Management of and Vomiting of after Discharge from the Emergency Department Cathy Yeulet/Thinkstock.com

ausea and vomiting of pregnancy (NVP) is a common condition that affects N­almost 70% of women in the US and globally.1,2 Patients with NVP present with nausea and vomiting with or without , usually before 9 weeks of gestation.3,4 Secondary symptoms of NVP can include excessive salivation or a bitter/metallic taste in the mouth. Abdominal , fever, and headache are not usually seen. Pa- tients who present to the emergency department (ED) will likely have more severe symptoms and may have already sought treatment as an outpatient from their pri- mary care provider or obstetrician. The most severe form of NVP is (HG), which affects approximately 1.2% of women and often leads to hospitalization.1 Those who have progressed to HG may additionally present with signs of acute starvation, weight loss, ketonuria, electrolyte imbalance, and , kidney, and thyroid abnormalities.

Publication of this supplement is made possible through a restricted grant from Duchesnay USA. This supplement is also available on www.EM-News.com.

LWW-EMN_May 2016_Supplement_Sample.indd 1 07/04/16 3:55 PM The total cost of treating NVP in the US was more or vomiting in hospitalized patients with HG.7 In the than $1.7 billion in 2012, including the direct cost of absence of evidence-based guidelines or evidence of healthcare and indirect costs associated with lost work superior efficacy, the choice of medication or the need for additional caregivers in the home.5 The in the ED for acute treatment of NVP should take more than 240,000 ED visits for NVP and HG in 2012 into account the severity of symptoms, patient status, were estimated to cost approximately $250 million.5 and the safety of each medication, carefully weighed Total medical care costs increased with the severity of against the potential benefits.3 NVP symptoms and the use of second- and third-line Hospital admission is reserved for the most severe medications such as and ondanse- forms of NVP. Hospitalization for treatment and obser- tron.5 Effective treatment of NVP in the ED and at vation is recommended for patients who cannot tolerate discharge is critical to reduce symptom progression oral liquids without vomiting, do not respond to anti­ and the number of repeat ED visits or hospitalization emetic medication, and continue to lose weight.3 for severe NVP or HG, thereby reducing the cost of care.3 Discharge Therapy for NVP Once a patient’s symptoms have been stabilized in the Treatment of NVP in the ED ED, a decision must be made about post-discharge in- Overall, the goals of NVP treatment are to reduce the structions to control NVP symptoms at home. These severity and impact of symptoms, and to reduce the instructions may include dietary and lifestyle recom- risk of progression to more severe NVP or HG while mendations, non-pharmacologic approaches, and phar- minimizing any adverse effects of treatment on the macologic therapies. . The immediate priorities for a woman present- Patients may have already attempted to reduce NVP ing to the ED with NVP are to replace fluids if the symptoms with dietary or lifestyle changes prior to their patient is dehydrated, using intravenous (IV) hydra- ED visit, and they should be encouraged to continue tion, and to correct ketosis and vitamin deficiency.3 these practices to help keep symptoms under control.3,8 Thiamine may be needed to prevent Wernicke en- Non-pharmacologic options include (vita- cephalopathy. It is also important to determine which min B6) and ginger,9-11 though these may not be suitable therapies the patient has already tried to control her for women who initially presented to the ED with mod- NVP symptoms, including dietary or lifestyle changes, erate to severe symptoms. herbal remedies, or over-the-counter treatments, as Women may be cautious about taking medication for well as any prescription medications. NVP out of concern for the potential effects on the Intravenous (IV) or oral pharmacotherapy may be fetus.8,12 As with acute treatment in the ED, the choice used to reduce nausea and vomiting in the ED. It is of antiemetic to prescribe at discharge should take into important to note that no studies have compared the account all available data on maternal and fetal safety, efficacy of antiemetic medications used for treatment weighed against the benefits of treatment. Decisions of acute symptoms of NVP in the ED, and there are about antiemetic­ medications for NVP prescribed at no evidence-based guidelines for the emergency treat- discharge can be guided by evidence-based recommen- ment of NVP. A recent retrospective study of 439 dations from the American College of Obstetricians women with NVP who were treated in the ED over a and Gynecologists (ACOG).3,13 The use of ACOG period of two years evaluated the time from treatment guidelines for treatment decision-making at ED dis- administration to ED discharge as a proxy for treat- charge will facilitate continuity of care with the patient’s ment efficacy.6 Patients were given (48%), obstetrician or primary care provider, and may produce metoclopramide (38%), (1%), or better outcomes for women with NVP and reduce the (13%), and 9% of patients were given risk of repeat ED visits or hospitalization. more than one medication. Each medication had a similar mean time from administration to discharge, Delayed-Release /Pyridoxine as suggesting no difference in efficacy for acute manage- First-Line Pharmacotherapy at Discharge ment of NVP in the ED. Another recent randomized ACOG recommends that pyridoxine alone or in combi- controlled trial also found no difference between on- nation with doxylamine (an 1 [H1] receptor dansetron and metoclopramide in reducing nausea blocker) be considered as first-line pharmacotherapy for

2 may 2016

LWW-EMN_May 2016_Supplement_Sample.indd 2 07/04/16 3:55 PM the treatment of NVP (Figure).3 A recent matched co- Emergency Department hort study of 160 women with NVP found a greater Acute Management of NVP effect of the combination of doxylamine and pyridox- ine compared with pyridoxine alone for reducing the Discharge symptoms of NVP, particularly in women with moder- ate to severe symptoms.14 In the US, a delayed-release Doxylamine 10 mg/pyridoxine 10 mg delayed-release tabletsa formulation of doxylamine 10 mg and pyridoxine ( A) 10 mg (marketed as Diclegis®) is currently the only medication approved for use for the treatment of NVP in ­patients who have not responded to conservative treatment, including dietary and lifestyle changes.15,16 ADD The combination of doxylamine 10 mg/pyridox- (Pregnancy Category B) 50-100 mg every 4-6 hoursb ine 10 mg was available in the US from 1958 to 1983, marketed as Bendectin®. During that time pe- riod, up to 30% of all pregnant women (an estimated 33 million women) received Bendectin for NVP.17 ADD Case reports of teratogenic effects of Bendectin Metoclopramide (Pregnancy Category B) eventually led to its voluntary removal from the US 5-10 mg every 8 hours before breakfast, lunch, dinner, bedtimec market in 1983, despite evidence from several large OR cohort studies and meta-analyses demonstrating the Promethazine (Pregnancy Category C) maternal and fetal safety of doxylamine/pyridox- 12.5-25 mg every 4 hours, orally or rectally ine.18-20 While the removal of Bendectin from the market did not result in a change in the overall num- ber of reported birth defects in the US, as would be Ondansetron (Pregnancy Category B) expected for a teratogen, the number of severe NVP 4-8 mg orally, every 6-8 hours cases resulting in hospitalization doubled.17 In Can- ada, a delayed-release combination of doxylamine 10 mg/pyridoxine 10 mg (Diclectin®) remained on the market and no increases in birth defects have been Methylprednisolone noted. These epidemiological and ecological data pro- (Pregnancy Category C)d vided strong support for the safety and efficacy of 16 mg every 8 hours for 3 days delayed-release doxylamine/pyridoxine for treatment Figure. Pharmacotherapeutic Approach to NVP of NVP, and its return to the US market as Diclegis after Discharge from the Emergency Department: in 2013. Application of American College of Obstetricians 3,34 A phase 3 placebo-controlled study was conducted and Gynecologists (ACOG) Guidelines aIf 2 tablets/day, take 2 at bedtime; if 3 tablets/day, take 1 in the in the US as part of the Diclegis New Applica- ­morning and 2 at bedtime; if 4 tablets/day, take 1 in the morning, tion to the FDA.21 The study included 131 women 1 mid-afternoon, and 2 at bedtime. bNot to exceed 400 mg per day. Not to exceed 200 mg per day if randomized to Diclegis and 125 randomized to pla- ­patient also is taking doxylamine to reduce sedation effect. cebo who were in weeks 7-14 of pregnancy and were cIf frequent vomiting, take 30-45 minutes prior to doxylamine/­ pyridoxine. experiencing symptoms of NVP that were not respon- dCorticosteroids are associated with an increased risk of oral clefts sive to dietary or lifestyle changes. Delayed-release when used during the first 10 weeks of gestation, and should be used as a last resort in patients with severe NVP or HG that is not respon- doxylamine/pyridoxine was found to be superior to sive to other medications. After 3 days, taper over 2 weeks to lowest placebo in reducing NVP symptoms, with improve- ­effective dose. If beneficial, limit total duration of use to 6 weeks. ment in quality of life after two weeks, less need for concomitant therapies, and fewer days of work ­focused on maternal safety using data from the phase 3 missed.21 was the only adverse reaction study found that the adverse event rate with delayed- seen with greater than 5% frequency in both the treat- release doxylamine/pyridoxine was no different from ment and placebo groups, likely due to the anticholin- that of placebo for cardiac, gastrointestinal, and nerv- ergic effects of doxylamine. A secondary analysis ous system disorders.22

may 2016 3

LWW-EMN_May 2016_Supplement_Sample.indd 3 07/04/16 3:55 PM Delayed-release doxylamine/ Table. FDA Pregnancy Categories54 pyridoxine is the only pharma- cologic option for NVP that has Category A Adequate and well-controlled studies have failed to demon- strate a risk to the fetus in the first trimester of pregnancy an FDA Pregnancy Category A (and there is no evidence of risk in later trimesters). rating (Table). This rating is based on numerous epidemio- Category B Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled logical studies, including the studies in pregnant women. findings of two separate meta- analyses of cohort and case-­ Category C Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled stud- control studies performed ies in humans, but potential benefits may warrant use of the ­between 1963 and 1991, that drug in pregnant women despite potential risks. found no increased risk of fetal Category D There is positive evidence of human fetal risk based on ad- abnormalities with the com- verse reaction data from investigational or marketing experi- bined use of doxylamine and ence or studies in humans, but potential benefits may warrant pyridoxine during the first tri- use of the drug in pregnant women despite potential risks. 19,20 mester of pregnancy. A more Category X Studies in animals or humans have demonstrated fetal abnor- recent study examined the ef- malities and/or there is positive evidence of human fetal risk fects of maternal exposure to based on adverse reaction data from investigational or market- delayed-release doxylamine/ ing experience, and the risks involved in use of the drug in pyridoxine on the long-term pregnant women clearly outweigh potential benefits. neurodevelopment of children Category N FDA has not classified the drug. exposed in utero.23 The study compared three groups of mother-child pairs: mothers who had NVP and took one tablet in the morning. A fourth tablet can be taken delayed-release doxylamine/pyridoxine (n=45), those mid-afternoon to control evening symptoms.16 Due to who had NVP but did not take delayed-release doxy- the severity of their NVP symptoms, patients dis- lamine/pyridoxine (n=47), and those who did not have charged from the ED may require the maximum of NVP (n=29). ­Children were assessed at 3 to 7 years of four tablets per day. age. The study found no evidence of an adverse effect of delayed-­release doxylamine/pyridoxine exposure on Other Antiemetic Medications as the children’s IQ, verbal fluency, phonological process- Second-Line or Third-Line ing, or numerical memory. Pharmacotherapy at Discharge Based on efficacy and fetal safety data, Diclegis According to the ACOG treatment guidelines, additional should be prescribed when women are discharged from can be added to the doxylamine/pyridoxine the ED. Women should be informed that Diclegis is a combination, if required. Although the use of these delayed-release formulation designed to release the ac- medications would be off-label and fetal safety data may tive ingredients 4-6 hours after ingestion, and hence, be limited, maternal benefits may warrant use. should be taken daily as prescribed and not on an as- needed basis.16 Over-the-counter (OTC) immediate-­ release doxylamine is not therapeutically equivalent to Other H1-antihistamines have been used for the treat- the delayed-release combination, and due to safety ment of NVP, including dimenhydrinate (Dramamine)24 concerns with the sedating effects of OTC doxylamine, and (Benadryl).25 These medications which is indicated as a aid, the use of this are considered second-line therapies that can be taken ­immediate-release therapy should not be recommended.15 after or in addition to doxylamine/pyridoxine (Figure). To match the peak serum concentration with onset of Meta-analyses of first-trimester exposure to H1-recep- symptoms, delayed-release doxylamine/pyridoxine is tor blockers, including doxylamine, found no adverse prescribed as a starting dose of two tablets at bedtime fetal effects.26,27 Both dimenhydrinate and diphenhy- each day to control morning symptoms of NVP. If dramine are FDA classified as Pregnancy Category B, symptoms persist into the afternoon, patients can add with no well-controlled studies of fetal safety.24,25

4 may 2016

LWW-EMN_May 2016_Supplement_Sample.indd 4 07/04/16 3:55 PM Antidopaminergic Medications Ondansetron continues to be prescribed for NVP, Metoclopramide is a dopamine receptor antagonist28 despite the emergence of concerning maternal and that is commonly used off-label to treat intraoperative fetal safety data associated with ondansetron use.38,39 and postoperative nausea in women undergoing Cesar- Several studies have examined the possible fetal effects ean section29 and in hospitalized women with HG.7,30 of ondansetron exposure in early pregnancy. A popula- Metoclopramide is FDA classified as Pregnancy Cate- tion-based case-control study reported a higher risk of gory B based on several large cohort studies that found cleft palate with exposure to ondansetron in the first no adverse pregnancy or fetal outcomes with metoclo- trimester of pregnancy (n=55; adjusted OR=2.37, pramide use in early pregnancy.31-33 Metoclopramide 95% CI 1.18-4.76).42 Another study of 1349 women has a black box warning on the association between identified in the Swedish Medical Birth Register who tardive dyskinesia, a severe movement disorder, and took ondansetron in early pregnancy were found to extended use of metoclopramide for more than 12 have a higher risk of cardiovascular defects (OR=1.62, weeks. At higher doses, metoclopramide blocks seroto- 95% CI 1.04-2.14) and cardiac septum defects nin receptors.28 Women who take metoclopramide with (RR=2.05, 95% CI 1.19-3.28) among their infants.43 other medications that increase serotonin levels, such as The results of a similar registry study in Denmark also certain medications, may be at increased showed an increased risk of congenital heart defects risk of developing serotonin syndrome.34 ACOG rec- among children whose mothers filled a prescription for ommends that metoclopramide be considered as a ondansetron during the first trimester of pregnancy third-line treatment for NVP (Figure).13 (n=1248; adjusted OR=2.0, 95% CI 1.3-3.1).44 Other Other antidopaminergic medications used for NVP studies have reported no adverse pregnancy outcomes include the , such as promethazine35 and or fetal abnormalities with ondansetron use in early prochlorperazine.36 Promethazine is also an H1 antihis- pregnancy for NVP.45,46 tamine, and is listed by ACOG as a second-line agent for There may also be maternal risks associated with NVP after doxylamine/pyridoxine (Figure);13 however, IV ondansetron use. In June 2012, the FDA issued a promethazine is classified as Pregnancy Category C,35 warning of possible serious QT prolongation and and therefore should only be considered in cases where increased risk of torsades de pointes with intravenous the maternal benefits outweigh the fetal risks. The fetal (IV) ondansetron.47 The FDA subsequently recom- safety of prochlorperazine has been less studied. There mended that IV ondansetron doses be limited to have been some reports of adverse fetal effects with 16 mg48 and that patients should undergo electrolyte phenothiazines, though the effect differs across medica- or ECG monitoring if they have a history of arrhyth- tions in the class.37 mias, heart failure, hypokalemia, or hypomagne- semia, or are taking other medications that cause QT Antiserotonergic Medications prolongation prior to starting IV ondansetron.3,49 A The selective serotonin inhibitor ondansetron is not ap- recent analysis concluded that a single oral dose of proved for use for NVP,38 but is commonly prescribed ondansetron is not associated with a significant risk off-label39 based on evidence of its efficacy in non- of .49 pregnant patients, particularly in the treatment of Because ondansetron is a serotonin inhibitor, the chemotherapy-induced and postoperative nausea and FDA has called for additional warnings and precautions vomiting. Two studies have demonstrated the efficacy of to be included in the labeling regarding the risk of sero- IV or oral ondansetron compared with metoclopramide tonin syndrome when taking ondansetron with other in treating severe NVP or HG.7,40 A recent small, single- medications that promote serotonin activity.38,50 center randomized study (n=30) showed that daily oral Given the limited and contradictory data on ondan- ondansetron 4 mg controlled nausea and vomiting bet- setron maternal and fetal safety, ACOG does not rec- ter than daily immediate-release doxylamine 12.5 mg/ ommend the use of ondansetron as a first-line treatment pyridoxine 25 mg during a 5-day treatment period as for NVP; its use is restricted to patients who fail on reported by patients using a visual analog scale.41 Note first- and second-line therapies (Figure).3 As such, pa- that this study did not compare ondansetron with tients discharged from the ED should not receive oral ­delayed-release doxylamine 10 mg/pyridoxine 10 mg, ondansetron unless they have not responded to other which would be taken up to 4 times per day. medications.13

may 2016 5

LWW-EMN_May 2016_Supplement_Sample.indd 5 07/04/16 3:55 PM Corticosteroids 3. American College of Obstetricians and Gynecologists. Corticosteroids such as methylprednisolone have been Practice Bulletin No. 153: Nausea and Vomiting of Preg- shown to improve symptoms in patients hospitalized nancy. Obstet Gynecol. 2015;126(3):e12-24. for HG, though the findings have been mixed.51,52 Sev- 4. Ebrahimi N, Maltepe C, Bournissen FG, Koren G. Nausea eral studies have reported an increased risk in oral and vomiting of pregnancy: using the 24-hour Pregnancy- clefts with methylprednisolone exposure,42,53 leading Unique Quantification of Emesis (PUQE-24) scale. J Ob- ACOG to recommend it as a last-resort treatment stet Gynaecol Can. 2009;31(9):803-807. after 10 weeks of gestation, limited to patients with 5. Piwko C, Koren G, Babashov V, Vicente C, Einarson TR. severe, refractory NVP or HG, and given for no more Economic burden of nausea and vomiting of pregnancy than 3 days (Figure).3 in the USA. J Popul Ther Clin Pharmacol. 2013;20(2): e149-160. Conclusion 6. M ayhall EA, Gray R, Lopes V, Matteson KA. Compari- NVP is a common medical condition with symptoms of son of antiemetics for nausea and vomiting of pregnancy nausea and vomiting that can range from mild to severe. in an emergency department setting. Am J Emerg Med. Women with NVP who present to the ED have more 2015;33(7):882-886. severe symptoms, and may be dehydrated. Treatment 7. Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron of NVP not only alleviates symptoms and improves compared with metoclopramide for hyperemesis quality of life, but also reduces the risk of progression to gravidarum: a randomized controlled trial. Obstet Gynecol. more severe NVP or HG, which is associated with seri- 2014;123(6):1272-1279. ous complications that may lead to repeat ED visits and 8. M altepe C. Surviving successfully: from hospitalization. Acute treatment of NVP in the ED in- patient’s perception to rational management. J Popul Ther volves replacement of fluids and reduction of symptoms Clin Pharmacol. 2014;21(3):e555-564. with pharmacologic therapies. In the absence of 9. Thomson M, Corbin R, Leung L. Effects of ginger for ­evidence-based guidelines for acute treatment of NVP nausea and vomiting in early pregnancy: a meta-analysis. in the ED, treatment decisions should take into account J Am Board Fam Med. 2014;27(1):115-122. the safety of each treatment weighed against the sever- 10. Viljoen E, Visser J, Koen N, Musekiwa A. A systematic ity of the symptoms and the potential benefits of treat- review and meta-analysis of the effect and safety of gin- ment. ACOG recommends the use of pyridoxine alone ger in the treatment of pregnancy-associated nausea and or in combination with doxylamine as first-line pharma- vomiting. Nutr J. 2014;13:20. cotherapy for outpatient treatment of NVP. A delayed- 11. M atthews A, Haas DM, O’Mathúna DP, Dowswell T. release formulation of doxylamine/pyridoxine is the Interventions for nausea and vomiting in early preg- only NVP treatment option that is indicated for NVP nancy. Cochrane Database Syst Rev. 2015;9:CD007575. and classified as Pregnancy Category A by the FDA 12. M adjunkova S, Maltepe C, Koren G. The Leading Con- based on evidence from large, well-controlled studies in cerns of American Women with Nausea and Vomiting pregnant women, and as such, should be prescribed of Pregnancy Calling Motherisk NVP Helpline. Obstet first-line for women discharged from the ED. Several Gynecol Int. 2013;2013:752980. other antiemetic medications have been used off-label 13. American College of Obstetricians and Gynecologists for NVP, and although none are indicated for the treat- Practice Bulletin: nausea and vomiting of pregnancy. ment of NVP or considered safe for use in pregnant Obstet Gynecol. 2004;103(4):803-814. women, their use may be warranted as second- or third- 14. Pope E, Maltepe C, Koren G. Comparing pyridoxine line therapy. and doxylamine succinate-pyridoxine HCl for nausea and vomiting of pregnancy: A matched, controlled co- References hort study. J Clin Pharmacol. 2015;55(7):809-814. 1. Einarson TR, Piwko C, Koren G. Prevalence of nausea 15. M adjunkova S, Maltepe C, Koren G. The delayed-release and vomiting of pregnancy in the USA: a meta analysis. combination of doxylamine and pyridoxine (Diclegis®/ J Popul Ther Clin Pharmacol. 2013;20(2):e163-170. Diclectin®) for the treatment of nausea and vomiting of 2. Einarson TR, Piwko C, Koren G. Quantifying the global pregnancy. Paediatr . 2014;16(3):199-211. rates of nausea and vomiting of pregnancy: a meta analy- 16. Declegis [package insert]. Bryn Mawr, PA: Duchesnay sis. J Popul Ther Clin Pharmacol. 2013;20(2):e171-183. USA, Inc; 2013.

6 may 2016

LWW-EMN_May 2016_Supplement_Sample.indd 6 07/04/16 3:55 PM 17. Kutcher JS, Engle A, Firth J, Lamm SH. Bendectin and 32. Pasternak B, Svanstrom H, Mølgaard-Nielsen D, Melbye birth defects. II: Ecological analyses. Birth Defects Res A M, Hviid A. Metoclopramide in pregnancy and risk of Clin Mol Teratol. 2003;67(2):88-97. major congenital malformations and fetal death. JAMA. 18. Duchesnay Inc. Bendectin history. 2013; http://www.­ 2013;310(15):1601-1611. bendectin.com/en. Accessed January 26, 2016. 33. Sørensen HT, Nielsen GL, Christensen K, et al. Birth 19. Einarson TR, Leeder JS, Koren G. A method for meta- outcome following maternal use of metoclopramide. analysis of epidemiological studies. Drug Intell Clin Pharm. The Euromap study group. Br J Clin Pharmacol. 1988;22(10):813-824. 2000;49(3):264-268. 20. M cKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendec- 34. Niebyl JR, Briggs GG. The pharmacologic management tin and birth defects: I. A meta-analysis of the epidemio- of nausea and vomiting of pregnancy. J Fam Pract. logic studies. Teratology. 1994;50(1):27-37. 2014;63(2 Suppl):S31-37. 21. Koren G, Clark S, Hankins GD, et al. Effectiveness of 35. Phenergan [package insert]. Philadelphia, PA: Wyeth delayed-release doxylamine and pyridoxine for nausea Pharmaceuticals Inc.; 2005. and vomiting of pregnancy: a randomized placebo 36. Compazine [package insert]. Research Triangle Park, ­controlled trial. Am J Obstet Gynecol. 2010;203(6):571 NC: GlaxoSmithKline; 2004. e571-577. 37. Magee LA, Mazzotta P, Koren G. Evidence-based view 22. Koren G, Clark S, Hankins GD, et al. Maternal safety of safety and effectiveness of pharmacologic therapy of the delayed-release doxylamine and pyridoxine com- for nausea and vomiting of pregnancy (NVP). Am J bination for nausea and vomiting of pregnancy; a ran­ Obstet Gynecol. 2002;186(5 Suppl Understanding): domized placebo controlled trial. BMC Pregnancy Childbirth. S256-261. 2015;15:59. 38. Zofran [package insert]. Research Triangle Park, NC: 23. Nulman I, Rovet J, Barrera M, et al. Long-term neu- GlaxoSmithKline; 2014. rodevelopment of children exposed to maternal nausea 39. Koren G. Treating morning sickness in the United and vomiting of pregnancy and diclectin. J Pediatr. States—changes in prescribing are needed. Am J Obstet 2009;155(1):45-50, 50 e41-42. Gynecol. 2014;211(6):602-606. 24. Dramamine [package insert]. Schaumburg, IL: APP 40. Kashifard M, Basirat Z, Kashifard M, et al. Ondanse- Pharmaceuticals, LLC; 2008. trone or metoclopromide? Which is more effective in 25. Benadryl [package insert]. Washington, PA: McNeil- ­severe nausea and vomiting of pregnancy? A rand- PPC, Inc.; 2012. omized trial double-blind study. Clin Exp Obstet Gynecol. 26. Seto A, Einarson T, Koren G. Pregnancy outcome fol- 2013;40(1):127-130. lowing first trimester exposure to antihistamines: meta- 41. Oliveira LG, Capp SM, You WB, et al. Ondansetron analysis. Am J Perinatol. 1997;14(3):119-124. compared with doxylamine and pyridoxine for treatment 27. Chin JW, Gregor S, Persaud N. Re-analysis of safety of nausea in pregnancy: a randomized controlled trial. data supporting doxylamine use for nausea and Obstet Gynecol. 2014;124(4):735-742. ­vomiting of pregnancy. Am J Perinatol. 2014;31(8): 42. Anderka M, Mitchell AA, Louik C, et al. Medications 701-710. used to treat nausea and vomiting of pregnancy and the 28. Reglan [package insert]. Deerfield, IL: Baxter Health- risk of selected birth defects. Birth Defects Res A Clin Mol care Corporation; 2010. Teratol. 2012;94(1):22-30. 29. M ishriky BM, Habib AS. Metoclopramide for nausea 43. Danielsson B, Wikner BN, Källén B. Use of ondanse- and vomiting prophylaxis during and after Caesarean tron during pregnancy and congenital malformations in delivery: a systematic review and meta-analysis. Br J the infant. Reprod Toxicol. 2014;50:134-137. Anaesth. 2012;108(3):374-383. 44. Andersen JT, Jimenez-Solem E, Andersen NL, Poulsen 30. Tan PC, Khine PP, Vallikkannu N, Omar SZ. Prometh- HE. Ondansetron use in early pregnancy and the risk of azine compared with metoclopramide for hyperemesis congenital malformations-a registry based nationwide gravidarum: a randomized controlled trial. Obstet Gynecol. cohort study. Abstract presented at: 29th International 2010;115(5):975-981. Conference on Pharmacoepidemiology & Therapeutic 31. M atok I, Gorodischer R, Koren G, et al. The safety of Risk Management; August 25-28, 2013; Montreal, Can- metoclopramide use in the first trimester of pregnancy. ada. Pharmacoepidemiol Drug Saf. 2013;22(suppl 1):13-14. N Engl J Med. 2009;360(24):2528-2535. Abstract 25.

may 2016 7

LWW-EMN_May 2016_Supplement_Sample.indd 7 07/04/16 3:55 PM 45. Einarson A, Maltepe C, Navioz Y, et al. The safety of 50. US Food and Drug Administration. Serotonin-3 (5-HT3) ondansetron for nausea and vomiting of pregnancy: Receptor Antagonists: Safety Labeling Changes Ap- a prospective comparative study. BJOG. 2004;111(9): proved By FDA Center for Drug Evaluation and Re- 940-943. search (CDER). Published September 2014. http:// 46. Pasternak B, Svanström H, Hviid A. Ondansetron in www.fda.gov/Safety/MedWatch/SafetyInformation/ pregnancy and risk of adverse fetal outcomes. N Engl J ucm418818.htm. Accessed February 9, 2016. Med. 2013;368(9):814-823. 51. Safari HR, Fassett MJ, Souter IC, et al. The efficacy of 47. US Food and Drug Administration. FDA Drug Safety methylprednisolone in the treatment of hyperemesis Communication: New information regarding QT pro- gravidarum: a randomized, double-blind, controlled longation with ondansetron (Zofran). Published June 29, study. Am J Obstet Gynecol. 1998;179(4):921-924. 2012. http://www.fda.gov/Drugs/DrugSafety/ 52. Yost NP, McIntire DD, Wians FH Jr., et al. A rand- ucm310190.htm. Accessed February 9, 2016. omized, placebo-controlled trial of corticosteroids for 48. US Food and Drug Administration. FDA Drug Safety hyperemesis due to pregnancy. Obstet Gynecol. 2003; Communication: Updated information on 32 mg 102(6):1250-1254. ­intravenous ondansetron (Zofran) dose and pre-mixed 53. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth ondansetron products. Published December 4, 2012. ­defects after maternal exposure to corticosteroids: http://www.fda.gov/Drugs/DrugSafety/ucm330049. ­prospective cohort study and meta-analysis of htm. Accessed January 26, 2016. ­epidemiological studies. Teratology. 2000;62(6): 49. Freedman SB, Uleryk E, Rumantir M, et al. Ondansetron 385-392. and the risk of cardiac : a systematic review 54. Drugs.com. FDA Pregnancy Categories. http://www. and postmarketing analysis. Ann Emerg Med. 2014;64(1): drugs.com/pregnancy-categories.html. Accessed 19-25 e16. ­February 11, 2016.

8 may 2016

LWW-EMN_May 2016_Supplement_Sample.indd 8 07/04/16 3:55 PM