur J Clin Pharmacol1989;36:521-4.5. American Academy of Pediatrics Committeeon Drugs. Transfer of drugs and other chem-icals into human milk. Pediatrics 2001;108:776-89.6. Montgomery A, Hale TW. Academy ofBreastfeeding Medicine Protocol number 15:analgesia and anesthesia for the breastfeedingmother. Breastfeeding Med 2006;1:271-7.7. US Food and Drug Administration. Contentand format of labeling for human prescriptiondrug and biological products; requirements forpregnancy and lactation labeling, 73 Fed. Reg.30831-68 (May 29, 2008). Available at: http://www.regulations.gov/#!documentDetail;D¼FDA-2006-N-0515-0027. Accessed Feb. 20, 2014.8. US Food and Drug Administration. Drugdevelopment and approval process: pregnancyand lactation labeling. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm. Accessed Feb. 20, 2014.9. Briggs GG, Freeman RK, Yaffe SJ. Drugs inpregnancy and lactation: a reference guide tofetal and neonatal risk, 9th ed. Philadelphia:Lippincott Williams and Wilkins; 2011.

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