Nausea and of JEFFREY D. QUINLAN, LCDR, MC, USN, Naval Hospital, Jacksonville, Florida D. ASHLEY HILL, M.D., Florida Hospital, Orlando, Florida

Nausea and vomiting of pregnancy, commonly known as “,” affects approximately 80 percent of pregnant women. Although several theories have been pro- posed, the exact cause remains unclear. Recent research has implicated as one possible cause. Nausea and vomiting of pregnancy is generally a mild, self-limited condition that may be controlled with conservative measures. A small percentage of preg- nant women have a more profound course, with the most severe form being . Unlike morning sickness, hyperemesis gravidarum may have negative impli- cations for maternal and fetal health. Physicians should carefully evaluate patients with nonresolving or worsening symptoms to rule out the most common pregnancy-related and nonpregnancy-related causes of severe vomiting. Once pathologic causes have been ruled out, treatment is individualized. Initial treatment should be conservative and should involve dietary changes, emotional support, and perhaps alternative therapy such as gin- ger or acupressure. Women with more complicated nausea and vomiting of pregnancy also may need pharmacologic therapy. Several , including and doxy- lamine, have been shown to be safe and effective treatments. Pregnant women who have severe vomiting may require hospitalization, orally or intravenously administered corti- costeroid therapy, and total . (Am Fam Physician 2003;68:121-8. Copy- right© 2003 American Academy of Family Physicians.)

See page 18 for defi- ausea and vomiting of preg- and (more than 5 percent of body nitions of strength-of- nancy begins between the weight). Multiple gestation, gestational tropho- evidence levels. fourth and seventh week after blastic disease, triploidy, trisomy 21 syndrome the last menstrual period in (Down syndrome), and hydrops fetalis have 80 percent of pregnant women been associated with an increased incidence of Nand resolves by the 20th week of gestation in all hyperemesis gravidarum.5 but 10 percent of these women.1 The condition has been shown to be more common in urban Etiology and women than in rural women.2 One study3 The etiology of nausea and vomiting of identified increased risk in housewives and pregnancy remains unknown, but a number decreased risk in “white collar” or professional of possible causes have been investigated. white women who consumed alcohol before Although many physicians were taught conception, and in women over 35 years of age that psychologic factors are responsible for with a history of infertility. nausea and vomiting of pregnancy and Hyperemesis gravidarum, a severe form of hyperemesis gravidarum, few data support nausea and vomiting, affects one in 200 preg- this theory. In one well-known study,4 the nant women.4 Although the definition of this Cornell Medical Index was administered condition has not been standardized, accepted to 44 pregnant women with hyperemesis and clinical features include persistent vomiting, 49 pregnant women without hyperemesis; the , , disturbances, Minnesota Multiphasic Personality Inventory (MMPI) was administered only to the preg- nant women with hyperemesis. The MMPI Few data support the theory that psychologic factors are data suggested that women with hyperemesis have hysteria, excessive dependence on their responsible for nausea and vomiting of pregnancy. The roles of mothers, and infantile personalities. However, human chorionic gonadotropin and are controversial. the study findings were not conclusive because comparative testing was not performed.

JULY 1, 2003 / VOLUME 68, NUMBER 1 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 121 dysfunction also has with hyperemesis have suppressed thyrotropin- been suggested as a cause of nausea and vom- stimulating (TSH) levels. Work is iting of pregnancy. In one study6 in which ongoing to elucidate the interaction of hCG and was prescribed to nonpregnant TSH in pregnant women with hyperemesis.5 women, resultant nausea and vomiting sug- A recent study10 suggested that chronic gested that delayed gastric motility caused by infection with Helicobacter pylori may play a progesterone may be responsible for the condi- role in hyperemesis gravidarum. In this study, tion. Another study7 reviewed many potential 61.8 percent of pregnant women with hyper- gastrointestinal causes of nausea and vomiting emesis were found to be positive for the of pregnancy, including abnormalities of gas- H. pylori genome, compared with 27.6 percent tric electrical rhythm (gastric dysrhythmias). of pregnant women without hyperemesis. Many reports have suggested that may cause nausea and vomiting of pregnancy and Evaluation and hyperemesis gravidarum. In one compara- A thorough history and a complete physical tive study,8 women with nausea and vomiting of examination are important in the evaluation of pregnancy were found to have elevated levels of pregnant women who present with persistent human chorionic gonadotropin (hCG); how- vomiting. Nausea and vomiting in early preg- ever, another study9 did not support this find- nancy is usually a self-limited condition. When ing. Some studies have shown elevated estrogen the condition is more severe, potentially serious levels in women with this condition; others have causes need to be ruled out (Table 1).5 If nausea not.7 Hence, the roles of hCG and estrogen and vomiting begin after nine weeks of gesta- remain controversial. Many pregnant women tion, other causes should be investigated. If the findings of the history and physical examination suggest a specific cause, testing is TABLE 1 directed toward confirming that cause. For Differential Diagnosis of Persistent Vomiting in Pregnancy example, the findings may suggest pyelo- nephritis, a common condition in pregnancy. Gastrointestinal disorders Metabolic disorders Ultrasonography may be helpful in ruling out Diabetic gallbladder, liver, and kidney disorders. In Biliary tract disease Porphyria addition to hyperemesis gravidarum, preg- Addison’s disease nancy-related causes of persistent vomiting Intestinal obstruction include acute fatty liver and preeclampsia. Neurologic disorders Nonpregnancy-related causes include gas- Pseudotumor cerebri trointestinal, genitourinary, metabolic, and Vestibular lesions neurologic disorders. Genitourinary tract disorders Migraine Pyelonephritis Central tumors Maternal and Fetal Outcomes Uremia Pregnancy-related conditions Women with uncomplicated nausea and Degenerating uterine leiomyoma Nausea and vomiting of pregnancy* vomiting of pregnancy (“morning sickness”) Torsion Acute fatty liver of pregnancy have been noted to have improved pregnancy Kidney stones Preeclampsia outcomes, including fewer , pre- Drug toxicity or intolerance term deliveries, and , as well as fewer instances of fetal low , growth *—Including hyperemesis gravidarum. retardation, and mortality.11,12 In contrast, Adapted with permission from Goodwin TM. Hyperemesis gravidarum. Clin hyperemesis gravidarum has been associated Obstet Gynecol 1998;41:597-605. with increases in maternal adverse effects, including splenic avulsion, esophageal rup-

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ture, Mallory-Weiss tears, pneumothorax, , and preeclampsia, as Nonpharmacologic measures for treating nausea and vomiting well as increases in fetal growth restriction and of pregnancy include dietary changes, emotional support, mortality.13-15 and acupressure. Treatment The management of nausea and vomiting of pregnancy depends on the severity of the domestic violence is suspected, or evidence of symptoms. Treatment measures range from substance abuse or psychiatric illness exists. dietary changes to more aggressive approaches Acupressure. Several studies17,18 have sug- involving medications, hospitaliza- gested acupressure as a treatment for nausea. tion, or even total parenteral nutrition (TPN). The most common location for acupressure is We prefer to start with dietary changes and the pericardium 6 or Neiguan point, which then add medications as necessary. A Cochrane is located three fingerbreadths above the wrist review of various nonpharmacologic and phar- on the volar surface.Various commercial prod- macologic treatments for nausea and vomiting ucts for relieving motion sickness (e.g., Sea- of pregnancy and hyperemesis gravidarum was Band, ReliefBand) apply pressure to this area. recently published.16 [Evidence level B, system- One review19 of data from seven trials involv- atic review of variable-quality randomized ing Neiguan point acupressure indicated that controlled trials (RCTs)] these products are helpful for controlling morning sickness in early pregnancy; how- NONPHARMACOLOGIC THERAPY ever, a recent study20 demonstrated no benefit Dietary Measures. Initial treatment of for acupressure in pregnant women. women with mild nausea and vomiting of Further data are necessary to determine pregnancy (i.e., morning sickness) should whether acupressure is a viable treatment for include dietary changes. Affected pregnant nausea and vomiting of pregnancy. However, women should be instructed to eat frequent, acupressure is a nonpharmacologic interven- small meals and to avoid smells and food tex- tion without known adverse side effects. Some tures that cause nausea. Solid foods should be physicians may wish to offer it to their patients. bland tasting, high in carbohydrates, and low . A popular alternative treatment for in fat. Salty foods (e.g., salted crackers, potato morning sickness, ginger has been used in chips) usually can be tolerated early in the teas, preserves, ginger ale, and capsule form. morning, and sour and tart liquids (e.g., One European study21 demonstrated that gin- lemonade) often are tolerated better than ger powder (1 g per day) was more effective water. Family members should be informed than in reducing the symptoms of that pregnant women with nausea and vomit- hyperemesis gravidarum. ing of pregnancy may need to alter mealtimes There have been no published reports of and other home routines. fetal anomalies associated with the use of gin- Emotional Support. Although nausea and ger. However, one investigator22 warned that vomiting of pregnancy and hyperemesis ginger root contains thromboxane synthetase gravidarum are not strongly associated with inhibitor, which may interfere with testos- psychologic illness, some women may become terone receptor binding in the . Other depressed or exhibit other affective changes. investigators23 noted that although safety data It is important that these women receive are lacking, people in many cultures use gin- appropriate support from family members ger as a spice; the amounts used are similar to and medical and nursing staff. Consultation is those commonly prescribed for the treatment indicated if a pregnant woman is depressed, of nausea and vomiting of pregnancy.

JULY 1, 2003 / VOLUME 68, NUMBER 1 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 123 Pyridoxine- is available in Pharmacologic therapies not known to be associated with an Canada under the trade name Diclectin increased risk of birth defects include pyridoxine, , (10 mg of pyridoxine and 10 mg of doxy- lamine in a delayed-release tablet). Diclectin , and . typically is prescribed in a dosage of two tablets at night for mild symptoms and in a dosage of up to four tablets per day for more PHARMACOLOGIC THERAPY severe symptoms.

Pyridoxine (Vitamin B6) and Doxylamine. . If the previously discussed ther- Pyridoxine can be used as a single agent or in apies are unsuccessful, a trial of antiemetics is conjunction with doxylamine. One small warranted. The prochlor-

study demonstrated that vitamin B6 in a dosage perazine (Compazine) and chlorpromazine of 25 mg taken orally every eight hours (75 mg (Thorazine) have been shown to reduce nau- per day) was more effective than placebo for sea and vomiting of pregnancy compared with controlling nausea and vomiting in pregnant placebo.25 A reasonable regimen is prochlor- women.24 [Evidence level A, RCT] In pharma- perazine administered rectally in a dosage of

cologic doses, vitamin B6 has not been found 25 mg every 12 hours (50 mg per day) or to be teratogenic. A single 25-mg doxylamine (Phenergan) given orally or rec- (Unisom) tablet taken at night can be used tally in a dosage of 25 mg every four hours alone or in combination with pyridoxine (150 mg per day). (25 mg three times daily). If treatment with or pro- In the 1970s, a combining pyri- methazine is unsuccessful, some physicians doxine and doxylamine (Bendectin) commonly try other antiemetics, such as trimethobenza- was used to treat women with nausea and vom- mide (Tigan) or (Zofran). In a iting of pregnancy. Although multiple studies small study26 of in showed no increased risk of birth defects, the women with hyperemesis gravidarum, no manufacturer voluntarily withdrew Bendectin increased benefit was demonstrated for from the market in 1983 because of litigation. ondansetron over promethazine. Although Pyridoxine-doxylamine is still the only medica- one study27 of 315 pregnant women demon- tion that the U.S. Food and Drug Administra- strated a slightly increased risk of birth defects tion has specifically labeled for the treatment of when phenothiazines were given during the nausea and vomiting of pregnancy. first trimester, a larger study28 showed no asso- ciation with fetal malformations. Women with severe nausea and vomiting of pregnancy or hyperemesis gravidarum The Authors may benefit from droperidol (Inapsine) and JEFFREY D. QUINLAN, LCDR, MC, USN, is program director of the family practice resi- diphenhydramine (Benadryl). One study29 dency program at Naval Hospital, Jacksonville, Fla. After graduating from the Univer- found that continuous intravenous adminis- sity of Pittsburgh School of Medicine, Dr. Quinlan completed a family medicine resi- dency at Naval Hospital, Camp Pendleton, Calif., and an fellowship at tration of both droperidol and diphen- Florida Hospital, Orlando. hydramine resulted in significantly shorter D. ASHLEY HILL, M.D., is associate director of the Department of Obstetrics and Gyne- hospitalizations and fewer readmissions cology at Florida Hospital’s family practice residency program, Orlando. Dr. Hill received compared with a variety of other inpatient his medical degree from the University of South Florida College of Medicine, Tampa, antiemetic therapies. where he also completed a residency in obstetrics and gynecology. and Anticholinergics. Mecli- Address correspondence to Jeffrey D. Quinlan, LCDR, MC, USN, Associate Program zine (Antivert), (Dramamine), Director, Family Practice Residency Program, Naval Hospital, 2080 Child St., Jack- sonville, FL 32214 (e-mail: [email protected]; [email protected]). and diphenhydramine have been used to con- Reprints are not available from the authors. trol nausea and vomiting during pregnancy. All

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have been shown to be more effective than placebo.25 Although meclizine was previously TABLE 2 thought to be teratogenic, studies have demon- Pharmacologic Therapy for Nausea and Vomiting of Pregnancy strated its safety during pregnancy.28 One study30 found an association between diphen- Pregnancy hydramine and cleft lip and palate, but a subse- Medication Dosage* category quent study31 did not support this finding. Pyridoxine (Vitamin B6)† 25 mg orally three times daily A‡ Motility Drugs. Metoclopramide (Reglan) Doxylamine (Unisom)† 25 mg orally once daily § acts by increasing pressure at the lower Antiemetics esophageal sphincter, as well as speeding Chlorpromazine 10 to 25 mg orally two to four C transit through the . This drug has (Thorazine) times daily been shown to be more effective than placebo Prochlorperazine 5 to 10 mg orally three or four C in the treatment of hyperemesis gravi- (Compazine) times daily darum.32 Metoclopramide has not been asso- Promethazine 12.5 to 25 mg orally every four C ciated with an increased incidence of congen- (Phenergan) to six hours Trimethobenzamide 250 mg orally three or four times C ital malformations. (Tigan) daily . A randomized, double- Ondansetron (Zofran) 8 mg orally two or three times daily B 33 blind, controlled study found no hospital Droperidol (Inapsine) 0.5 to 2 mg IV or IM every three or C readmissions for recurrent vomiting in four hours women with hyperemesis gravidarum who Antihistamines and were treated with orally administered methyl- anticholinergics (Medrol), compared with five Diphenhydramine 25 to 50 mg orally every four to B readmissions in those who received oral (Benadryl) eight hours promethazine therapy. The authors of the Meclizine (Antivert) 25 mg orally every four to six hours B study suggested that , in a Dimenhydrinate 50 to 100 mg orally every four to B (Dramamine) six hours dosage of 16 mg three times daily (48 mg per day) followed by tapering over two weeks, is a Motility drug Metoclopramide (Reglan) 5 to 10 mg orally three times daily B worthwhile treatment for women with refrac- tory hyperemesis gravidarum. Of note, these and other authors have found Methylprednisolone 16 mg orally three times daily; C (Medrol) then taper that almost all women with hyperemesis gravidarum can tolerate oral corticosteroid IV = intravenously; IM = intramuscularly. therapy. We have used the two-week tapering regimen in pregnant women who have been *—These regimens usually are administered only as needed. †—Although some research supports the effectiveness and safety of combina- refractory to standard antiemetic therapy and tion pyridoxine-doxylamine (Bendectin),16 the manufacturer voluntarily withdrew have noted a subjective decrease in hospital- the medication from the U.S. market in 1983 after isolated studies raised ques- ization rates and readmissions. tions about potential teratogenicity. The product remains available in Canada Corticosteroid therapy generally is consid- under the trade name Diclectin (10 mg of pyridoxine and 10 mg of doxylamine ered safe during pregnancy. However, a in a delayed-release tablet). Diclectin typically is prescribed in a dosage of two 34 tablets at night for mild symptoms and in a dosage of up to two tablets three recent meta-analysis demonstrated a mar- times daily (six tablets per day) for more severe symptoms. ginally increased risk of major malformation ‡—The pregnancy category for doxylamine relates to its use as a vitamin supplement. and a 3.4-fold increased risk of oral cleft in §—According to the Physicians’ Desk Reference for Nonprescription Drugs and infants exposed to corticosteroids in the first Dietary Supplements,36 doxylamine should not be taken by pregnant women or trimester. women who are nursing a baby; however, some research supports its efficacy Pharmacologic treatments for nausea and and safety. vomiting of pregnancy and hyperemesis gravi- Information from references 16, 23, 35, 36, and 37. darum are summarized in Table 2.16,23,35-37

JULY 1, 2003 / VOLUME 68, NUMBER 1 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 125 Nausea and Vomiting of Pregnancy

Nausea and vomiting in a pregnant woman

Rule out nonpregnancy causes (see Table 1).

Positive findings (i.e., nonpregnancy Negative findings cause identified)

Dietary changes and Treat or refer as appropriate. emotional support

No resolution Resolution

Options: pyridoxine (vitamin B6), Routine prenatal doxylamine (Unisom),* care acupressure, ginger

No resolution Resolution

Check ketone and Routine electrolyte levels.

Abnormal Normal

Options: intravenous fluids, Options: antiemetics, antihistamines, hospitalization, antiemetics, anticholinergics, corticosteroids antihistamines, anticholinergics, corticosteroids

No resolution Resolution

No resolution Resolution Routine prenatal care

Consider total parenteral Routine prenatal care nutrition. Obtain maternal-fetal medicine consultation.

*—According to the Physicians’ Desk Reference for Nonprescription Drugs and Dietary Supplements,36 doxyl- amine should not be taken by pregnant women or women who are nursing a baby; however, some research supports its efficacy and safety.

FIGURE 1. Algorithm for the suggested evaluation and management of women with nausea and vomiting of pregnancy.

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construed as official or as reflecting the views of the OTHER TREATMENTS Medical Department of the U.S. Navy or the U.S. Naval Service at large. Intravenous Fluids. Pregnant women who,

despite the previously discussed treatments, REFERENCES are unable to keep down liquids will probably require intravenous fluids. Normal saline or 1. Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during lactated Ringer’s solution is the mainstay of pregnancy. Br J Gen Pract 1993;43:245-8. intravenous fluid therapy. Many physicians 2. Semmens JP. Female sexuality and life situations. use solutions that contain dextrose; however, An etiologic psycho-socio-sexual profile of weight gain and nausea and vomiting in pregnancy. it may be advisable to give (vitamin Obstet Gynecol 1971;38:555-63. 5 B1) first, because of the theoretic risk of Wer- 3. Weigel MM, Weigel RM. The association of repro- nicke’s encephalopathy. ductive history, demographic factors, and alcohol and tobacco consumption with the risk of devel- Intravenous fluid may provide relief from oping nausea and vomiting in early pregnancy. Am nausea and vomiting, but many pregnant J Epidemiol 1988;127:562-70. women also require an antiemetic adminis- 4. Fairweather DV. Nausea and vomiting in preg- nancy. Am J Obstet Gynecol 1968;102:135-75. tered orally, rectally, or by infusion with the 5. Goodwin TM. Hyperemesis gravidarum. Clin fluid. Depending on the severity of the symp- Obstet Gynecol 1998;41:597-605. toms, intravenous fluid therapy may be given 6. Walsh JW, Hasler WL, Nugent CE, Owyang C. Pro- gesterone and estrogen are potential mediators of in the hospital or at home by a visiting nurse. gastric slow-wave dysrhythmias in nausea of preg- Enteral or Parenteral Nutrition. Enteral tube nancy. Am J Physiol 1996;270(3 pt 1):G506-14. feeding and TPN are last-resort treatments for 7. Broussard CN, Richter JE. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am 1998; pregnant women who continue to vomit and 27:123-51. lose weight despite aggressive treatment with 8. Masson GM, Anthony F, Chau E. Serum chorionic any or all of the previously discussed modali- gonadotrophin (hCG), schwangerschaftsprotein 1 (SP1), progesterone and oestradiol levels in ties. Few studies have evaluated enteral nutri- patients with nausea and vomiting in early preg- tion, although all seven women in one small nancy. Br J Obstet Gynaecol 1985;92:211-5. study38 tolerated feedings using an 8-French 9. Soules MR, Hughes CL Jr, Garcia JA, Livengood CH, Prystowsky MR, Alexander E 3d. Nausea and vom- Dobbhoff nasogastric tube and infusion rates iting of pregnancy: role of human chorionic of up to 100 mL per hour. gonadotropin and 17-hydroxyprogesterone. Obstet TPN is administered through a central Gynecol 1980;55:696-700. 10. Hayakawa S, Nakajima N, Karasaki-Suzuki M, venous catheter. Its content is determined by Yoshinaga H, Arakawa Y, Satoh K, et al. Frequent the pregnant woman’s daily caloric require- presence of Helicobacter pylori genome in the ments and any existing electrolyte abnormal- saliva of patients with hyperemesis gravidarum. Am J Perinatol 2000;17:243-7. ities. Consultation with a perinatologist 11. Brandes JM. First-trimester nausea and vomiting as experienced in parenteral nutrition, as well as related to outcome of pregnancy. Obstet Gynecol a gastroenterologist or inpatient parenteral 1967;30:427-31. 12. Jarnfelt-Samsioe A, Samsioe G, Velinder GM. Nau- nutrition service, may be prudent. Both TPN sea and vomiting in pregnancy—a contribution to and central venous access can result in signif- its epidemiology. Gynecol Obstet Invest 1983;16: icant complications, including sepsis. 221-9. 13. Zhang J, Cai WW. Severe vomiting during preg- An algorithm for the suggested evaluation nancy: antenatal correlates and fetal outcomes. and management of women with nausea and Epidemiology 1991;2:454-7. vomiting of pregnancy is provided in Figure 1. 14. Wood P, Murray A, Sinha B, Godley M, Goldsmith HJ. Wernicke’s encephalopathy induced by hyper- emesis gravidarum. Case reports. Br J Obstet The authors indicate that they do not have any con- Gynaecol 1983;90:583-6. flicts of interest. Sources of funding: none reported. 15. Gross S, Librach C, Cecutti A. Maternal weight loss associated with hyperemesis gravidarum: a predic- The opinions and assertions contained herein are tor of fetal outcome. Am J Obstet Gynecol 1989; the private views of the authors and are not to be 160:906-9.

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