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  • 1. The n e w e ng l a n d j o u r na l of m e dic i n e clinical practice Nausea and Vomiting in Pregnancy Jennifer R. Niebyl, M.D. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 25-year-old woman presents with persistent nausea and vomiting 8 weeks after her last menstrual period in her first pregnancy. Her primary care provider is reluctant to give her medications. She has lost 5 lb (2.3 kg) in 6 weeks. How should she be treated? The Cl inic a l Probl emFrom the Department of Obstetrics and About 50% of women have nausea and vomiting in early pregnancy, and an addi-Gynecology, University of Iowa Hospitals tional 25% have nausea alone.1,2 The popular term “morning sickness” is a misno-and Clinics, Iowa City. Address reprintrequests to Dr. Niebyl at the Department mer, since this condition often persists throughout the day.2 In about 35% of wom-of Obstetrics and Gynecology, University en who have this condition, nausea and vomiting are clinically significant, resultingof Iowa Hospitals and Clinics, 200 in lost work time and negatively affecting family relationships.3,4 In a small minor-Hawkins Dr., Iowa City, IA 52242, or atjennifer-niebyl@uiowa.edu. ity of patients, the symptoms lead to dehydration and weight loss requiring hospi- talization.5 The reported incidence of hyperemesis gravidarum is 0.3 to 1.0%; thisN Engl J Med 2010;363:1544-50. condition is characterized by persistent vomiting, weight loss of more than 5%,Copyright © 2010 Massachusetts Medical Society. ketonuria, electrolyte abnormalities (hypokalemia), and dehydration (high urine specific gravity).5,6 Although the cause of nausea and vomiting in pregnancy is unclear, the obser- vation that pregnancies with a complete hydatidiform mole (no fetus) are associ- ated with clinically significant nausea and vomiting indicates that the stimulus is produced by the placenta, not the fetus. The onset of the nausea is within 4 weeks An audio version after the last menstrual period in most patients. The problem typically peaks at of this article approximately 9 weeks of gestation. Sixty percent of cases resolve by the end of is available at the first trimester, and 91% resolve by 20 weeks of gestation.1 Nausea and vomit- NEJM.org ing are less common in older women, multiparous women, and smokers; this observation has been attributed to the smaller placental volumes in these women. In one study, 63% of multiparous women who had nausea and vomiting also had symptoms in a previous pregnancy.1 Nausea and vomiting are associated with a decreased risk of miscarriage.7 The clinical course of nausea and vomiting during pregnancy correlates closely with the level of human chorionic gonadotropin (hCG) (Fig. 1).8 It is theorized that hCG may stimulate estrogen production from the ovary; estrogen is known to increase nausea and vomiting. Women with twins or hydatidiform moles, who have higher hCG levels than do other pregnant women, are at higher risk for these symptoms. Another theory is that vitamin B deficiency may contribute, since the use of multivitamins containing vitamin B reduces the incidence of nausea and vomiting. Although it has been suggested that nausea and vomiting may be caused by psychological factors, there are no good data to support this. Preventable rare maternal complications of hyperemesis gravidarum include1544 n engl j med 363;16 nejm.org october 14, 2010 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 2. clinical pr acticeperipheral neuropathies due to vitamin B6 andB12 deficiencies and, most serious, Wernicke’s 90,000encephalopathy due to thiamine (vitamin B1) 80,000deficiency.9 Characterized by the triad of oph- 70,000thalmoplegia, gait ataxia, and confusion, this hCG hCG (mIU/ml) 60,000condition may occur after at least 3 weeks of 50,000persistent vomiting. If patients are treated with 40,000intravenous dextrose without thiamine, metabo- 30,000 Nausea and 20,000lism of the dextrose rapidly consumes the avail- vomiting 10,000able B1, triggering acute encephalopathy. In one 0case series involving 19 patients in whom this 4 5 6 7 8 9 10 11 12 13 14 15 16 17complication developed, 74% had neurologic ab- Week of Peak Symptomsnormalities on follow-up.9 In some cases, the Figure 1. Relation between Peak Nausea and Vomiting Symptoms and Humandiagnosis is made only at autopsy. Chorionic Gonadotropin (hCG) Levels. Infants of mothers who have lost weight inearly pregnancy, as compared with infants ofwomen whose weight increased or stayed the emesis do not have clinical findings of Graves’same, have lower mean birth weights and lower disease or thyroid antibodies.13 If the level of freepercentile weights for gestational age, and they T4 is elevated in the absence of other evidence ofare more likely to be in less than the 10th per- Graves’ disease, this test should be repeated latercentile of birth weight at delivery.10 in gestation, at around 20 weeks’ gestation, since the level usually normalizes by then in the ab- S t r ategie s a nd E v idence sence of hyperthyroidism.13 Ultrasonographic test- ing should be performed to detect multiple gesta-Evaluation tion or hydatidiform mole.Hyperemesis gravidarum must be distinguishedfrom other conditions that may cause persistent Managementvomiting in pregnancy, including gastrointesti- Women should be advised to avoid exposure tonal conditions (e.g., appendicitis, hepatitis, pan- odors, foods, or supplements that appear to trig-creatitis, or biliary tract disease), pyelonephritis, ger nausea14; common triggers include fatty orand metabolic disorders such as diabetic ketoaci- spicy foods and iron tablets. Clinical experiencedosis, porphyria, or Addison’s disease. An onset suggests that eating small amounts of food sev-of nausea and vomiting more than 8 weeks after eral times a day and drinking fluids betweenthe last menstrual period is rare in pregnancy.1 meals may be helpful, as may bland, dry, andThe presence of fever, abdominal pain, or head- high-protein foods.15 Traditionally, patients haveache is atypical in women with hyperemesis and been advised to manage nausea by keeping crack-suggests another cause. Laboratory testing should ers at the bedside in the morning and avoidinggenerally include measurement of levels of urinary an empty stomach. Data from randomized trialsketones, blood urea nitrogen, creatinine, alanine are lacking to compare different types of dietsaminotransferase, aspartate aminotransferase, for the management of nausea and vomiting inelectrolytes, amylase, and thyrotropin (as well as pregnancy. In one crossover study involving 14free thyroxine [T4] if thyrotropin is suppressed). pregnant women with nausea, protein-predomi- Because hCG cross-reacts with thyrotropin and nant meals reduced nausea more than mealsstimulates the thyroid gland, thyrotropin is typi- containing equal amounts of calories from car-cally suppressed in these patients. This apparent bohydrates and fat or noncaloric meals.16hyperthyroidism usually resolves spontaneously, Women who have persistent nausea and vom-and treatment with propylthiouracil does not al- iting and high concentrations of ketones requireleviate the nausea and vomiting.11 Patients with intravenous hydration with multivitamins, in-primary hyperthyroidism rarely have vomiting.12 cluding thiamine, with follow-up measurementThe levels of T4 and thyrotropin in patients with of levels of urinary ketones and electrolytes.hyperemesis may be similar to those in patients Antiemetic agents should be prescribed in thesewith Graves’ disease, but patients with hyper- patients (Fig. 2).17 n engl j med 363;16 nejm.org october 14, 2010 1545 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 3. The n e w e ng l a n d j o u r na l of m e dic i n e severe symptoms) was 4.3 for women receiving active treatment versus 1.8 for controls. Also, in Initiate treatment with vitamin B6 the Hungarian Family Planning Program, a peri- conceptional multivitamin trial,20 women ran- domly assigned before conception to a daily multivitamin (containing vitamin B6, 2.6 mg) were Add doxylamine significantly less likely than those randomly as- signed to placebo to report nausea, vomiting, and vertigo (3.4% vs. 7.4%) or to require a physician visit for nausea and vomiting (3.0% vs. 6.6%).20 Substitute promethazine or dimenhydrinate for doxylamine However, in another prospective study, there was no correlation between serum vitamin B6 levels and the occurrence of morning sickness.21 A combination of vitamin B6 and the antihis- tamine doxylamine (Bendectin) was removed from No dehydration Dehydration the U.S. market by the manufacturer in 1983 because of allegations of teratogenicity; these allegations were subsequently shown to be un- justified.22 This drug combination still remains Intravenous fluid replacement available in Canada in a sustained-released for- mulation (Diclectin), and its use has been asso- ciated with a decreased incidence of hospitaliza- tion for nausea and vomiting in pregnancy in Add metoclopramide Add intravenous metoclopramide observational studies.23,24 Oral vitamin B6 and or or doxylamine (Unisom SleepTabs) are available trimethobenzamide intravenous ondansetron or or over the counter in the United States. This com- ondansetron intramuscular promethazine bination has been studied in more than 6000 patients and controls, with no evidence of tera- togenicity,25 and, in randomized trials, it has Add methylprednisolone been associated with a 70% reduction in nausea after 10 wk of gestation and vomiting.26 It is recommended by the Amer- ican College of Obstetricians and Gynecologists Figure 2. Pharmacologic Therapy for Nausea and Vomiting in Pregnancy. (ACOG) as first-line therapy for nausea and vom- Ginger may be added to pharmacologic therapy at any time. At any step, iting in pregnancy.26 enteral or parenteral nutrition may be considered if dehydration or persistent Other antihistamines used for nausea and weight loss is noted; it should be limited to patients with persistent nausea vomiting in pregnancy are listed in Table 1. and weight loss who do not tolerate enteral nutrition. None of these agents have been shown to be teratogenic.23,27 A phenothiazine or metoclopramide is usually Pharmacologic Therapies prescribed if antihistamines fail. Prochlorpera- Approximately 10% of women with nausea and zine (Compazine) is also available as a buccal vomiting in pregnancy require medication. Phar- tablet (Bukatel), which is usually associated with macologic therapies include vitamin B6, antihista- less drowsiness and sedation than oral tablets.28 mines, prokinetic agents, and other medications. Metoclopramide (Reglan) is a prokinetic agent, Randomized, placebo-controlled trials have a dopamine antagonist. It has been associated in shown the effectiveness of vitamin B6 (10 to 25 mg rare cases with tardive dyskinesia, and the Food every 8 hours) in the treatment of nausea and and Drug Administration (FDA) has issued a vomiting in pregnancy.18,19 In one trial, the “dif- black-box warning concerning the use of this drug ference in nausea” score after treatment, as in general. The risk of the development of this measured on a visual analogue scale ranging complication increases with the duration of treat- from 1 to 10 (with higher scores indicating more ment and the total cumulative dose; treatment for1546 n engl j med 363;16 nejm.org october 14, 2010 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 4. clinical pr actice Table 1. Pharmacologic Treatment of Nausea and Vomiting in Pregnancy.* FDA Agent Oral Dose Side Effects Category† Comments Vitamin B6 (pyridoxine) 10–25 mg every 8 hr A Vitamin B6 or vitamin B6−anti- histamine combination rec- ommended as first-line treatment Vitamin B6−doxylamine com- Pyridoxine, 10–25 mg every 8 hr; Sedation A bination doxylamine, 25 mg at bedtime, 12.5 mg in the morning as needed plus 12.5 mg in the af- ternoon as needed Vitamin B6–doxylamine combina- 10 mg pyridoxine and 10 mg doxyl- tion, delayed-release formula- amine, extended release; 2 tab- tion (Diclectin, Canada) lets at bedtime, 1 tablet in the morning as needed plus 1 tab- let in the afternoon as needed Antihistamines Sedation Doxylamine (Unisom SleepTabs) 12.5–25 mg every 8 hr A Diphenhydramine (Benadryl) 25–50 mg every 8 hr B Meclizine (Bonine) 25 mg every 6 hr B Hydroxyzine (Atarax, Vistaril) 50 mg every 4–6 hr C Dimenhydrinate (Dramamine) 50–100 mg every 4–6 hr B Phenothiazines Extrapyramidal symp- toms, sedation Promethazine (Phenergan) 25 mg every 4–6 hr C Severe tissue injuries with in- travenous use (black-box warning); oral, rectal, or in- tramuscular administration preferred Prochlorperazine (Compazine) 5–10 mg every 6 hr C Also available as buccal tablet Dopamine antagonists Sedation, anticholinergic effects Trimethobenzamide (Tigan) 300 mg every 6–8 hr C Metoclopramide (Reglan) 10 mg every 6 hr Tardive dyskinesia B Treatment for more than 12 wk (black-box warning) increases risk of tardive dyskinesia Droperidol (Inapsine) 1.25 mg to 2.5 mg intramuscularly C Black-box warning regarding or intravenously only torsades de pointes 5-hydroxytryptamine3−receptor Constipation, diarrhea, antagonist headache, fatigue Ondansetron (Zofran) 4–8 mg every 6 hr B Also available as oral disinte- grating tablet; more costly than oral ondansetron tablets Glucocorticoid Methylprednisolone (Medrol) 16 mg every 8 hr for 3 days, then Small increased risk of C Avoid use before 10 wk of ges- taper over 2 wk cleft lip if used before tation; maximum duration 10 wk of gestation of therapy 6 wk to limit seri- ous maternal side effects Ginger extract 125–250 mg every 6 hr Reflux, heartburn C Available over the counter as food supplement* This list of agents is not exhaustive. FDA denotes Food and Drug Administration.† FDA categories are as follows: A, controlled studies show no risk; B, no evidence of risk in humans; C, risk cannot be ruled out; D, positive evidence of risk; and X, contraindicated in pregnancy. n engl j med 363;16 nejm.org october 14, 2010 1547 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 5. The n e w e ng l a n d j o u r na l of m e dic i n e more than 12 weeks should be avoided. There corticoids before 10 weeks of gestation was associ- have not been other safety concerns specific to ated with a risk of cleft lip with or without cleft pregnancy. In a recent randomized trial, intrave- palate that was increased by a factor of 3 to 4; nous metoclopramide and intravenous prometha- higher doses were associated with greater risks. zine (Phenergan) had similar efficacy in the treat- Thus, it is recommended that glucocorticoids be ment of hyperemesis, but metoclopramide caused used only after 10 weeks of gestation.36 less drowsiness and dizziness.29 An Israeli cohort study involving 3458 women who were exposed to Alternative and Complementary Therapies metoclopramide in the first trimester (in most Alternative therapies such as acupuncture and cases for 1 to 2 weeks) showed no significant as- ginger have also been studied for nausea and sociation between exposure and the risk of con- vomiting in pregnancy, with inconsistent results. genital malformations, low birth weight, preterm In one randomized trial involving 33 patients delivery, or perinatal death.30 with hyperemesis gravidarum, acupuncture re- The 5-hydroxytryptamine3-receptor antago- duced symptoms, as compared with sham acu- nists, such as ondansetron (Zofran), are increas- puncture,37 whereas a trial comparing traditional ingly used for hyperemesis in pregnancy, but versus sham acupuncture in 55 patients with hy- information is limited to inform their use in peremesis gravidarum showed no differences in pregnant women.31 A randomized trial compar- outcomes between the two study groups.38 ing ondansetron and promethazine in pregnan- Randomized trials of acupressure on the Nei- cy showed similar efficacy, but ondansetron was guan P6 point on the wrist with the use of the less sedating.32 In a case series involving 169 Sea-Band or BioBand39,40 have yielded inconsis- infants exposed to ondansetron in the first tri- tent results and have been limited by a lack of mester, 3.6% had major malformations; this rate blinded testing. In the largest study,39 no benefi- was not significantly different from the rates in cial effect of acupressure was noted. In a ran- two control groups.31 domized trial of the ReliefBand, which emits an Droperidol (Inapsine) has been used effectively electrical current to stimulate the P6 acupunc- for nausea and vomiting in pregnancy, but it is now ture point,41 patients who were randomly as- used infrequently because of its risks. Droperidol signed to the active device, as compared with can cause a prolonged QT interval on electrocar- those assigned to a sham device, were reported diographic (ECG) testing and even torsades de to have significantly less nausea and vomiting pointes, a potentially fatal arrhythmia; deaths have and were more likely to gain weight (77% vs. been reported in patients who received doses that 54%, with an average weight gain of 5.5 lb vs. were lower than the standard doses of this agent. 2.9 lb [2.5 kg vs. 1.3 kg]); however, this study also As a result, there is a black-box warning associated was limited by a lack of blinded assessment of with its use in all patients, and it is recommended the outcomes. that all patients undergo 12-lead ECG testing be- Randomized, double-blind trials have pro- fore, during, and 3 hours after administration.33 vided support for a benefit of ginger in the man- Methylprednisolone is an option in refractory agement of nausea and vomiting in pregnancy.42 cases. In a randomized trial involving 40 wom- In four randomized trials with a total of 675 en,34 methylprednisolone was superior to pro- participants, ginger in capsules (tasteless) was methazine for treating nausea and vomiting in superior to placebo,43-45 and in two trials, the pregnancy. However, a larger trial, involving 110 efficacy of ginger was similar to that of vitamin women, showed no difference in the rate of re- B6.42 Adverse effects of ginger (reflux and heart- hospitalization for women who received methyl- burn) were not serious. In one observational prednisolone as compared with those who received cohort study involving 187 patients, ginger, as placebo.35 In the latter trial, all patients received compared with other nonteratogenic agents, was promethazine at a dose of 25 mg and metoclo- not associated with clinically significant side ef- pramide (Reglan) at a dose of 10 mg intrave- fects or with increased risks of an adverse preg- nously, as well as the glucocorticoid regimen. nancy outcome.45 Ginger is considered to be not In a meta-analysis of four studies, use of gluco- a drug but rather a food supplement, and there-1548 n engl j med 363;16 nejm.org october 14, 2010 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
  • 6. clinical pr acticefore, it is not regulated by the FDA. It may not be C onclusions a ndavailable in hospital pharmacies. R ec om mendat ionsManagement of Refractory Cases The woman described in the vignette has nauseaPatients with nausea and vomiting that are not and vomiting in the first trimester of pregnancy,controlled with outpatient regimens require in- and she is losing weight, so pharmacologic ther-travenous hydration and nutritional supplemen- apy is warranted. It is also important to considertation. Enteral tube feeding may be effective, al- other causes of nausea and vomiting in early preg-though some patients continue to have persistent nancy such as migraine headaches or gastroin-emesis.46 Total parenteral nutrition is associated testinal disorders. Levels of blood urea nitrogen,with a substantial risk of line sepsis (25%)47; ste- creatinine, alanine aminotransferase, aspartateatohepatitis may also occur with the use of lipid aminotransferase, electrolytes, and amylase shouldemulsion during pregnancy. Given these risks, to- be assessed. Dietary advice (e.g., frequent smalltal parenteral nutrition should be reserved for pa- meals) may be helpful. Given data from random-tients with clinically significant weight loss (>5% ized trials suggesting that vitamin B6 and doxyla-of body weight) who have had no response to an- mine are beneficial, I would recommend this com-tiemetic regimens and whose condition cannot be bination (vitamin B6 [pyridoxine], 10 to 25 mgmanaged with enteral feedings.12,26 every 8 hours, and doxylamine, 25 mg at bedtime and 12.5 mg each in the morning and afternoon). A r e a s of Uncer ta in t y If this regimen is not effective, a phenothiazine, metoclopramide, or ondansetron can be tried inThe cause or causes of nausea and vomiting in succession. Methylprednisolone should be reservedpregnancy remain unclear. The mechanism of for refractory cases after 10 weeks of gestation.action of vitamin B6 is unknown. Few large trials Alternative remedies such as ginger and acupunc-have identified the optimal therapy for nausea ture may be tried at any time.and vomiting in pregnancy, and data are lacking Pregnant women with dehydration should re-to identify factors predicting the response to ceive intravenous fluid replacement with multivi-therapies. Vitamin B6 levels do not predict the tamins, especially thiamine. If, after 12 hours ofresponse to therapy with vitamin B6.21 intravenous therapy, the vomiting continues, hos- pitalization may be required. Enteral48 or paren- Guidel ine s from Profe ssiona l teral nutrition should be reserved for patients in So cie t ie s whom weight loss continues despite pharmaco- logic therapies.26The ACOG has published an algorithm for the No potential conflict of interest relevant to this article wasmanagement of nausea and vomiting in preg- reported.nancy (Fig. 2),26 and the recommendations in Disclosure forms provided by the author are available with the full text of this article at NEJM.org.this article are concordant with these guidelines. I thank Dr. Barbara Stegmann for her expertise in epidemiol-The Society of Obstetricians and Gynaecologists ogy and help in characterizing the cited studies and Dr. T. Murphyof Canada has published similar guidelines.48,49 Goodwin for providing data for Figure 1.References1. Gadsby R, Barnie-Adshead AM, Jag- vomiting of pregnancy in the United darum. Clin Obstet Gynecol 1998;41:597-ger C. A prospective study of nausea and States. Am J Obstet Gynecol 2002;186: 605.vomiting during pregnancy. Br J Gen Suppl:S220-S227. 6. Bashiri A, Neumann L, Maymon E,Pract 1993;43:245-8. 4. Mazzotta P, Stewart D, Atanackovic Katz M. Hyperemesis gravidarum: epide-2. Lacroix R, Eason E, Melzack R. G, Koren G, Magee LA. Psychosocial mor- miologic features, complications and out-Nausea and vomiting during pregnancy: bidity among women with nausea and come. Eur J Obstet Gynecol Reprod Biola prospective study of its frequency, inten- vomiting of pregnancy: prevalence and 1995;63:135-8.sity, and patterns of change. Am J Obstet association with anti-emetic therapy. 7. Weigel MM, Weigel RM. Nausea andGynecol 2000;182:931-7. J Psychosom Obstet Gynaecol 2000;21: vomiting of early pregnancy and preg-3. Attard CL, Kohli MA, Coleman S, et al. 129-36. nancy outcomes: an epidemiological study.The burden of illness of severe nausea and 5. Goodwin TM. Hyperemesis gravi- Br J Obstet Gynaecol 1989;96:1304-11. n engl j med 363;16 nejm.org october 14, 2010 1549 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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Hum Nutr sure to corticosteroids: prospective cohort Copyright © 2010 Massachusetts Medical Society. Clin Nutr 1985;39:75-9. study and meta-analysis of epidemiologi- 22. McKeigue PM, Lamm SH, Linn S, cal studies. Teratology 2000;62:385-92.1550 n engl j med 363;16 nejm.org october 14, 2010 The New England Journal of Medicine Downloaded from www.nejm.org on October 13, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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