Treatment of Severe Nausea and Vomiting of Pregnancy with Subcutaneous Medications

Transcription

1 Treatment of Severe Nausea and Vomiting of Pregnancy with Subcutaneous Medications Chad K. Klauser, M.D., 1,2 Nathan S. Fox, M.D., 1,2 Niki Istwan, R.N., 3 Debbie Rhea, M.P.H., 3 Andrei Rebarber, M.D., 1,2 Cheryl Desch, R.N., M.S., 3 Beverly Palmer, R.Ph., 3 and Daniel Saltzman, M.D. 1,2 ABSTRACT We examined treatment outcomes in women with severe nausea and vomiting of pregnancy (NVP) receiving outpatient nursing support and either subcutaneous metoclopramide or subcutaneous ondansetron via a microinfusion pump. Among women receiving outpatient nursing services, we identified those diagnosed with severe NVP having a Pregnancy-Unique Quantification of Emesis (PUQE) score of greater than 12 at enrollment and prescribed either metoclopramide (n ¼ 355) or ondansetron (n ¼ 521) by their physician. Maternal characteristics, response to treatment, and start versus stop values were compared between the medication groups. Allocation to group was based on intention-totreat protocol. Maternal characteristics were similar between the groups. Days to reduction in PUQE score levels were similar (median 2 days, metoclopramide; 3 days, ondansetron; p ¼ 0.206). Alteration from metoclopramide to ondansetron (31.8%) was more frequent than alteration from ondansetron to metoclopramide (4.4%; p < 0.001). Improvement of NVP symptoms and reduced need for hospitalization was noted with both medications. Treatment with either metoclopramide or ondansetron resulted in significant improvement of NVP symptoms with half of women showing a reduction from severe symptoms to moderate or mild symptoms within 3 days of treatment initiation. Alteration in treatment was significantly greater in patients initially prescribed metoclopramide. KEYWORDS: NVP, nausea and vomiting of pregnancy, subcutaneous metoclopramide, subcutaneous ondansetron Nausea and vomiting of pregnancy (NVP) is considered one of the most common complications in pregnancy, affecting 50 to 90% of women. 1,2 Symptoms of NVP range from mild to the more severe hyperemesis gravidarum, which affects up to 2% of pregnancies. 3,4 Severe NVP has a negative impact on a women s quality of life. 5,6 The social and psychological impacts of NVP include reduced job efficiency, lost work time, negative impact on family relationships and mental health, and occasionally a termination of an otherwise desired pregnancy. The severity of NVP can be assessed using an index called the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE). The PUQE score is based on three physical symptoms of NVP: the extent of nausea per day in hours; the quantity of daily retching/ 1 Maternal Fetal Medicine Associates, PLLC; 2 Mount Sinai Medical Center, Obstetrics and Gynecology, New York, New York; 3 Alere Health, Women s and Children s Health, Department of Clinical Research, Atlanta, Georgia. Address for correspondence and reprint requests: Niki Istwan, R.N., Alere Women s and Children s Health, 3200 Windy Hill Road; Suite B-100, Atlanta, GA ( niki.istwan@ alere.com). Am J Perinatol 2011;28: Copyright # 2011 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) Received: January 21, Accepted after revision: March 10, Published online: June 10, DOI: ISSN

2 716 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 28, NUMBER dry heaves episodes; and the number of daily vomiting episodes in the past 12 hours. 7 The PUQE s total score ranges between 3 and 15, with three to six representing mild NVP; 7 to 12, moderate NVP; and >12, severe NVP. 7 Treatment for women with NVP depends on the severity of symptoms. 8 Initial care for milder forms of NVP includes dietary changes, alternative and complementary therapies, and first-line antiemetic medications. 8,9 If the patient does not respond to these initial interventions, dehydration may occur and intravenous (IV) fluid replacement may be initiated. If NVP persists, more aggressive interventions such as prolonged hospitalization, total parenteral nutrition (TPN), and/or continuous subcutaneous antiemetic therapy may be prescribed. Subcutaneous metoclopramide and ondansetron are among antiemetic medications used by many obstetricians in the treatment of severe NVP. The decision regarding which antiemetic medication to prescribe is typically based on the patient s medical history, response to previous antiemetics, and physician preference. The purpose of this analysis was to examine treatment outcomes in women with severe NVP enrolled in an outpatient program providing nursing support and antiemetic therapy with either continuous subcutaneous metoclopramide or ondansetron therapy via a microinfusion pump. METHODS The study sample for this observational analysis was identified retrospectively from a large centralized database containing deidentified clinical information collected from women throughout the United States receiving outpatient perinatal nursing services through Alere Health. The Women s and Children s Health Division of Alere Health provides outpatient nursing services for conditions that place a pregnancy at risk for adverse outcome. The NVP program is comprehensive and aimed at helping pregnant women alleviate symptoms of severe NVP, correcting hydration and electrolyte balance, stabilizing weight loss, maintaining adequate nutrition, and, thus, reducing the need for hospitalization. Referral for outpatient NVP management was made by each patient s health care provider, and outpatient services were in addition to routine prenatal care. The health care provider prescribed continuous subcutaneous metoclopramide or ondansetron therapy after other first-line treatment options failed to provide relief from severe NVP symptoms. The decision regarding which antiemetic to prescribe was based on physician preference, maternal medical history, and payer formulary. At initiation of therapy, informed consent was obtained from each patient acknowledging their understanding of antiemetic therapy including potential risks of therapy. Written permission was also received allowing the use of their deidentified personal health information for research and reporting activities. For this analysis, we identified database records of pregnant women enrolled in the outpatient NVP program between January 2006 and September 2007 who were prescribed either continuous subcutaneous metoclopramide or continuous subcutaneous ondansetron. Women diagnosed with severe NVP by their physician and having a PUQE score of >12 at initiation of outpatient services were selected for analysis. While enrolled in the program, data were collected prospectively for medication usage, dosage, treatment responses, side effects, and hospitalizations. Pregnancy outcomes were collected from the mother postdelivery. At the initiation of outpatient NVP services, a home visit was conducted by a skilled perinatal nurse. During the home visit, maternal, fetal, and environmental assessments were performed including an education session regarding the patients clinical condition. Dietary consultation with nutritional management for the special individual needs of each patient was also included. Throughout enrollment, telephonic nursing assessments were performed on a daily and as-needed basis. Severity of NVP symptoms, intake and output, maternal weight, urine ketones, antiemetic medication compliance, and presence of any medication side effects were assessed. Emotional support and encouragement were also provided as needed. To assess response to treatment, the patient s PUQE score was calculated each day by assessing the extent of the nausea in hours, the quantity of daily retching/ dry heave episodes, and the number of daily vomiting episodes. The prescribed antiemetic medication (metoclopramide or ondansetron) was administered subcutaneously via a continuous microinfusion pump. Individualized dosing of metoclopramide or ondansetron infusion was provided per internally validated, weight-based dosing guidelines and/or per obstetric pharmacist consult. An optional initial intramuscular, IV, or subcutaneous loading dose was given based on presence or timing of previous antiemetics received. Ongoing adjustments in continuous infusion rate and utilization of demand or scheduled bolus doses were based on the patient s symptoms and/or side effects. The infusion rate was maintained once the patient reported cessation of severe NVP symptoms and then decreased, as the patient was able to tolerate fluids and food orally. Subcutaneous medication and outpatient services were discontinued once adequate oral nutrition was established, or per patient or physician request. Each patient received instruction on management of the infusion device, site care, and syringe changes. Adjunctive IV hydration therapy was administered as needed per physician orders. Home delivery of medication, equipment, and supplies was provided as part of the program. Highrisk obstetric nurse and obstetric pharmacist support for

3 TREATMENT OF SEVERE NVP WITH SUBCUTANEOUS MEDICATIONS/KLAUSER ET AL 717 primary and adjunct medication dosing consultation was also available 24 hours, 7 days per week. Detailed clinical reports were provided to the physicians and case managers weekly and as needed. When initiating subcutaneous metoclopramide infusion therapy, a loading dose of 5 to 10 mg may be utilized, followed by a continuous daily infusion ranging from 20 to 40 mg/d (typically 30 mg/d). Dosages may be titrated up or down, based on patient response or tolerance, and are usually titrated in increments of 6 mg/d. Demand boluses of 2 to 5 mg may be administered for acute episodes of nausea and/or vomiting. Subcutaneous ondansetron infusion is initiated with a loading dose of 2 to 8 mg, followed by a continuous daily infusion ranging from 16 to 28 mg/d (usually 24 mg/d). Dosages are titrated in increments of 4 mg/d, with demand boluses of 1 to 2 mg are given as needed per patient response. Maternal characteristics and response to treatment were compared between women receiving continuous subcutaneous metoclopramide versus ondansetron therapy via a microinfusion pump using Mann- Whitney U and Pearson chi-square statistics. Clinical characteristics at initiation of treatment and end of treatment were compared within each medication group using Wilcoxon signed ranks and McNemar chi-square statistics. Allocation to group was based on intention-to-treat protocol. A p value of < 0.05 was considered significant. RESULTS Records for 876 women receiving continuous subcutaneous metoclopramide (n ¼ 355) or subcutaneous ondansetron (n ¼ 521) for treatment of severe NVP (PUQE > 12) were examined. Maternal characteristics are presented in Table 1. Women receiving metoclopramide or ondansetron had a similar mean age at treatment Table 1 initiation of years and years, respectively. Marital status, nulliparity, prepregnancy weight, history of eating disorders or thyroid dysfunction, and rate of smoking were also similar between the groups. No difference in the rate of twin gestation was observed with 4.5% in the metoclopramide group and 4.2% in the ondansetron group. Approximately half of the women in each group had a history of hyperemesis in a previous pregnancy (47.6% of women prescribed metoclopramide therapy and 53.7% prescribed ondansetron, p ¼ 0.074). Not surprisingly, women prescribed metoclopramide were less likely to have a history of depression than those prescribed ondansetron (14.6% versus 20.3%, p ¼ 0.031). The NVP treatment profile is presented in Table 2. The mean gestational age at start of treatment was weeks among women in the metoclopramide group versus weeks among women in the ondansetron group. The mean number of treatment days until marked improvement of NVP symptoms (PUQE score in the severe range to scores in the moderate or mild range) was similar between the medication groups: days in the metoclopramide group versus days in the ondansetron group (p ¼ 0.206). The total number of treatment days was in the metoclopramide group versus in the ondansetron group (p ¼ 0.008). Women receiving ondansetron were more likely to receive adjunctive IV hydration (50.1% versus 42.3%; p ¼ 0.022) or TPN (6.0% versus 2.3%; p ¼ 0.009) than women receiving metoclopramide. Women receiving metoclopramide were more likely to have an alteration of treatment to ondansetron (31.8% versus 4.4%, n p < 0.001). NVP treatment outcomes within each medication group are presented in Table 3. Improvement of NVP symptoms measured by PUQE score was noted with both metoclopramide (PUQE score at start to Comparison of Maternal Characteristics for Metoclopramide versus Ondansetron Groups Metoclopramide (n ¼ 355) Ondansetron (n ¼ 521) p Value Maternal age (y) (16, 41) 29 (17, 47) Married (%) Smoker (%) Primigravida (%) Twin gestation (%) Hyperemesis in previous pregnancy (%) History of eating disorder (%) History thyroid dysfunction (%) History of depression (%) Prepregnancy weight (lbs) (88, 309) 152 (89, 334) Data presented as mean standard deviation, median (min, max), or percentage as indicated.

4 718 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 28, NUMBER Table 2 NVP Treatment Profile Metoclopramide (n ¼ 355) Ondansetron (n ¼ 521) p Value GA at treatment initiation (wk) (5.9, 23.9) 10.3 (5.4, 23.7) GA at stop of treatment (wk) (7.0, 39.1) 17.0 (7.0, 40.9) Days to symptom improvement (severe NVP to moderate or mild) (1, 132) 3 (1, 41) Days of NVP treatment (1, 202) 46 (2, 216) Adjunctive IV hydration at home (%) Adjunctive TPN at home (%) PRN adjunctive use of herbs, antacids, acid blockers, or other oral antiemetics (%) Alteration of NVP treatment (%) <0.001 Data presented as mean standard deviation, median (min, max), or percentage as indicated. GA, gestational age; NVP, nausea and vomiting of pregnancy; TPN, total parenteral nutrition at stop, p < 0.001) and ondansetron medication (PUQE score at start to at stop, p < 0.001). Maternal weight increased significantly from start to stop of treatment in both medication groups from to pounds in the metoclopramide group and from to pounds in the ondansetron group. Urine ketones 1 þ decreased significantly in both groups from 24.8 to 4.8% among women receiving metoclopramide and from 29.4 to 4.8% in women with ondansetron. The ability to tolerate a regular diet improved from 9.0% at treatment initiation to 34.9% treatment discontinuation of women in the metoclopramide group and from 4.0 to 28.6% in the Table 3 Outcomes of NVP Treatment with Metoclopramide or Ondansetron ondansetron group, both p < Prior to initiation of outpatient subcutaneous antiemetic therapy, 67.0% of metoclopramide patients and 74.1% of ondansetron patients were hospitalized for at least 24 hours. Once enrolled for outpatient nursing services and subcutaneous antiemetics, the percent of patients requiring rehospitalization decreased significantly: in the metoclopramide group from 67.0% prior to enrollment to 14.4% during treatment and in the ondansetron group from 74.1% prior to enrollment to 19.2% during treatment (both p < 0.001). Treatment alteration, defined as discontinuation of one medication and immediate initiation of the Start NVP Treatment Stop NVP Treatment p Value PUQE score Metoclopramide <0.001 Median (min, max) 15 (13, 15) 4 (3, 14) Ondansetron <0.001 Median (min, max) 15 (13, 15) 5 (3, 15)* Maternal weight (lbs) Metoclopramide <0.001 Median (min, max) 148 (81, 294) 151 (89, 288) Ondansetron <0.001 Median (min, max) 144 (82, 319) 151 (85, 320) Urine ketones 1 þ (%) Metoclopramide <0.001 Ondansetron <0.001 Regular diet (%) Metoclopramide <0.001 Ondansetron 4.0* 28.6 <0.001 *p < 0.05 metoclopramide versus ondansetron groups. Data presented as mean standard deviation, median (min, max), or percentage as indicated. NVP, nausea and vomiting of pregnancy; PUQE, Pregnancy-Unique Quantification of Emesis.

5 TREATMENT OF SEVERE NVP WITH SUBCUTANEOUS MEDICATIONS/KLAUSER ET AL 719 other, occurred at a higher rate in women initially prescribed metoclopramide than those initially prescribed ondansetron. Almost one-third (31.8%) of women initially prescribed metoclopramide were transitioned to ondansetron, and only 4.4% transitioned from ondansetron to metoclopramide. We further examined within the metoclopramide group reasons for medication change and if there were differences in maternal characteristics between those remaining on metoclopramide (n ¼ 242) compared with those with treatment alteration to ondansetron (n ¼ 113). For those women with an alteration from metoclopramide to ondansetron, the mean days to treatment alteration was At time of medication change, 32/113 (28.3%) continued to have PUQE scores in the severe range, and 26/113 (23.0%) reported medication side effects. Compared with those remaining on metoclopramide, women with treatment alteration were at an earlier gestational age at metoclopramide initiation (median, 9.7 versus 11.0 weeks, p ¼ 0.011), less likely to be tolerating any solid food at NVP program enrollment (16.8% versus 5.8%, p ¼ 0.001), and more likely to require IV hydration (58.4% versus 34.7%, p < 0.001) or TPN (5.3% versus 0.8%, p ¼ 0.008). Maternal age, multiple gestation, smoking, nulliparity, prepregnancy weight, weight loss, history of hyperemesis, eating disorder, thyroid dysfunction or depression, PUQE score, and ketonuria at start of treatment were similar between the groups with or without treatment alteration. DISCUSSION Although mild to moderate nausea and vomiting are common and often expected pregnancy complications, severe and prolonged NVP is a debilitating condition with both psychosocial and physiological consequences. In the present study, we examined records for women with severe NVP (PUQE score > 12) who failed to find relief with first-line treatment options. We found that treatment with either metoclopramide or ondansetron via continuous subcutaneous infusion administered within a program of daily telephonic nursing support and clinical pharmacy intervention resulted in significantly reduced symptoms of NVP. The treatment of NVP in the home is not unprecedented. Naef et al conducted a retrospective, matched control study to evaluate whether medical therapy in the home for patients with hyperemesis was safe and effective compared with hospitalization. 10 They found that management in the home was safe, effectual, and cost-effective. The use of outpatient continuous subcutaneous antiemetics in women with NVP has also been reported by other authors. In 2000, Buttino et al described the use of continuous subcutaneous metoclopramide within a comprehensive outpatient program for the treatment of women with hyperemesis gravidarum. 11 Continuous subcutaneous metoclopramide was prescribed to 646 women after other first-line treatments failed, though PUQE scores at initiation of treatment were not reported. Along with continuous subcutaneous administration of medication, patients enrolled in the outpatient program received individualized dietary instruction, daily and as-needed telephone assessment and support by a perinatal nurse, and home nursing visits as needed. Mean gestational age at initiation of continuous subcutaneous metoclopramide was weeks and the mean gestational age at treatment discontinuation was weeks. Treatment outcomes showed that 63.9% of women reported complete resolution of their hyperemesis symptoms during treatment with metoclopramide. During treatment, 6.7% of women required hospitalization, 6.2% required IV hydration, and 1.9% required TPN, compared with the 14.4% requiring hospital admission, 42.3% receiving IV hydration, and 2.3% receiving TPN in the present study. We believe these differences are due to the documented severe level of hyperemesis symptoms in patients selected for the present study, while the prior report did not stratify results based on symptom severity. In 2004, Lombardi et al described the clinical and economic outcomes of 428 patients diagnosed with NVP and enrolled in an outpatient program utilizing nursing support and subcutaneous metoclopramide. 12 The mean PUQE score at initiation of treatment was , 45% lower than the score for women receiving metoclopramide in the present study. Improvement in symptoms was achieved in 89.3% of women and 10.7% required alteration of therapy to subcutaneous ondansetron. Patients failing metoclopramide treatment were more likely to have PUQE scores of 13 or more at treatment initiation and were at an earlier gestational age at treatment initiation than those women with successful treatment. Outpatient management of NVP was determined to be cost-effective through reduced need for hospitalization. Metoclopramide and ondansetron are frequently prescribed for the management of nausea and vomiting in many different patient populations. In the present study, we have shown both medications to be effective in reducing NVP symptoms and need for recurrent hospitalization in women with severe symptoms. We did find that a greater number of women initially prescribed metoclopramide had an alteration of treatment to ondansetron. This finding, taken in context with those of Lombardi et al, 12 may support a decision to choose ondansetron over metoclopramide in women presenting with severe NVP symptoms. We believe this also speaks to the unique character of NVP symptoms in that each patient may respond differently to treatment and that indeed one size does not fit all when it comes to their

6 720 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 28, NUMBER management. Often when determining which treatment to initially prescribe, the clinician examines the patient s history to identify any contraindications to either medication. Contraindications for metoclopramide include gastric hemorrhage, perforation or obstruction, seizure disorder, or pheochromocytoma. Warnings and precautions relative to the use of metoclopramide include a risk for depression, extrapyramidal symptoms, Parkinsonlike symptoms, and fluid retention. The risk for development of tardive dyskinesia increases with duration of treatment >12 weeks and high total cumulative dose. Other than known ondansetron hypersensitivity, there are no specific contraindications to the use of ondansetron. Reported side effects such as diarrhea, constipation, headache, dizziness, and fatigue have been reported with the use of ondansetron. 13 When making a treatment decision, a payer s formulary may also be a determining or limiting factor regarding which medication is prescribed. As with any medication given during pregnancy, safety is of utmost importance. Metoclopramide and ondansetron are both classified as FDA Pregnancy Category B. A recent study investigating the safety of metoclopramide use during the first trimester of pregnancy found that among a large cohort of 3458 women, exposure to metoclopramide was not associated with significantly increased risk of severe adverse outcomes including major congenital malformations, low birth weight, preterm delivery, or perinatal death. 14 In another study, Berkovitch et al conducted a prospective multicenter international study investigating the effect of metoclopramide on the fetus. 15 They found that rates of major malformations in the metoclopramide group did not differ from the control group and metoclopramide exposure did not appear to be associated with an increased risk of malformations, spontaneous abortions, or decreased birth weights. 15 Sørensen et al also examined the safety of metoclopramide during pregnancy and found no increase in risk of adverse pregnancy outcomes. 16 In a randomized controlled trial by Tan et al, the authors compared intravenous promethazine with intravenous metoclopramide for hyperemesis in hospitalized patients. 17 Although there were no significant differences in therapeutic effects, the adverse effects profile was better with metoclopramide, and therapy was less likely to be curtailed. There is limited information regarding the use of ondansetron during pregnancy. A prospective comparative observational study conducted by Einarson et al examined the safety of ondansetron for NVP in 176 pregnancies. 18 In a comparison of three groups of women who were exposed to (1) ondansetron, (2) other antiemetics, or (3) drugs considered safe in pregnancy or who had not used any medications, they found no statistical differences between the three groups for live births, miscarriages, stillbirths, therapeutic abortions, gestational age, or risk of major malformations. 18 Therapeutic effectiveness was not compared. The present study is unique in that our purpose was to examine treatment outcomes in women with severe NVP enrolled for outpatient nursing support and treated with metoclopramide or ondansetron using PUQE scores to measure physical symptoms of NVP. We acknowledge that the retrospective, nonrandomized, descriptive design of our study limits our ability to make conclusions regarding superiority of one medication versus the other. We are unable to prove that either intervention is effective or ineffective without a control group of women with similar severity of NVP who did not receive either treatment. Lack of information regarding specific medication side effects or long-term infant outcomes limits our ability to speak to safety of either medication. As all patients received treatment within a specially designed outpatient NVP program that included both telephonic nursing and clinical pharmacy support, we do not know how either medication might perform without this high level of outpatient supervision. The etiology of NVP remains largely unknown. NVP affects each woman differently. In view of its potential complexity, health care providers should be well informed about the condition and a multimodal approach to its management employed, including dietary and lifestyle advice, psychosomatic counseling and support, antiemetic drugs, and IV fluid and nutritional replacement as needed. 1 Treatment decisions are based on severity of symptoms and tailored for each patient s clinical presentation and specific psychosocial circumstances. A recent (2010) meta-analysis of RCTs for NVP interventions by Matthews et al examined the effectiveness and safety of interventions for NVP including antiemetic drugs. 19 They were unable to pool findings from the studies for most outcomes due to heterogeneity in study participants, interventions, comparison groups, and outcomes measured or reported. Telephone-care management strategies and health coaching designed to promote patients self-management skills have been shown to reduce medical costs and hospitalizations in patients with select medical conditions. 20 There is also evidence that consultation with clinical pharmacists can promote optimal medication therapy and improve patient outcomes in the outpatient setting. 21 In the present study, we have shown statistically significant improvement in key clinical measures (weight gain, ketonuria, PUQE scores, and hospitalizations) in women with severe NVP enrolled in an outpatient program with telephonic nursing and pharmacist support and using either subcutaneous metoclopramide or ondansetron. A comprehensive outpatient NVP management program utilizing either continuous subcutaneous metoclopramide or ondansetron therapy allows for close follow-up of patient symptoms and is a viable treatment option for women suffering with severe NVP.

7 TREATMENT OF SEVERE NVP WITH SUBCUTANEOUS MEDICATIONS/KLAUSER ET AL 721 NOTE Presented at the 57th Annual Meeting of the American College of Obstetricians and Gynecologists. Chicago, Illinois, May 2 to 6, REFERENCES 1. Jueckstock JK, Kaestner R, Mylonas I. Managing hyperemesis gravidarum: a multimodal challenge. BMC Medicine 2010;8: 46. Available at: 8/46. Accessed November 24, Miller F. Nausea and vomiting in pregnancy: the problem of perception is it really a disease? Am J Obstet Gynecol 2002;186(5, Suppl Understanding):S182 S Eliakim R, Abulafia O, Sherer DM. Hyperemesis gravidarum: a current review. Am J Perinatol 2000;17: Goodwin TM. Hyperemesis gravidarum. Obstet Gynecol Clin North Am 2008;35: ; viii 5. Attard CL, Kohli MA, Coleman S, et al. The burden of illness of severe nausea and vomiting of pregnancy in the United States. Am J Obstet Gynecol 2002;186(5, Suppl Understanding):S220 S Lacasse A, Rey E, Ferreira E, Morin C, Bérard A. Nausea and vomiting of pregnancy: what about quality of life? BJOG 2008;115: Koren G, Boskovic R, Hard M, Maltepe C, Navioz Y, Einarson A. Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol 2002;186(5, Suppl Understanding):S228 S Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med 2010;363: American College of Obstetrics and Gynecology. ACOG (American College of Obstetrics and Gynecology) Practice Bulletin: nausea and vomiting of pregnancy. Obstet Gynecol 2004;103: Naef RW III, Chauhan SP, Roach H, Roberts WE, Travis KH, Morrison JC. Treatment for hyperemesis gravidarum in the home: an alternative to hospitalization. J Perinatol 1995;15: Buttino L Jr, Coleman SK, Bergauer NK, Gambon C, Stanziano GJ. Home subcutaneous metoclopramide therapy for hyperemesis gravidarum. J Perinatol 2000;20: Lombardi DG, Istwan NB, Rhea DJ, O Brien JM, Barton JR. Measuring outpatient outcomes of emesis and nausea management in pregnant women. Manag Care 2004;13: Drugs.com. Ondansetron side effects. Available at: Accessed May 23, Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med 2009;360: Berkovitch M, Mazzota P, Greenberg R, et al. Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study. Am J Perinatol 2002;19: Sørensen HT, Nielsen GL, Christensen K, Tage-Jensen U, Ekbom A, Baron J. ; Euromap Study Group. Birth outcome following maternal use of metoclopramide. The Euromap study group. Br J Clin Pharmacol 2000;49: Tan PC, Khine PP, Vallikkannu N, Omar SZ. Promethazine compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol 2010;115: Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG 2004; 111: Matthews A, Dowswell T, Haas DM, Doyle M, O Mathúna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010:CD Wennberg DE, Marr A, Lang L, O Malley S, Bennett G. A randomized trial of a telephone care-management strategy. N Engl J Med 2010;363: Altavela JL, Jones MK, Ritter M. A prospective trial of a clinical pharmacy intervention in a primary care practice in a capitated payment system. J Manag Care Pharm 2008;14: