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org Editorials

Pain relief: determining the safety of


ibuprofen with postpartum preeclampsia
Jonathan S. Hirshberg, MD; Alison G. Cahill, MD, MSCI

H ypertensive disorders effect up to 10% of pregnancies.1


They are a significant contributor to maternal and
perinatal morbidity and mortality worldwide.2 Hypertensive
inhibit aldosterone and prostaglandin metabolism, potentially
worsening vasoconstriction.10 Nonsteroidal medications
produce vasoconstriction of the afferent renal arteriole,
disease that originates or persists into the postpartum period reducing glomerular filtration rate, and obstruct sodium
contributes to prolonged hospitalizations and hospital read- excretion, with a combined effect of inhibiting diuresis.11,12
missions.3 Presence of these conditions in the peripartum Cytochrome-450 induction and cyclooxygenase (COX) inhi-
period has also been linked to lifelong cardiovascular risk.4 bition may lead to the accumulation of vasoactive metabolites
The American Congress of Obstetricians and Gynecologists of arachidonic acid.13
(ACOG) Task Force on Hypertension in Pregnancy released Recent attention to this clinical question has generated data
guidelines for the clinical care of hypertension in pregnancy from multiple retrospective cohorts. Viteri et al14 found no
in 2013. These guidelines included a statement which sug- difference in clinically significant hypertensive episodes in
gested that nonsteroidal antiinflammatory drugs (NSAIDs) their 399 patients regardless of NSAID exposure. Of note,
should be withheld from patients with hypertension that they also found no difference between rates of renal injury,
persists for >1 day postpartum.5 There are 2 likely sources for pulmonary edema, and intensive care unit admission. This
this recommendation. The first is based in data from the replicates the findings of Wasden et al,15 who in addition,
general medicine literature, which suggests a role of NSAIDs showed that there were no increased antihypertensive re-
in precipitating hypertension in nonpregnant adults.6,7 The quirements in those who received NSAIDs.
second may draw from previously published case reports of A single prospective trial was completed in Panama and
postpartum hypertension that were thought to be NSAID published in 2017.16 Vigil-De Gracia and colleagues16 ran-
induced.8 There has been a paucity of data from the obstetric domized women with severe preeclampsia to acetaminophen
literature to support or rebuff this recommendation. or ibuprofen for postpartum pain control. The cohort,
As the opioid crisis worsens in the United States, additional limited to women after vaginal birth, showed a statistically
attention and resources have focused on limiting the use of higher rate of hypertension (systolic blood pressure >150
narcotic medications. The effective employment of nonopioid mm Hg or diastolic >100 mm Hg) after the first 24 hours
analgesics has been shown to reduce narcotic use.9 Ibuprofen postpartum in those who received ibuprofen. There was no
and other NSAIDs are the most effective and most commonly difference in rates of severe range blood pressures (>160/110
prescribed analgesics for postpartum pain, but clinicians now mm Hg). This study was limited by its small sample size (n ¼
find themselves stuck between the tasks force recommenda- 113), exclusion of those delivered by cesarean delivery, and
tions and their efforts to limit unnecessary opioid open-label randomization.
prescriptions. A double masked, randomized controlled trial completed by
There are multiple mechanisms that contribute to a bio- Blue et al17 and published in this edition of the Journal, does
logic possibility that NSAIDs negatively impact postpartum not replicate these findings. Key results from this well-designed
hypertension. In vivo studies have demonstrated that NSAIDs and executed study show no difference in the duration of severe
range blood pressures in the ibuprofen vs acetaminophen
groups. Excluding their assigned randomization group, the
From the Department of Obstetrics and Gynecology, Washington
University School of Medicine in St Louis, St. Louis, MO. cohort of 100 women with preeclampsia with severe features
Received April 11, 2018; accepted April 17, 2018.
were otherwise managed and monitored per ACOG guidelines.
This study provides a rich collection of data that showed no
The authors report no conflict of interest.
difference in mean arterial pressures, need for antihyperten-
Dr Cahill is supported by the Eunice Kennedy Shriver National Institute of
Child Health and Human Development (R01HD061619-01, principal
sives, or laboratory evidence of end-organ dysfunction between
investigator Cahill), which partially supported this work. The contents of the treatment groups. Follow-up was carried out to 6 weeks’
this publication are solely the responsibility of the authors and do not postpartum, providing insights into the possible intermediate-
necessarily represent the official view of the National Institutes of Health. term effects of analgesic use. While 23% of the cohort was lost
Corresponding author: Jonathan S. Hirshberg, MD. Jhirshberg@wustl. to follow-up by 6 weeks, the remaining patients showed no
edu difference between treatment groups.
0002-9378/free While this study is a key step in understanding what
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.04.026
impact, if any, NSAIDs have on postpartum hypertension, it
has limitations to consider. The study was designed and
Related article, page 616. powered as a superiority trial. Thus, its findings suggest that
acetaminophen is not superior to ibuprofen. A negative
JUNE 2018 American Journal of Obstetrics & Gynecology 547
Descargado para demetrio rufino guarniz capristan (ethangc_66@hotmail.com) en Colegio Medico Del Peru de ClinicalKey.es por Elsevier en julio 24, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
Editorials ajog.org

superiority trial should not be misinterpreted as proof that 4. Theilen LH, Fraser A, Hollingshaus MS, et al. All-cause and cause-
there is no difference between the groups. Equivalence and specific mortality after hypertensive disease of pregnancy. Obstet
Gynecol 2016;128:238-44.
noninferiority trials require larger sample sizes and alternate 5. American College of Obstetricians and Gynecologists; Task Force on
statistical measures. Hypertension in Pregnancy. Executive summary: hypertension in preg-
We would speculate that much of the concern that lead to nancy. Obstet Gynecol 2013;122:1122-31.
the task force recommendation is based on potentially rare 6. Johnson AG, Nguyen TV, Day RO. Do non-steroidal anti-inflammatory
complications of NSAID use and not a diffuse mild elevation drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:
289-300.
in mean arterial pressures. Much of the data from the 7. Snowden S, Nelson R. The effects of nonsteroidal anti-inflammatory
nonpregnant population show that there may be a small drugs on blood pressure in hypertensive patients. Cardiol Rev 2011;19:
subset of people particularly susceptible to NSAID-induced 184-91.
hypertension.18 Unfortunately, ruling out rare events will 8. Makris A, Thornton C, Hennessy A. Postpartum hypertension and
require much larger sample sizes as we move forward. nonsteroidal analgesia. Am J Obstet Gynecol 2004;190:577-8.
9. White PF. The changing role of non-opioid analgesic techniques in the
In addition, the comparison of acetaminophen to management of postoperative pain. Anesth Analg 2005;101(Suppl):
ibuprofen does not necessarily mimic actual clinical practice. S5-22.
It is the practice at our institution, and we assume many 10. Knights KM, Mangoni AA, Miners JO. Non-selective nonsteroidal
others, to use both acetaminophen and ibuprofen in combi- anti-inflammatory drugs and cardiovascular events: is aldosterone the
nation for postpartum analgesia. A more precise clinical silent partner in crime? Br J Clin Pharmacol 2006;61:738-40.
11. Scaife PJ, Mohaupt MG. Salt, aldosterone and extrarenal Na-
question might ask what is the effect of prescribing vs with- sensitive responses in pregnancy. Placenta 2017;56:53-8.
holding NSAIDs in addition to the standard analgesic care. 12. Hörl WH. Nonsteroidal anti-inflammatory drugs and the kidney.
This becomes important as we understand that acetamino- Pharmaceuticals (Basel) 2010;3:2291-321.
phen is also a COX-2 inhibitor and has some inhibitory effect 13. Rahman M, Wright JT Jr, Douglas JG. The role of the cytochrome
on prostaglandin synthesis.19 In fact, retrospective data from P450-dependent metabolites of arachidonic acid in blood pressure
regulation and renal function: a review. Am J Hypertens 1997;10:
the Nurses’ Health Study II showed that in otherwise healthy 356-65.
young women, acetaminophen use was more strongly asso- 14. Viteri OA, England JA, Alrais MA, et al. Association of nonsteroidal
ciated with hypertension than NSAIDs.20 antiinflammatory drugs and postpartum hypertension in women with
While this study by Blue and colleagues17 takes a crucial preeclampsia with severe features. Obstet Gynecol 2017;130:830-5.
step toward understanding the safety of NSAID use in women 15. Wasden SW, Ragsdale ES, Chasen ST, Skupski DW. Impact of non-
steroidal anti-inflammatory drugs on hypertensive disorders of preg-
with preeclampsia, many clinical questions remain. While nancy. Pregnancy Hypertens 2014;4:259-63.
research groups work to shed more light on this topic, cli- 16. Vigil-De Gracia P, Solis V, Ortega N. Ibuprofen versus acetamino-
nicians will continue to struggle with the task force recom- phen as a post-partum analgesic for women with severe pre-eclampsia:
mendations and their individual patients’ care. - randomized clinical study. J Matern Fetal Neonatal Med 2017;30:
1279-82.
17. Blue NR, Murray-Krezan C, Drake-Lavelle S, et al. Effect of ibuprofen
vs acetaminophen on postpartum hypertension in preeclampsia with
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548 American Journal of Obstetrics & Gynecology JUNE 2018


Descargado para demetrio rufino guarniz capristan (ethangc_66@hotmail.com) en Colegio Medico Del Peru de ClinicalKey.es por Elsevier en julio 24, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.

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