Original Research

Day Care Compared With Inpatient Management of Nausea and Vomiting of Pregnancy A Randomized Controlled Trial Fergus P. McCarthy, MD, PhD, Aileen Murphy, PhD, Ali S. Khashan, PhD, Brendan McElroy, PhD, Niamh Spillane, RGN, RM, Zibi Marchocki, MD, Rupak Sarkar, MD, and John R. Higgins, MD OBJECTIVE: To examine day care treatment of nausea and vomiting of pregnancy compared with the traditional inpatient management of this condition. METHODS: We conducted an open-label, single-center, randomized controlled trial to examine the differences between day care and inpatient management of pregnant women with nausea and vomiting of pregnancy. Primary outcome was total number of inpatient nights related to nausea and vomiting of pregnancy. RESULTS: Ninety-eight women were randomized to initial day care management (n542) or inpatient management (n556). Results are calculated from the time of randomization until resolution of nausea and vomiting of pregnancy. Women randomized to inpatient care experienced a median (interquartile range) of 2 (1–4) inpatient days compared with 0 (0–2) inpatient days for women randomized to day care (P,.001). Women randomized to initial treatment as an inpatient had significantly more median total number of inpatient admissions (one [1–2] compared with zero [0–1] admissions; P,.001) compared with women randomized to day care. No significant differences were observed in day care visits (median From the Anu Research Centre, Department of Obstetrics and Gynaecology, Cork University Maternity Hospital, Wilton, and the School of Economics, University College Cork, Cork, Ireland. Dr. McCarthy was funded by a PhD fellowship grant awarded by Molecular Medicine Ireland. The authors thank all the pregnant women who participated in the trial and all staff at Cork University Maternity Hospital for facilitating the trial process. Corresponding author: Fergus P. McCarthy, MD, PhD, Anu Research Centre, Department of Obstetrics and Gynaecology, Cork University Maternity Hospital, Wilton, Cork, Ireland; e-mail: [email protected] Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14

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[interquartile range] one [1–4] compared with two [1–4]; P5.30). Women randomized to inpatient care were as satisfied with their care as those randomized to day care (median [interquartile range]: 67 [57–69] compared with 63 [58–71] Client Satisfaction Questionnaire score; P5.7). CONCLUSION: Day care treatment of nausea and vomiting of pregnancy reduced hospital inpatient stay and was acceptable to patients. CLINICAL TRIAL REGISTRATION: ISRCTN http://www.isrctn.org, ISRCTN05023126.

Register,

(Obstet Gynecol 2014;124:743–8) DOI: 10.1097/AOG.0000000000000449

LEVEL OF EVIDENCE: I

U

p to 80% of all pregnant women experience some form of nausea and vomiting during pregnancy.1–3 Approximately 5% of women experience the more severe form of nausea and vomiting of pregnancy, termed hyperemesis gravidarum, which is defined by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, as persistent and excessive vomiting starting before the end of the 22nd week of gestation.4 Approximately 50% of women presenting with hyperemesis gravidarum will require inpatient treatment.5 Hyperemesis gravidarum is estimated to cost a minimum of $200 million annually in in-house hospitalizations in the United states alone.6 When other factors are taken into account such as emergency department treatments, potential complications of severe vomiting, and the fact that up to 35% of women with paid employment will lose time from work through nausea and vomiting, the actual cost of this condition to the economy is significantly higher.2,7–11 Historically the treatment of nausea and vomiting of pregnancy has been performed in an inpatient

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743

setting. Day care has proven to be a beneficial and safe mode of care for patients in other clinical settings such as preeclampsia.12 To examine the safety, efficacy, and outcomes of day care treatment of nausea and vomiting of pregnancy, we conducted an openlabel, single-center, randomized controlled trial of day care compared with inpatient treatment.

MATERIALS AND METHODS The trial was conducted at Cork University Maternity Hospital, a tertiary referral maternity hospital serving the southwest of Ireland, with more than 9,000 deliveries per year. Pregnant women were considered eligible for the trial if they had nausea and vomiting of pregnancy with two or more of the following criteria: ongoing viable intrauterine pregnancy before 22 weeks of gestation, persistent vomiting (more than three episodes of vomiting per 24 hours) not attributable to other causes, severe nausea not attributable to other causes, dehydration diagnosed by the presence of ketonuria, or electrolyte imbalance not attributable to other causes. Women with a confirmed urinary tract infection (midstream urine isolation of a single strain of uropathogen greater than 105 bacteria/mL) or with molar pregnancy or with nonviable pregnancies were excluded. Women who had already received treatment for nausea and vomiting of pregnancy outside of the trial or pregnant women who presented to the hospital but were not residents in the southwest of Ireland, that is, day care treatment would not have been an option, were also excluded. The study protocol was prepared in line with the Consolidated Standards of Reporting Trials (CONSORT) guidelines and is available online at www. ClinicalTrials.gov (NCT00795561).13,14 The trial protocol and all supporting trial documentation used are available in the Appendix, available online at http://links.lww.com/AOG/A549. Patients were allocated to the study groups by simple randomization. A computer-generated randomization list was drawn up by the study statistician (A.S.K.) and given to the trial coordinator (F.P.M.). F.P.M. then prepared the trial packs according to the randomization sequence. The trial packs consisted of 124 sealed, opaque, sequentially numbered envelopes. The trial packs were given to the recruiting physicians (Z.M. and N.S.) who were unaware of their contents. After informed written consent, the appropriate numbered envelope was opened by the recruiting physician in the presence of a staff midwife and the patient. The card inside indicated group assignment (day care or inpatient management). At recruitment, data were inserted to a prewritten trial ProForma by the recruiting

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physician or midwife. After delivery, charts were reviewed by the research midwife (N.S.) and all data inputted in a predetermined Excel spreadsheet. Although patients and physicians were not blinded to the study arms as a result of the nature of the intervention, the statistical analysis was performed in a blinded manner. The primary outcome was the number of inpatient nights spent in the hospital secondary to nausea and vomiting of pregnancy from initial presentation until 22 weeks of gestation. An inpatient night was defined as requiring an inpatient bed between the hours of 8:00 PM and 8:00 AM. Secondary outcomes included measuring quality of life using EQ-5D, total volume of intravenous fluids administered secondary to nausea and vomiting of pregnancy from initial presentation until 22 weeks of gestation, total amount of antiemetics administered secondary to nausea and vomiting of pregnancy from initial presentation until 22 weeks of gestation, total multivitamin complexes administered secondary to nausea and vomiting of pregnancy from initial presentation until 22 weeks of gestation, and patient satisfaction measured by the Client Satisfaction Questionnaire recorded after the first day care or inpatient treatment.15–17 The EQ-5D is a standardized instrument for use as a measure of health outcome (http://www. euroqol.org/). Other outcomes included neonate birth weight at delivery and gestational age at delivery. All patients underwent an ultrasound examination to confirm gestation and viability and to rule out multiple pregnancies and molar pregnancy. Day care treatment is the treatment of patients in the hospital as outpatients, avoiding admission to the hospital ward and overnight stay. It was performed ideally in the day care unit, which operates from 8:00 AM to 4:00 PM, Monday through Friday. Outside of these hours, patients received the day care protocol in the emergency department, which operates 24 hours per day 7 days per week, after which they returned home. Patients randomized to day care received 2 L of fluid (normal saline) intravenously over 5 hours. Antiemetics were administered when patients failed to respond to intravenous fluid administration. Antiemetics were administered using a standardized, pretyped stepwise drug ProForma (Appendix, http://links.lww. com/AOG/A549) on an as-needed basis. This included 10 mg metoclopramide stat intravenously until able to tolerate oral or 12.5 mg prochlorperazine orally, intramuscularly, as needed, or three times a day or 25 mg per rectum 12 hourly. If symptoms persisted or worsened despite maximum daily dose of metoclopramide or prochlorperazine, either 50 mg cyclizine orally or intramuscularly or 10 mg domperidone as needed or four times a day was administered. If symptoms

Management of Nausea and Vomiting of Pregnancy

OBSTETRICS & GYNECOLOGY

Fig. 1. Flow of participants recruited through the trial. McCarthy. Management of Nausea and Vomiting of Pregnancy. Obstet Gynecol 2014.

persisted or worsened despite maximum daily doses, 4 mg ondansetron twice a day intravenously or orally was administered.18–23 If the patient had prolonged nausea and vomiting of pregnancy, one ampule of multivitamin complexes was administered in 1 L of normal saline over 3 hours on a weekly basis. Admission of the patient was at the discretion of the attending physician. Patients randomized to inpatient admission received identical initial assessment followed by admission. Treatment after admission consisted of 1 L of fluid (normal saline) administered over 3 hours. The patient then received 1 L of fluid (normal saline) intravenously every 6 hours until able to tolerate oral fluids. Like with day care, antiemetics were considered when patients failed to respond to supportive management. Antiemetics were administered in the identical stepwise approach described previously. After admission, the decision for discharge was made by the managing obstetric team. The criteria for discharge were one or more of the following: less than three episodes of vomiting in a 24-hour period; the patient was able to tolerate oral fluids6food; or less than 2+ ketonuria on ward urine dipstick performed on the morning after admission. On discharge patients were instructed to represent if symptoms that led to the initial admission occurred again. Patients were treated until resolution of symptoms. On discharge after initial presentation, patients were asked to fill out a Client Satisfaction Questionnaire.

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After treatment in day care, the patient was reviewed by the managing physician. On their first discharge from day care, patients were asked to fill out a Client Satisfaction Questionnaire. Patients were instructed to present on a daily basis to the day care unit until resolution of symptoms. If the patient or managing physician felt that admission for inpatient treatment was necessary at any time, patients then were admitted for inpatient care as per the managing obstetric team. Before the start of our study, a retrospective chart review was conducted of 30 women who presented to Cork University Maternity Hospital with nausea and vomiting of pregnancy. The mean inpatient stay for women with nausea and vomiting of pregnancy of pregnancy was 3.5 days with a standard deviation of 1.47. To have an 80% statistical power of detecting a 1-day reduction in mean inpatient stay at P,.05 with a two-tailed test, we required 46 participants in each arm of the study. We anticipated that 25% of the participants would drop out from the study; therefore, the final sample size needed under the same assumptions was 62 patients in each group. The calculations were performed in Stata 10.0. All data analysis was carried out according to a preestablished statistical analysis plan. Data are reported as median and interquartile range or mean (standard deviation). If median was reported, the Mann-Whitney test was used for data analysis, whereas t test was used when the mean was reported.24 x2 test

Management of Nausea and Vomiting of Pregnancy 745

Table 1. Baseline Characteristics of Participants by Recruitment Status Characteristic Mean age (y) Irish nationality Nulliparous Current smoker (yes) No. of children Gestation at first presentation (wk) BMI (kg/m2) Medical conditions Diabetes Renal Hypertension Thyroid Other Hyperemesis in previous pregnancy (yes) Total days missed from usual activities secondary to nausea and vomiting of pregnancy (before randomization) Days before your first presentation to Cork University Maternity Hospital you vomited more than 3 times/d Days before your first presentation to Cork University Maternity Hospital you had severe nausea, ie, nausea that interferes with your daily activities Frequency of vomiting/d at first presentation Degree of ketonuria at recruitment 0 1+ 2+ 3+ 4+ Other remedies used for nausea and vomiting of pregnancy (yes) If yes, which remedy used Acupuncture Massage Ginger Chiropody Singleton pregnancy EQ-5D (visual analog scale)

Inpatient Care (n556)

Day Care (n542)

P

32.765.5 47 (83.9) 20 (35.7) 7 (13) 1 (0–1) 8 (7–10) 25.465.0

31.965.5 39 (92.6) 23 (54.8) 4 (10) 0 (0–1) 8 (7–11) 24.164.3

.45 .44 .14 .64 .20 .54 .18 .26

0 0 3 2 10 9 (16) 0 (0–8.5)

0 1 1 0 9 10 (24) 0 (0–7)

.34 .82

5 (3–14)

5 (2–14)

.75

9.5 (5–21)

10 (6–21)

.74

5 (4–10)

6 (4–8)

.68 .17

1 (2) 1 (2) 1 (2) 24 (43) 29 (52) 15 (27.3)

1 (2) 2 (4) 4 (10) 15 (36) 20 (48) 16 (38.1)

.26

1 1 13 1 52 (98.1) 4 (2–6)

2 1 14 0 39 (97.5) 3 (2–6)

.36 .87

BMI, body mass index. Data are mean6standard deviation, n (%), median (interquartile range), or n unless otherwise specified. If median was reported, Mann-Whitney was used for the test; t test was used when mean was reported. P values are for comparisons between the two groups using Student’s t test, Mann-Whitney test, or x2 test as appropriate, P,.05.

was used to compare proportions. Data were analyzed on an intention-to-treat basis. P,.05 was considered statistically significant. The study was approved by the Cork University Teaching Hospitals Clinical Research Ethics Committee (Reference ECM 5 [5] 02/09/09).

RESULTS One hundred four women were approached to participate in the trial, 98 of whom were recruited over a 35-month period between April 4, 2009, and the March 5, 2012. Although every effort was made to exclude women who did not intend to deliver at Cork University Maternity Hospital, four women

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moved from the area after receiving treatment for nausea and vomiting of pregnancy and delivered elsewhere (Fig. 1). One further patient was lost to follow-up resulting in pregnancy outcome data for 93 (95%) women. No significant differences were noted in demographics between those randomized to day care and those randomized to inpatient treatment (Table 1). Women randomized to initial inpatient care experienced a median of 2 inpatient days compared with 0 inpatient days for women randomized to day care (median [interquartile range] 2 [1–4] compared with 0 [0–2] days; P,.001) (Table 2) Some secondary outcomes differed between groups, whereas others did not (Table 2).

Management of Nausea and Vomiting of Pregnancy

OBSTETRICS & GYNECOLOGY

Table 2. Primary and Secondary Outcomes by Randomization Group Outcome No. of overnight stays Total no. of day care visits for hyperemesis gravidarum Total no. of inpatient admissions for hyperemesis gravidarum Client Satisfaction Questionnaire score Total liters of intravenous fluids administered Antiemetics used Patients who received Intravenous metoclopramide Oral metoclopramide Intramuscular prochlorperazine Oral prochlorperazine Intravenous cyclizine Oral cyclizine Oral domperidone Intravenous ondansetron Oral ondansetron Solvito or multivitamin administered Potassium chloride administered Gestational age at delivery (wk) Neonatal birth weight (g) Neonatal sex (female)

Inpatient Care (n556)

Day Care (n542)

P

2 (1–4) 1 (1–4) 1 (1–2) 67 (57–69) 5.5 (4–13) 40 (72.7)

0 (0–2) 2 (1–4) 0 (0–1) 63 (58–71) 4 (2–8) 34 (80.1)

,.001 .30 ,.001 .7 .01 .74

10 (18.2) 4 (7.3) 37 (67.3) 8 (14.6) 0 0 1 (1.8) 7 (13.0) 4 (7.3) 14 (25.4) 5 (9.1) 39 (38–40) 3,5566692 26 (50.1)

7 (16.7) 4 (9.5) 31 (73.8) 10 (24.4) 0 0 0 5 (11.9) 2 (4.8) 10 (23.8) 1 (2.4) 39 (38–40) 3,3276774 27 (71.1)

.85 .77 .61 .15 .1

Data are median (interquartile range), n (%), or mean6standard deviation unless otherwise specified. If median was reported, Mann-Whitney was used for the test; t test was used when mean was reported.

DISCUSSION This trial has demonstrated that initial treatment of nausea and vomiting of pregnancy in day care reduces hospital inpatient stay compared with inpatient treatment. Furthermore, day care was satisfactory to patients, as demonstrated by similar Client Satisfaction Questionnaire scores in both treatment arms. The provision of day care services resulted in the successful treatment for the majority of women randomized to day care with no resulting “rebound presentation” requiring prolonged admission. Day care may be acceptable and sufficient for the majority of women with nausea and vomiting of pregnancy, because 67% (28 of 42) of those women randomized to day care did not require any admission for further treatment. Seventy percent (39 of 56) of those women randomized to inpatient care received only one night of inpatient care, whereas 45% (25 of 56) women randomized to inpatient care presented at least one additional time for further treatment in day care. Our power calculation required us to recruit 92 patients in total. Initially we allowed for a 25% dropout. Therefore, at the start of this trial, we intended to recruit 128 patients. However, as the trial progressed, dropout was significantly lower than anticipated. Therefore, 98 patients in total were recruited. This change resulted in an uneven

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randomization of patients to treatment arms with 56 women being randomized to inpatient care and 42 being randomized to day care (recruitment to our full sample size would have lead to a 53–47% randomization proportion based on an evaluation of the group allocation in the unopened envelopes). This trial was not powered to examine adverse pregnancy outcomes in the two treatment arms; a much larger trial would be needed to evaluate such outcomes. In this trial we attempted to measure patient satisfaction through the use of the Client Satisfaction Questionnaire. These results should be interpreted with caution because day care patients completed their Client Satisfaction Questionnaire after their first day care treatment, whereas those randomized to inpatient care completed theirs before first discharge. Therefore, results may not be directly comparable. Also, the Client Satisfaction Questionnaire has not been validated in pregnancy. Overall, day care was a satisfactory place and mode of treatment for patients because only two patients randomized to day care informed the recruiting physician that they wished to opt out of the trial. In conclusion, the initial treatment of nausea and vomiting of pregnancy in day care reduces hospital inpatient stay, is satisfactory for patients, and is not associated with adverse outcomes.

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16. Attkisson CC, Greenfield TK. The Client Satisfaction Questionnaire (CSQ) scales and the Service Satisfaction Scale-30 (SSS-30). In Sederer LI, Dickey B, editors. Outcomes assessment in clinical practice. Baltimore (MD): Williams & Wilkins; 1995. p. 120–7.

4. World Health Organization. International statistical classification of diseases and related health problems, 10th Revision. Geneva (Switzerland): World Health Organization; 2007. 5. McCarthy FP, Khashan AS, North RA, Moss-Morris R, Baker PN, Dekker G, et al. A prospective cohort study investigating associations between hyperemesis gravidarum and cognitive, behavioural and emotional well-being in pregnancy. PloS One 2011;6:e27678. 6. Bailit JL. Hyperemesis gravidarium: epidemiologic findings from a large cohort. Am J Obst Gynecol 2005;193:811–4. 7. Chin RK, Lao TT. Low birth weight and hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1988;28:179–83. 8. Verberg MF, Gillott DJ, Al-Fardan N, Grudzinskas JG. Hyperemesis gravidarum, a literature review. Hum Reprod Update 2005;11:527–39. 9. Dodds L, Fell DB, Joseph KS, Allen VM, Butler B. Outcomes of pregnancies complicated by hyperemesis gravidarum. Obstet Gynecol 2006;107:285–92. 10. Weigel RM, Weigel MM. Nausea and vomiting of early pregnancy and pregnancy outcome. A meta-analytical review. Br J Obstet Gynaecol 1989;96:1312–8.

17. Attkisson CC, Greenfield TK. The Client Satisfaction Questionnaire-8 and the Service Satisfaction Scale-30. In: Maruish M, editor. The use of psychological testing for treatment planning and outcome assessment. Hillsdale (NJ): Lawrence Erlbaum Associates; 1994. p. 402–20. 18. Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. The Cochrane Database of Systematic Reviews 2003, Issue 9. Art. No.: CD000145. DOI: 10. 1002/14651858.CD000145.pub2. 19. Ismail SK, Kenny L. Review on hyperemesis gravidarum. Best Pract Res Clin Gastroenterol 2007;21:755–69. 20. Holmgren C, Aagaard-Tillery KM, Silver RM, Porter TF, Varner M. Hyperemesis in pregnancy: an evaluation of treatment strategies with maternal and neonatal outcomes. Am J Obstet Gynecol 2008;198:56.e1–4. 21. Källén B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002;11: 146–52.

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Management of Nausea and Vomiting of Pregnancy

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Day care compared with inpatient management of nausea and vomiting of pregnancy: a randomized controlled trial.

To examine day care treatment of nausea and vomiting of pregnancy compared with the traditional inpatient management of this condition...
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