Treating Pregnancy Related Pain in the ED

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Pain management in the emergency department setting can be challenging even without the added complexity of pregnancy. Clinical trial data is limited on pregnant patients so data is limited in evaluating safety of medications. This review focuses on commonly prescribed analgesics and the data surrounding their safety profiles in pregnancy ranging from evaluation of increased risk of spontaneous abortions, birth defects and long-term developmental outcomes in the child.

How common is analgesic use in pregnancy?

  • Pain medications are the most common medication consumed by pregnant women

  • Reports of up to 57% of patients in USA had at least 1+ visit to ED for complaint involving pain [1]

  • Studies in the United States showed that up to 65-70% of pregnant women reported acetaminophen use with increasing use as the pregnancy progresses

  • NSAIDs are used by 2-15% of women and consumption tends to decrease over the duration of pregnancy [2,3]

  • Opioid use reported by 6-14% of women during pregnancy and this is increasing, similar to that of rates of opioid use overall [4]

What are risks of inadequately controlling pain in pregnancy?

  • Increased chronic pain states that may worsen maternal stress and predispose to depression, sleep deprivation and hypertension [2]

WhoWhenGuidance
FDAJanuary 2015Drug Safety Communication: - Unable to make any new recommendations at that time due to the limited nature of the studies completed - Recommend weighing the pros and cons of pain medications before prescribing them during pregnancy - Recommend avoidance of NSAIDs during the 3rd trimester due to documented risk of closure of the premature ductus arteriosus [13]
Society for MFMMarch 2017Acetaminophen use in pregnancy: - Unable to provide safety recommendations for acetaminophen regarding neurodevelopmental outcomes due to lack of conclusive data published to date [14]
EMRAJuly 2020- Acetaminophen: gold standard - Ibuprofen: safe in 1st tri, avoid in 2nd and 3rd - Opioids: only use for severe pain or if no improvement with non-opioids; “start low, go slow” [15]

How can I determine the safety of medications in pregnancy?  

  • The United States has abandoned the A-X category system that was previously used for labeling the safety of medications

  • Recommendations are presented in writing by the FDA and specialty healthcare groups to provide more specifics [2]

Medications

Below we will cover data on recently posed questions regarding the most commonly used analgesics (as of 10.2020). As always this is data, not advice.

Quick links

Acetaminophen - NSAIDs - Opioids - Comparisons - Others

Acetaminophen

Will acetaminophen lead to long-term adverse neurodevelopmental outcomes?

Summary (TLDR)

  • Children exposed to acetaminophen had an increased risk of ADHD-like behavior, diagnosis of hyperkinetic disorder or prescription for ADHD medications

  • When controlling for same-sex sibling pairs and differences in exposure, they found that children with long-term exposure (>28 days) had worse neurodevelopmental outcomes (ex. motor development, communication, higher activity levels)

+ The Data

Acetaminophen has long been regarded as the “safest” pain medication to take in pregnancy. A prospective cohort study from 2014 studied 64,322 live-born children and mothers enrolled and their use of acetaminophen during pregnancy and 6 months postpartum. They found that children who were exposed to acetaminophen in utero had an increased likelihood of ADHD-like behavior, diagnosis of a hyperkinetic disorder or prescription for ADHD medication compared to children who were not exposed. They found stronger associations with increased acetaminophen use and continuance across multiple trimesters.[5]

A 2013 prospective cohort study evaluated 48,631 children born in Norway and evaluated exposure to acetaminophen via maternal questionnaires. They looked at psychomotor development, as well as behavioral problems and overall temperament evaluated at 3 years of age. They categorized exposure to acetaminophen being less than or greater than 28 days, as well as evaluating same-sex sibling pairs and whether they received the same exposure. Controlling for siblings demonstrated that those with >28 days exposure showed worse gross motor development, communication, internalizing behavior and higher activity levels. In comparison, those with exposure 1-27 days, defined as short-term, had worse gross motor outcomes.[6]

NSAIDS

Do NSAIDs increase the risk of spontaneous abortions in early trimesters?

Summary (TLDR)

  • Conflicting data between two large studies with one showing increased risk of spontaneous abortions and the other showing no increased risk aside from use of indomethacin.

+ The Data

It is well-circulated knowledge that NSAIDs should not be used in the 3rd trimester of pregnancy due to increased risk of premature closure of the ductus arteriosus, which negatively impacts fetal circulation and can predispose to pulmonary hypertension. However, more studies are investigating the use of NSAIDs in the 1st and 2nd trimesters to determine safety of their use.

A 2014 historical cohort study looked at women ages 14-45 in Israel to identify exposure to NSAIDs (non-selective COX-inhibitor vs COX-2 inhibitor) and the rate of spontaneous abortions. The patients were deemed as exposed to NSAIDs if a medication was dispensed between first day of last menstrual period and the day prior to hospital admit for spontaneous abortions; for patients who delivered a liveborn, 20 weeks of gestation was used. They found that there was no increased risk overall of spontaneous abortion for all medications, except for indomethacin.

Their reasoning includes suspicion that indomethacin may have been prescribed as a tocolytic to treat preterm as the median exposure was much higher than the other NSAIDs evaluated; after disregarding exposures occurring 4 days prior to spontaneous abortion, they found no association of increased risk with indomethacin. [7]

To contrast the above, a 2011 nested case-control study evaluated 4,705 women with spontaneous abortions with 47,050 controls to assess use of NSAIDs. They found a significant association of spontaneous abortion for all NSAIDs without a dose-response effect seen. They found that naproxen was the most commonly used medication and that the odds-ratio was higher if selectively analyzing the 2 weeks prior to spontaneous abortion. Their proposed mechanism reflects the maintenance of pregnancy by decreased uterine production of prostaglandins and blockage of this inhibitory pathway might contribute to spontaneous abortion. [8]

These papers were both published in the Canadian Medical Journal just 3 years apart with conflicting conclusions and both had significant limitations to the study designs put forth; these papers are just a sampling of the contradictory data available on NSAID use in the early trimesters of pregnancy and make it difficult to provide recommendations regarding their use in the 1st and 2nd trimesters.

Opioids

Do opioids increase the risk of birth defects early in pregnancy? When will they cause neonatal abstinence syndrome?

Summary (TLDR)

  • Opioids showed an increased association with cardiac and neural tube defects

  • Long-term opioids and use in 3rd trimester coupled with additional maternal risk factors lead to highest risk of NAS, whereas short-term, low-dose opioids even in the third trimester showed low absolute risk for NAS

+ The Data

A 2011 paper utilized the National Birth Defects Prevention study (1997-2005), a population-based case-control study, to identify birth defects by evaluating maternal prescription opioid use between one month prior to conception through the first trimester. Data was collected via interviews performed sometime between 6 weeks to 2 years after the delivery date. Notably, illicit drug use was an exclusion factor. They found an association with cardiac defects including conoventricular, atrioventricular septal and hypoplastic left heart syndrome, as well as spina bifida and gastroschisis.9

A 2015 observational cohort study used Medicaid data from 46 states to investigate the risk of neonatal abstinence syndrome (NAS) in liveborn infants between delivery and 30 days of life. They studied women who filled 1+ prescriptions for opioids at any point during pregnancy and compared short-term (<30 data-preserve-html-node="true" days) to long-term (<30 data-preserve-html-node="true" days), early use (1st and 2nd trimester) to late use (3rd trimester) and the cumulative dose in morphine equivalents. They identified NAS and maternal risk factors through chart review and identifying ICD-9 codes for diagnoses.

Of the over 200K women, 1,705 cases of NAS were identified for an absolute risk of 5.9 per 1,000 deliveries. The risk was increased with long-term use, as well as risk factors including known opioid abuse, alcohol/other drug abuse, exposure to other psychotropic medications (TCAs, SSRIs, SNRIs, benzodiazepines etc.) and smoking. Interestingly, with none of the previously listed risk factors, there was <1 data-preserve-html-node="true" case per 1,000 for short-term use and 4 cases per 1,000 for long-term use. [10]

A COMPARISON OF THE THREE

Is acetaminophen really safer than NSAIDs or opioids?

Summary (TLDR)

  • Compared to acetaminophen, NSAID and opioid use showed increased risk of birth defects, which was magnified overall when NSAIDs/opioids used in combination.

+ The Data

A 2017 study evaluated NSAID and/or opioid use to acetaminophen and the risks of certain birth defects based on use from one month prior to conception through the first trimester. Of the 29,078 cases, 57% reported periconceptional pain medication use and of the 10,962 control mothers, 54% reported periconceptional analgesic use.

NSAID use was associated with increased risk of the child having neural tube defects, facial structure defects, cardiopulmonary defects and genitourinary defects. Opioids were associated with significant cardiac defects. The combined use of NSAIDs with opioids demonstrated higher rates of gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome and pulmonary valve stenosis that was increased overall with the combination of both classes of medications. They conclude that these birth defects are more highly associated with NSAID and/or opioid use than with acetaminophen. [11]

Other Therapies - Ketamine

How about some pain dose ketamine?

Summary (TLDR)

  • Ketamine was used for 2 patients with severe sickle cell crises during pregnancy with possible improvement in pain and no documented adverse effects. 2 patients is not a study and this is not yet ready for routine use.

+ The Data

There is little data surrounding the use of ketamine in pregnancy nor are there case-control or cohort studies evaluating its safety profile.

A case report was published evaluating ketamine use in 2 patients presenting with sickle cell crisis. Unfortunately, sickle cell pain crises occur at an increased rate during pregnancy with >50% of patients with the disease having 1+ episodes. One of the patients received ketamine twice, once at 26 weeks for 9 days and at 30 weeks for 5 days during delivery of her child for preterm, premature rupture of membranes. She reported limited decrease in her pain, however she simultaneously decreased the use of her co-prescribed PCA. She had issues tolerating higher doses due to side effects such as visual hallucinations and lightheadedness.

The second patient received ketamine at 31 weeks for a total of 3 days, but additionally had an exchange transfusion during that time due to lack of improvement. She reported no adverse effects to the medication and her child was delivered safely at 37 weeks, but it is difficult to assess its efficacy due to the added exchange transfusion. Although neither patient had documented negative outcomes from this medication, it was not clear whether it provided benefit to either of these patients. [12]

Takeaway Points

  • Pregnancy is complicated: discuss with all patients the risks and benefits to prescribing analgesics during the preconceptional and gestational periods

MedicationRisksRecommendation
AcetaminophenLimited studies demonstrating increased associations with long-term neurodevelopmental outcomesStill regarded as the safest pain medication in pregnancy
NSAIDs3rd trimester risk of premature closure of the ductus arteriosus. Possible association with spontaneous abortions 1st/2nd trimestersNo use in the 3rd trimester. Be aware of possible risk of spontaneous abortion in 1st trimester
OpioidsMay show risks of birth defects when used early in pregnancy. Neonatal abstinence syndrome when used in large amounts near deliveryCan use low dose, short-term prescriptions near delivery as absolute risk of neonatal abstinence syndrome is low
KetamineLittle data / unknownNot currently an option other than consideration in refractory / severe conditions given lack of safety data

Post by Bronwyn Finney, MD

Dr. Finney is a PGY-1 in Emergency Medicine at the University of Cincinnati

Editing by James Li, MD and Ryan LaFollette, MD

Dr. Li is a PGY-4 and Chief Resident in Emergency Medicine at the University of Cincinnati. Dr. LaFollette is an Assistant Program Director at UC and Co-Editor of TamingtheSRU

References

  1. Vladutiu CJ, Stringer EM, Kandasamy V, Ruppenkamp J, Menard MK. Emergency Care Utilization Among Pregnant Medicaid Recipients in North Carolina: An Analysis Using Linked Claims and Birth Records. Matern Child Health J. 2019;23(2):265-276. doi:10.1007/s10995-018-2651-6

  2. Black E, Khor KE, Kennedy D, et al. Medication Use and Pain Management in Pregnancy: A Critical Review. Pain Practice. 2019;19(8):875-899. doi:10.1111/papr.12814

  3. Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA, the National Birth Defects Prevention Study. Use of over-the-counter medications during pregnancy. American Journal of Obstetrics and Gynecology. 2005;193(3):771-777. doi:10.1016/j.ajog.2005.02.100

  4. Bateman BT, Hernandez-Diaz S, Rathmell JP, et al. Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States. Anesthesiology. 2014;120(5):1216-1224. doi:10.1097/ALN.0000000000000172

  5. Liew Z, Ritz B, Rebordosa C, Lee P-C, Olsen J. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatrics. 2014;168(4):313-320. doi:10.1001/jamapediatrics.2013.4914

  6. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013;42(6):1702-1713. doi:10.1093/ije/dyt183

  7. Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014;186(5):E177-E182. doi:10.1503/cmaj.130605

  8. Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011;183(15):1713-1720. doi:10.1503/cmaj.110454

  9. Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. American Journal of Obstetrics and Gynecology. 2011;204(4):314.e1-314.e11. doi:10.1016/j.ajog.2010.12.039

  10. Desai RJ, Huybrechts KF, Hernandez-Diaz S, et al. Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study. BMJ. 2015;350. doi:10.1136/bmj.h2102

  11. Interrante JD, Ailes EC, Lind JN, et al. Risk comparison for prenatal use of analgesics and selected birth defects, National Birth Defects Prevention Study 1997–2011. Annals of Epidemiology. 2017;27(10):645-653.e2. doi:10.1016/j.annepidem.2017.09.003

  12. Gimovsky AC, Fritton K, Viscusi E, Roman A. Evaluating the Use of Ketamine for Pain Control With Sickle Cell Crisis in Pregnancy: A Report of 2 Cases. A & A Case Reports. 2018;10(1):20-22. doi:10.1213/XAA.0000000000000624

  13. Research C for DE and. FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. FDA. Published online February 9, 2019. Accessed October 17, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-has-reviewed-possible-risks-pain-medicine-use-during-pregnancy

  14. Prenatal acetaminophen use and outcomes in children. American Journal of Obstetrics & Gynecology. 2017;216(3):B14-B15. doi:10.1016/j.ajog.2017.01.021

  15. Bridwell, R. E., MD, Koyfman, A., MD, & Long, B., MD, FACEP. (july 2020). Ch. 14- Pain in Pregnancy. In Pain Management Guide (1st ed., Vol. 1). Emergency Medicine Residents' Association. https://www.emra.org/books/pain-management/Introduction/