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Nausea and Vomiting in Pregnancy
CHAPTER 54
Nausea and Vomiting in Pregnancy Andrea Gordon, MD • Abigail Love, MD, MPH
PATHOPHYSIOLOGY Nausea and vomiting in pregnancy (NVP) represent a conundrum for the pregnant woman. On the positive side, NVP are correlated with better fetal outcomes than the absence of these symptoms,1 but at the other extreme, NVP can interfere with nutrition and hydration for the mother and developing fetus. Symptoms may range from occasional mild nausea to multiple episodes of daily vomiting resulting in weight loss and electrolyte abnormalities. This severe manifestation is often referred to as hyperemesis gravidarum. Definitions of hyperemesis gravidarum vary, but commonly accepted criteria include weight loss (often more than 5% of prepregnancy weight), electrolyte disturbances, and ketonuria. Usually appearing before the ninth week of pregnancy, NVP will affect up to 85% of normal pregnancies, with symptoms generally remitting by the fourteenth week. Initial presentation of symptoms after the ninth week should prompt a workup to determine an alternative cause. NVP may be mild, but up to 20% of women find their symptoms so significant that they cannot continue to work.2 The reported incidence of hyperemesis gravidarum, the most severe end of the spectrum, varies from 0.5% to 2%. This severely debilitating condition is the most common reason for hospital admission in the first trimester and the second most common problem for which pregnant women are admitted to the hospital, after preterm labor.3 Even at the milder end of the symptom continuum, NVP can lead to a decreased quality of life and missed time from work. The aptly named Motherisk PregnancyUnique Quantification of Emesis and Nausea (PUQE) index has been shown to demonstrate a significant correlation between the presence and severity of NVP and poorer quality of life.4,5 This effect on quality of life and the economic impact of missed work emphasize the need to control these symptoms. Mild or moderate vomiting does not appear to have any significant effects on the fetus. Among women with severe hyperemesis, the reported incidence of low birth weight is higher, but increased reporting of birth defects has not been noted.6 In fact, several investigators suggested that NVP represent an evolutionary adaptation that helps protect the developing fetus from exposure to foods that may contain potential toxins.7,8 The cause of NVP is unknown. Both biological and psychological factors have been proposed. Human chorionic gonadotropin (HCG) and estrogen have been 542
studied as triggers for these symptoms. Suggestive evidence includes the finding that pregnant women with higher levels of HCG, which occur in molar pregnancies and multiple gestations, have significantly more episodes of vomiting and higher rates of hyperemesis gravidarum. This theory is also supported by the observations that nonpregnant women who experience nausea and vomiting after exposure to estrogens are more likely to experience NVP. Cigarette smoking is known to reduce both estrogen and HCG levels, and pregnant smokers are less likely to experience hyperemesis gravidarum.9 No controlled studies support the theory that NVP comprise a conversion disorder or an inability to respond to life stress.10,11 The association of high levels of HCG and estradiol with increasingly severe episodes of vomiting in pregnancy indicates a physiological origin, as do epidemiological factors. Daughters and sisters of women who had hyperemesis are more likely to have NVP as well. Other risk factors include a previous pregnancy affected by hyperemesis, a female fetus, and a history of motion sickness or migraines.12
INTEGRATIVE THERAPY When treatment is considered, risks and benefits must be clearly explained to the pregnant woman. Minimizing the risks of any treatment is desirable, but the presence of a developing fetus makes it more urgent to decrease any unnecessary exposures. This is an ideal time to use integrative approaches because drugs generally represent more risk than other modalities. In addition, some of the behavior modifications such as exercise are beneficial in and of themselves.
Lifestyle Although the efficacy of lifestyle modifications has not been studied, these interventions are safe and have been anecdotally reported to be useful.13 Avoid Odors Some women report that NVP are triggered by strong odors such as foods, cigarette smoke, or perfume. This is supported by a small study showing that women with congenital anosmia were less likely to develop NVP.14 Avoiding these stimuli may be helpful. Women should be supported in doing so, for example, by passing
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off cooking duties to someone else, avoiding tasks with strong odors such as feeding the dog, or politely asking coworkers not to wear perfume for a few weeks. Increase Rest Sleep requirements increase in early pregnancy.15 Women frequently report nausea in association with feelings of exhaustion. Caregivers should educate pregnant patients that fatigue is common and support them in trying to obtain the additional rest they need. Exercise Light to moderate aerobic exercise is associated with fewer NVP symptoms. Women who exercised at least three times a week for 20 minutes or more reported fewer symptoms of pregnancy, including nausea.16 Women who have already been exercising can remain active during uncomplicated pregnancies. Previously inactive women may benefit from gentle exercise but should be evaluated on an individual basis before recommendations for physical activity are made.17
Nutrition Low blood glucose levels seem to trigger nausea and subsequently vomiting in many women; thus small, frequent, high-protein, high-fiber meals are often recommended.18 A potentially helpful approach is to decrease simple carbohydrates that rapidly raise blood glucose and thus stimulate insulin secretion, which can cause rapidly falling blood glucose (see Chapter 87). However, this includes foods such as pasta, white rice, potatoes, and white bread, whose blandness seems desirable when patients are nauseated, so education is key. Some patients find that eating something as soon as they wake up and then every 2 hours can suppress nausea. Each pregnant woman may have specific foods she avoids because of a taste or smell that triggers nausea, but it may also be necessary to avoid spicy or fatty foods because they can exacerbate symptoms. Little published evidence exists on the efficacy of dietary changes, but benefit clearly outweighs harm. In one international survey, dietary interventions seemed to help 22% of women with hyperemesis gravidarum.19 Two studies found that taking a multivitamin before pregnancy or before 6 weeks of gestation was associated with a decreased incidence of NVP. Although this approach would not help a woman already suffering with symptoms, it could be helpful for women at risk for symptoms in their next pregnancy.20,21
Botanicals Ginger Root (Zingiber officinale) Historically, ginger has been effectively and safely used to treat nausea, including that of pregnancy. Randomized controlled trials have shown that ginger is effective for treating NVP,22 and it is the most thoroughly studied herb for this indication. Some trials have shown ginger to be not only more effective than placebo23 but also
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comparable to or better than vitamin B624,25 and comparable to dimenhydrinate.26 It will reduce overall nausea symptoms but not the number of vomiting episodes significantly.27 Patients should be advised that it may take longer for ginger to work: up to 3 days, rather than 1 day for dimenhydrinate. The U.S. Food and Drug Administration (FDA) has listed ginger as a food supplement that is generally recognized as safe,28 and studies have not shown any increased incidence of malformations in children of mothers using ginger.29 Ginger seems to work primarily in the gastrointestinal tract on serotonin receptors in the ileum, the same receptors affected by some antiemetics, such as ondansetron. Some evidence indicates that ginger constituents may also have some action in the central nervous system.30 No toxicity has been demonstrated, although ginger can cause abdominal discomfort or heartburn when it is taken in large doses, especially on an empty stomach.
Dosage Most of the studies have used 1000 mg daily, in two or four divided doses.23,26,28,31 A higher dose of 650 mg three times daily has also been used,32 but total doses of less than 1500 mg a day are more effective.34 Ginger is available in a variety of forms, and an evaluation of products purchased in pharmacies and health food stores found a wide variation in the amount of active ingredients and suggested serving sizes.35 Women may prefer one form over another, so approximate equivalents can be calculated. In general, 1 g of standardized extract is equivalent to 1 teaspoon of fresh grated ginger root, two droppers (2 mL) of liquid extract, four 8-oz cups of prepackaged ginger tea, four 8-oz cups of tea made with 0.5 teaspoon of grated ginger steeped for 5–10 minutes, 8 oz of ginger ale (made with real ginger—most commercial ginger ales are not effective), two pieces of crystallized ginger (1 inch square, 0.25 inches thick), or two teaspoons (10 mL) of ginger syrup.36 Capsules of ginger come in various dosages, ranging from 100 to 1000 mg, and chewable tablets may contain 67 to 500 mg, so attention to the dosing of the product used is advisable, with the goal a total of less than 1500 mg a day. Using ginger throughout the day is also helpful. Patients can incorporate ginger into their diet by sprinkling dried or candied ginger in oatmeal, having some ginger tea, and adding fresh ginger to soup or stir-fries. Precautions There is a theoretical risk for bleeding as ginger inhibits thromboxane synthetase and may inhibit platelet function. This has not been demonstrated, but precaution should be taken when ginger is used concomitantly with anticoagulants.
Chamomile (Matricaria chamomilla) Chamomile is a flowering plant that is often used for various types of gastrointestinal upset, including travel sickness, colic, and inflammatory diseases of the bowel. It is commonly used for NVP,37-39 although no research on this application has been published. Chamomile appears to be safe and well tolerated, however, and the FDA labels it as safe.40
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Dosage Prepare it as a tea, allowing it to steep for 5–7 minutes while covered, so it will retain the volatile active constituents, and sip as needed. Precautions Chamomile should be used with caution in patients who are allergic to the Asteraceae/Compositae family, which includes ragweed, daisies, and many other flowers. Some erroneous concern exists about teratogenicity, but that concern is based on a study with alpha-bisabolol at high doses that could not be achieved by someone drinking tea.41
Peppermint Leaf (Mentha piperita) Peppermint is another herb often used in pregnancy.42,43 The active parts are the stems, leaves, and flowers, as well as the peppermint oil that is distilled from these plant parts. Studies have shown peppermint oil to be effective for reducing bowel spasms in irritable bowel syndrome and for patients receiving barium enemas, but peppermint oil has not been studied in pregnancy.44 Its mechanism of action is reduction of spasm in smooth muscle, and it may help with NVP by reducing esophageal dysmotility. However, this effect can also reduce lower esophageal sphincter pressure, resulting in reflux. Theoretical concerns exist with using the essential oil in pregnancy because it may cross the placental barrier, but the amount of peppermint ingested in tea or food seems to be safe.41 Peppermint has been rated as safe by the FDA.40
Dosage The dose is two to three cups of tea daily. Many women find peppermint candies or gum to be effective in squelching nausea. A dose of 0.2 mL in 2 mL of isotonic saline solution used as aromatherapy has been used for postoperative nausea and can be tried if teas or foods containing peppermint are not tolerated.45 Precautions Peppermint can aggravate reflux by decreasing the lower esophageal sphincter tone.
Bioenergetics Acupressure: Stimulation of the P6 Neiguan Point Acupressure of the pericardium 6 (P6) Neiguan (meridian) point, which is located on the inner wrist, may be beneficial. Several small studies have found this to be effective, including a Korean trial, which found significantly less NVP in a group of women with hyperemesis gravidarum,46 and another that demonstrated self-administered nerve stimulation therapy over using a commercial device.47 However, a 2014 Cochrane analysis did not find P6 acupuncture or acupressure wristbands to be significantly more effective than placebo. Other studies using a
crossover design, which were not included in the Cochrane analysis, also showed benefit to using acupressure at the P6 point,46,48 and another trial revealed decreased nausea with P6 stimulation, but no change in the frequency of vomiting.49 Patients should be made aware of this mixed evidence; patients are willing to try acupressure because it is inexpensive and has no significant side effects. Patients can be taught to find the P6 point and treat themselves with either manual pressure or the application of “Sea-Bands” (Fig. 54.1). These elastic bands with attached plastic disks were originally used for motion sickness. Patients can create their own version of such bands by placing a small, round object such as a bead over the point and securing it with tape and then massaging the bead. This therapy has no known negative side effects. To have a patient accurately locate the P6 point, have her lay one hand palm up, with the other hand placed palm down at right angles to the upturned arm. The first three fingers of the palm-down hand are held close together, and the edge of the ring finger is placed at the crease of the wrist closest to the palm in alignment with the middle finger of the upturned hand. The P6 point, between the palmaris longus and flexor radialis tendons, is now readily palpable under the tip of the index finger of the examining hand (see Fig. 54.1A). This point is often tender, a characteristic that aids in its location. Many patients use this acupressure in conjunction with other interventions because it has no known side effects or interactions.
Patients can stimulate the P6 point at any time, but they should be cautioned against using any other acupressure points without consulting a trained practitioner. Some commonly used points, such as the Ho-Ku point that is located between first and second metacarpals (often used for headaches), can stimulate contractions. Patients must be instructed to press on the point when feeling nausea, as just wearing the bands may not provide significant relief.
Mind-Body Therapy Hypnosis Hypnosis has been studied as a treatment for hyperemesis gravidarum. A review of six studies showed encouraging effects, but methodological problems did not allow a definitive recommendation.50 This intervention is safe, however, and some women may want to try it for all levels of NVP. One approach has been to suggest to a woman that the “nausea center” in her brain is very sensitive to the hormones of pregnancy and that she is able to “turn down” that sensitivity as one would a thermostat.51 Another approach is to link the muscle tension in the stomach and throat or the nausea as a hypnotic cue to pleasant imagery.52 This imagery may be helpful for patients to use when nausea strikes. NVP may have an element of conditioned response, as noted with chemotherapy-associated vomiting. Some uncontrolled studies showed that hypnosis can reduce vomiting and anticipatory vomiting in patients
54 Nausea and Vomiting in Pregnancy
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PC6 NEIGUAN P-6
A
B FIG. 54.1 □ A, The P6 Neiguan acupressure point is located on the volar aspect of the forearm by placing the examining hand three fingerbreadths below the wrist crease. The patient’s finger widths should be used for measurement. The P6 point is essentially in the midline between the tendons of the palmaris longus and flexor radialis muscles. B, Location of this point. PC, pericardium
undergoing chemotherapy,10 so the potential exists for hypnosis to work for NVP. Because this treatment may require several sessions of training, the time and expense may be prohibitive for some patients. Counseling and Psychotherapy Although the general consensus is that NVP does not represent a conversion disorder and is not caused by emotional responses to the pregnancy,10 evidence indicates that women with NVP may be under more stress. Two investigators stated that NVP “could subject any normal expectant mother to stress sufficient to trigger adjustment disorders, generalized anxiety, or even depressive episodes.”10 In recognition of this extraordinary stress, counseling or psychotherapy may be helpful in coping with the symptoms and their effects on a woman’s life.
Supplements Vitamin B6 (Pyridoxine) Vitamin B6 is a water-soluble vitamin that is an effective treatment for nausea in pregnancy. The benefit in reducing vomiting episodes is less clear.53,54 The mechanism of action of pyridoxine remains unknown, but extensive analysis for teratogenicity has shown no negative effects on pregnancy outcome.55 Patients can expect a significant reduction of nausea with few side effects if they take vitamin B6, so this should be used as a first-line treatment of NVP.56
A popular medication for nausea and vomiting, known as Bendectin in the United States and Diclectin in Canada, contained pyridoxine and doxylamine. Bendectin was withdrawn from the United States market in 1983 out of safety concerns about teratogenicity, but no studies validated this possibility. Diclectin remains available in Canada and is one of the most widely studied and used medications in pregnancy today. Following removal of Bendectin from the market, no reduction in birth defects was reported, but hospitalization rates for NVP doubled.57 Diclectin, a combination of doxylamine 10 mg and pyridoxine 10 mg, is available in Canada and can be purchased online (www.canadadrugs.com). It is expensive, at more than a dollar a pill. A recommended and less expensive alternative is to combine Unisom (contains 25 mg doxylamine), one-half tablet at bedtime, with 25 mg of pyridoxine, as the combination reduces symptoms by 70%.56 [Category C] Dosage The most effective dosage of B6 appears to be 30–75 mg daily in three divided doses. Studies performed with the higher end of the dosing range have shown effectiveness against vomiting as well as nausea.53,54 When vitamin B6 alone is not effective, it may be combined with doxylamine to obtain relief from NVP. Precautions Pyridoxine can cause sensory neuropathy, which is related to the daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 g or more pose the most risk, so the doses that have been used for NVP appear generally to be safe.58
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Pharmaceuticals Antihistamines Several histamine (H1) receptor antagonists have been studied for the treatment of NVP. The most frequently studied and used is doxylamine (Unisom, an over-the-counter sleep aid). An extensive review of safety data revealed no adverse pregnancy outcomes from the use of doxylamine alone or in combination with pyridoxine.59 Other drugs in this group, which all have shown some evidence of efficacy and safety for controlling NVP, are dimenhydrinate (Dramamine), cetirizine (Zyrtec), meclizine (Antivert), hydroxyzine (Vistaril), and diphenhydramine (Benadryl).60 Dosage Most patients should use 12.5 mg of doxylamine, the amount in one-half of a scored tablet. This is the amount of doxylamine that was present in Bendectin. Indeed, many women try to “make” a form of Bendectin by combining doxylamine with vitamin B6. This safe option can be suggested if vitamin B6 alone or with ginger or P6 point stimulation is not working adequately. Diphenhydramine, given in 25- to 50-mg doses up to every 6 hours, is also safe and easily obtained. Precautions All antihistamines can cause drowsiness.
Phenothiazines The phenothiazines used to treat NVP include promethazine (Phenergan), prochlorperazine (Compazine), chlorpromazine (Thorazine), and perphenazine (Trilafon). Only promethazine has randomized controlled study data supporting its efficacy and safety.60,61 However, some evidence indicates that all medications in this group have some efficacy in the treatment of NVP.55 These medications may be used in the outpatient setting, but therapy is often not started until hospital admission for treatment of dehydration or intractable vomiting. The variable dosing forms are advantageous for NVP: these drugs can be self-administered orally or rectally or given intramuscularly by medical personnel if needed. Dosage For promethazine, begin with 12.5 mg per rectum or by mouth and progress to 25 mg every 4 hours as needed. Precautions Side effects of promethazine include sedation, hypotension, dystonia, and extrapyramidal symptoms. If needed, diphenhydramine 25 mg can be given orally every 6 hours to treat dystonia or extrapyramidal side effects.
Dopamine Antagonists Two dopamine antagonists have been studied for the treatment of NVP: trimethobenzamide (Tigan) and metoclopramide (Reglan). Trimethobenzamide has been shown to be safe,62 but it has been largely studied for
nausea in other settings such as chemotherapy.63 Only one double-blind trial focused on the effectiveness of trimethobenzamide in treating NVP.64 This study showed that trimethobenzamide, alone or in combination with pyridoxine, significantly improved symptoms of nausea and vomiting compared with placebo.64 Metoclopramide is not associated with malformation risk,65,66 and it has been shown to be effective in hyperemesis gravidarum, with or without promethazine.67,68 A combination of vitamin B6 and metoclopramide was shown to be more effective than prochlorperazine or promethazine for NVP.69
Dosage Metoclopramide can be given orally in 5- to 10-mg doses three times daily before meals. Precautions The side effects of metoclopramide are similar to those of the phenothiazines, but occur less frequently.
5-Hydroxytryptamine3 Receptor Agonists Ondansetron (Zofran), a 5-hydroxytryptamine3 receptor agonist, is a potent antiemetic originally used for treatment of chemotherapy-induced nausea and vomiting. Data on NVP are limited, but several small studies have found it to be as effective as promethazine,70 or as effective as metoclopramide in women with hyperemesis gravidarum.71 Another trial, which more accurately reflects what is often used in practice, demonstrated ondansetron to be superior to the combination of pyridoxine and doxylamine.72 Dosage Ondansetron is given orally or intravenously, 4–8 mg up to every 8 hours. Ondansetron is available in an orally disintegrating tablet. This can be useful if one becomes too nauseated to swallow any medication. Precautions Adverse reactions to ondansetron include headache, fever, and bowel dysfunction, although this agent has been reported to be better tolerated by patients than promethazine, with no dystonic or extrapyramidal side effects. Two recent studies found no significant increase in major fetal malformations or outcomes,73,74 and the FDA has labeled ondansetron Pregnancy Category B. However, patients do need to be informed that there is a demonstrated association with an increased risk of cardiac septum defects, mainly atrial septal defect and ventricular septal defect.74,75 In light of this evidence, as well as cost considerations, it is prudent to try the other measures and medications discussed previously prior to considering the use of ondansetron, and then discussing the risks with patients. “No statistically significantly increased risk for a major malformation was found with ondansetron. The risks for a cardiovascular defect and notably a cardiac septum defect were increased and statistically significant (OR = 1.62, 95% CI 1.04–2.14, and RR 2.05, 95% CI 1.19–3.28, respectively). The teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely.”74
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Corticosteroids Several small studies have evaluated corticosteroids, primarily methylprednisolone, for efficacy in reducing NVP and hyperemesis. Methylprednisolone reduced symptoms of NVP along with hospital readmission rates for hyperemesis.76 Another trial found that promethazine worked more rapidly than prednisolone, but after a week both medications worked equally well, and the prednisolone group had fewer side effects.77 Various oral and intravenous dosages have been studied, but the most common regimen is 16 mg of methylprednisolone 3 times daily, with attempts to taper after 3 days. Most patients respond within 3 days, so if no improvement has been seen by that time, longer treatment is generally not indicated. Methylprednisolone may be continued for up to 6 weeks, but longer use may result in adverse maternal effects related to prolonged steroid exposure.76,78 Evidence also indicates that a shorter course of hydrocortisone is effective for treating intractable hyperemesis.79 A meta-analysis found an increased risk of oral clefts associated with prednisone use.80
Dosage The dose of methylprednisolone is 16 mg orally or intravenously every 8 hours for up to 2 weeks (tapered course to avoid adrenal suppression). The dose of hydrocortisone is 300 mg intravenously daily for 3 days, then tapered over one week. Precautions Avoid corticosteroid use before 10 weeks of gestation if possible. Avoid prolonged use for more than 6 weeks to reduce the risk of maternal side effects.
Intravenous Fluids Intravenous fluids have not been specifically studied for the treatment of hyperemesis, but they are often coadministered with other medications in the hospital setting for the treatment of dehydration. Intravenous fluid is generally recommended when patients fail to tolerate oral fluids for a prolonged period or show electrolyte abnormalities indicating dehydration. Dextrose and intravenous thiamine can be added to fluids when vomiting has been prolonged and persistent.12,81
Extreme Measures for Intractable Nausea and Vomiting in Pregnancy Enteral or Parenteral Feedings Evidence to support enteral or parenteral feedings comes from case reports and small series.82,83 In general, the prudent approach is to start with enteral feedings and move on to peripheral parental nutrition and finally to total parental nutrition if all other methods fail. Serious and even life-threatening complications have been
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reported with parenteral nutrition, so it is used only as a last resort.84 Therapeutic Abortion With current medical interventions such as intravenous hydration and medications, it is rare for NVP to be so severe as to be life threatening. This was not the case in the early twentieth century, when severe NVP represented an important cause of maternal deaths.85 However, maternal morbidity in the form of Wernicke encephalopathy caused by vitamin B1 deficiency, esophageal rupture, acute tubular necrosis, and splenic avulsion have all been reported to be caused by intractable vomiting of pregnancy.1 When the maternal condition is deteriorating as a consequence of hyperemesis gravidarum despite aggressive medical intervention, pregnancy termination may be indicated (Fig. 54.2). Fortunately, symptoms usually subside rapidly as HCG levels fall. Integrative therapy, Bioenergetics, and Mind-Body Therapy (these are additive methods below)
If dehydration significant can add IV fluids at any point
Vitamin B6 30–75 mg PO divided 3 times per day May concomitantly use ginger, P6 Acupressure
Add: Doxylamine 12.5 mg PO 3 or 4 times per day
Add or substitute: Promethazine 12.5–25 mg PO/PR/IM q 4–6 hrs
Add or substitute: Ondansetron 8 mg IV/PO q 8–12 hrs
Add or substitute: Metoclopramide 5–10 mg PO/IM q 8 hrs
Add or substitute: Methylprednisolone 16 mg PO/IV q 8hrs for 3 days then taper over 2 weeks to lowest effective dose (total duration of therapy not to exceed 6 weeks)
If symptoms persist consider hospitalization along with enteral or parenteral feedings
Consider therapeutic abortion if maternal condition deteriorates despite all measures above FIG. 54.2 □ Integrative therapy, bioenergetics, and mind-body therapy algorithm. IM, intramuscularly; IV, intravenous; PO, orally; PR, per rectum; q, every.
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Therapies to Consider Homeopathy No studies have evaluated the efficacy of homeopathic remedies in the treatment of NVP. Practitioners cite anecdotal evidence of homeopathy use, but choosing the correct remedy can be complex because many subtle differences in symptoms are taken into account. Some of the remedies commonly used include nux vomica, sepia, and ipecac.86 Because homeopathic preparations are extensively diluted, they should be safe for pregnant women and unlikely to have any adverse effects if they are not helpful. Some investigators recommend avoiding any remedies with potencies (dilutions) greater than 12C.87 Traditional Chinese Medicine Practitioners of traditional Chinese medicine (TCM) may recommend acupuncture, acupressure, and herbs,
but they also use certain foods such as umeboshi plums (a very salty preserved fruit) to combat nausea. In addition, these clinicians may use practices such as moxibustion, cupping, or massage. The TCM views of health and the body’s function are different from those in Western medicine, and different patterns of symptoms lead to different treatments,88 so a certified TCM practitioner should advise about the use of these approaches.89 Information about training and accreditation of TCM practitioners can be found at the National Certification Center for Acupuncture and Oriental Medicine (www.nccaom.org). Umeboshi plums can be found in most Asian grocery stores. If the plum itself is too salty, some women obtain relief from nausea by sucking on the pit only. Another option is to use one-fourth to one-half a plum at a time.
PREVENTION PRESCRIPTION • T ake a multivitamin prior to pregnancy or before 6 weeks of gestation.20,21 • Eat frequent, small meals that are high in protein to avoid low blood glucose levels. • Avoid overconsumption of simple carbohydrates such as cakes, candy, and starchy foods because they may lead to rebound low glucose levels, which could stimulate more nausea.
• C onsider trying more salty foods and tart liquids because these are reported by some women to be better tolerated. • Avoid triggers such as pungent odors or unpleasant visual stimuli that may worsen nausea. • Increase rest as needed early in pregnancy. • Do light to moderate exercise for 20 minutes three times a week.
THERAPEUTIC REVIEW Lifestyle, botanical, bioenergetic, and mind-body therapies are additive to all the other methods listed here. If dehydration is significant, add intravenous fluids at any point. BIOENERGETICS • Acupuncture (P6)
B
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MIND-BODY THERAPY • Hypnotherapy
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SUPPLEMENTS • Vitamin B6: 30–75 mg PO divided three times per day • Ginger: 250 mg powdered in capsules four times daily or 500 mg twice daily PHARMACEUTICALS • Doxylamine: 12.5 mg orally three to four times daily
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• Add or substitute promethazine: 12.5–25 mg orally, B 2 rectally, or intramuscularly every 4–6 hours • Add or substitute ondansetron: 8 mg intravenously A 3 or orally every 8–12 hours • Add or substitute metoclopramide: 5–10 mg orally or B 2 intramuscularly every 8 hours • Add methylprednisolone: 16 mg orally or intravenously every 8 hours for 3 days then taper over 2 weeks to the lowest effective dose (total duration of B 2 therapy not to exceed 6 weeks) • If symptoms persist, consider hospitalization along C 3 with enteral or parenteral feedings. SURGERY • Consider therapeutic abortion if the maternal condition deteriorates despite all the measures described here and in Fig. 54.2.
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54 Nausea and Vomiting in Pregnancy
Key Web Resources Motherisk morning sickness information: This website contains a treatment algorithm for hyperemesis gravidarum. Evidence-Based Approaches to Managing Nausea and Vomiting in Early Pregnancy: This article provides an overview of NVP and treatment options. It also contains the PUQE index. Registration is required to access this website. BMJ Clinical Evidence: A systematic review of treatments for NVP. Registration is required to access this website.
REFERENCES References are available online at ExpertConsult.com.
http://www.motherisk.org/prof/morningSickness.jsp http://www.medscape.com/viewarticle/712662_3
http://clinicalevidence.bmj.com/ceweb/conditions/ pac/1405/1405.jsp
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REFERENCES 1. Tierson FD, Olsen CL, Hook EB: Nausea and vomiting of pregnancy and association with pregnancy outcome, Am J Obstet Gynecol 155:1017–1022, 1986. 2. Vellacott ID, Cooke EJ, James CE: Nausea and vomiting in early pregnancy, Int J Gynaecol Obstet 27:57–62, 1988. 3. Adams MM, Harlass FE, Sarno AP, et al.: Antenatal hospitalization among enlisted servicewomen, 1987–1990, Obstet Gynecol 84: 35–39, 1994. 4. Lacasse A, Rey E, Ferreira E, et al.: Nausea and vomiting of pregnancy: what about quality of life? Br J Obstet Gynaecol 115: 1484–1493, 2008. 5. Lacasse A, Rey E, Ferreira E, et al.: Validity of a modified pregnancy-unique quantification of emesis and nausea (PUQE) scoring index to assess severity of nausea and vomiting of pregnancy, Am J Obstet Gynecol 198:71.e1–71.e7, 2008. 6. Dodds L, Fell DB, Joseph KS, et al.: Outcomes of pregnancies complicated by hyperemesis gravidarum, Obstet Gynecol 107: 285–292, 2006. 7. Sherman PW, Flaxman SM: Nausea and vomiting of pregnancy in an evolutionary perspective, Am J Obstet Gynecol 186(Suppl): S190–S197, 2002. 8. Flaxman SM, Sherman PW: Morning sickness: a mechanism for protecting mother and embryo, Q Rev Biol 75:113–148, 2000. 9. Goodwin TM: Nausea and vomiting of pregnancy: an obstetric syndrome, Am J Obstet Gynecol 186(Suppl):S184–S189, 2002. 10. Buckwalter JG, Simpson SW: Psychological factors in the etiology and treatment of severe nausea and vomiting in pregnancy, Am J Obstet Gynecol 186(Suppl):S210–S214, 2002. 11. Simpson SW, Goodwin TM, Robins SB, et al.: Psychological factors and hyperemesis gravidarum, J Womens Health Gend Based Med 10:471–477, 2001. 12. American College of Obstetrics and Gynecology: ACOG (American College of Obstetrics and Gynecology) practice bulletin: nausea and vomiting of pregnancy, Obstet Gynecol 103:803–814, 2004. 13. Chandra K, Magee L, Einarson A, Koren G: Nausea and vomiting in pregnancy: results of a survey that identified interventions used by women to alleviate their symptoms, J Psychosom Obstet Gynaecol 24:71–75, 2003. 14. Heinrichs L: Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum, and migraine headache, Am J Obstet Gynecol 186(Suppl 5):S215, 2002. 15. Arsenault MY, Lane CA, MacKinnon CJ, et al.: The management of nausea and vomiting of pregnancy, J Obstet Gynaecol Can 24: 817–831, 2002. quiz 32–33. 16. Sternfeld B, Quesenberry Jr CP, Eskenazi B, Newman L: Exercise during pregnancy and pregnancy outcome, Med Sci Sports Exerc 27:634–640, 1995. 17. Exercise during pregnancy and the postpartum period: ACOG Committee Opinion No. 267. American College of Obstetricians and Gynecologists, Obstet Gynecol 99:171–173, 2002. 18. Jednak MA, Shadigian EM, Kim MS, et al.: Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy, Am J Physiol 277:G855–G861, 1999. 19. Goodwin TM, Poursharif B, Korst LM, et al.: Secular trends in the treatment of hyperemesis gravidarum, Am J Perinatol 25:141–147, 2008. 20. Czeizel AE: Prevention of hyperemesis gravidarum is better than treatment, Am J Obstet Gynecol 174:1667, 1996. 21. Emelianova S, Mazzotta P, Einarson A, Koren G: Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation, Clin Invest Med 22:106–110, 1999. 22. Natural Medicines Comprehensive Database: Ginger: http://naturaldatabase.therapeuticresearch.com, 2011. Accessed September 12, 2011. 23. Vutyavanich T, Kraisarin T, Ruangsri R: Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial, Obstet Gynecol 97:577–582, 2001. 24. Borrelli F, Capasso R, Aviello G, et al.: Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting, Obstet Gynecol 105:849–856, 2005. 25. Ensiyeh J, Sakineh MA: Comparing ginger and vitamin B6 for the treatment of nausea and vomiting in pregnancy: a randomised controlled trial, Midwifery 25:649–653, 2009.
26. Pongrojpaw D, Somprasit C, Chanthasenanont A: A randomized comparison of ginger and dimenhydrinate in the treatment of nausea and vomiting in pregnancy, J Med Assoc Thai 90:1703–1709, 2007. 27. Viljoen E, Visser J, Koen N, Musekiwa A: A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting, Nutr J 13:20, 2014. Epub 2014 Mar 19. 28. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U: Ginger treatment of hyperemesis gravidarum, Eur J Obstet Gynecol Reprod Biol 38:19–24, 1991. 29. Portnoi G, Chng LA, Karimi-Tabesh L, et al.: Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy, Am J Obstet Gynecol 189:1374–1377, 2003. 30. Lumb AB: Mechanism of antiemetic effect of ginger, Anaesthesia 48:1118, 1993. 31. Smith C, Crowther C, Willson K, et al.: A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy, Obstet Gynecol 103:639–645, 2004. 32. Chittumma P, Kaewkiattikun K, Wiriyasiriwach B: Comparison of the effectiveness of ginger and vitamin B6 for treatment of nausea and vomiting in early pregnancy: a randomized double-blind controlled trial, J Med Assoc Thai 90:15–20, 2007. 33. Deleted in author review. 34. Vilojoen E, Visser J, Koen N, Musekiwa A: A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting, Nutr J 13:20, 2014, http://dx.doi.org/10.1186/1475-2891-13-20. 35. Schwertner HA, Rios DC, Pascoe JE: Variation in concentration and labeling of ginger root dietary supplements, Obstet Gynecol 107:1337–1343, 2006. 36. Bryer E: A literature review of the effectiveness of ginger in alleviating mild-to-moderate nausea and vomiting of pregnancy, J Midwifery Womens Health 50:e1–e3, 2005. 37. Forster DA, Denning A, Wills G, et al.: Herbal medicine use during pregnancy in a group of Australian women, BMC Pregnancy Childbirth 6:21, 2006. 38. Wilkinson JM: What do we know about herbal morning sickness treatments? A literature survey, Midwifery 16:224–228, 2000. 39. Moussally K, Oraichi D, Berard A: Herbal products use during pregnancy: prevalence and predictors, Pharmacoepidemiol Drug Saf 18:454–461, 2009. 40. U.S. Food and Drug Administration: Everything added to food in the United States (EAFUS): http://www.fda.gov/food/foodingredientspackaging/ucm115326.htm, 2011. Accessed September 12, 2011. 41. Romm A: Botanical medicine for women’s health, St Louis, 2009, Elsevier. 42. Westfall RE: Use of anti-emetic herbs in pregnancy: women’s choices, and the question of safety and efficacy, Complement Ther Nurs Midwifery 10:30–36, 2004. 43. Gibson PS, Powrie R, Star J: Herbal and alternative medicine use during pregnancy: a cross-sectional survey, Obstet Gynecol 97 (Suppl 1):S44–S45, 2001. 44. Kligler B, Chaudhary S: Peppermint oil, Am Fam Physician 75:1027–1030, 2007. 45. Anderson LA, Gross JB: Aromatherapy with peppermint, isopropyl alcohol, or placebo is equally effective in relieving postoperative nausea, J Perianesth Nurs 19:29–35, 2004. 46. Shin HS, Song YA, Seo S: Effect of Nei-Guan point (P6) acupressure on ketonuria levels, nausea and vomiting in women with hyperemesis gravidarum, J Adv Nurs 59:510–519, 2007. 47. Rosen T, de Veciana M, Miller HS, Stewart L, Rebarber A, Slotnick RN: Obstet Gynecol 102:129, 2003. 48. Evans AT, Samuels SN, Marshall C, Bertolucci LE: Suppression of pregnancy-induced nausea and vomiting with sensory afferent stimulation, J Reprod Med 38:603–606, 1993. 49. Belluomini J, Litt RC, Lee KA, Katz M: Acupressure for nausea and vomiting of pregnancy: a randomized, blinded study, Obstet Gynecol 84:245–248, 1994. 50. McCormack D: Hypnosis for hyperemesis gravidarum, J Obstet Gynaecol 30:647–653, 2010. 51. Baram DA: Hypnosis in reproductive health care: a review and case reports, Birth 22:37–42, 1995. 52. Simon EP, Schwartz J: Medical hypnosis for hyperemesis gravidarum, Birth 26:248, 1999.
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53. Sahakian V, Rouse D, Sipes S, et al.: Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study, Obstet Gynecol 78:33–36, 1991. 54. Vutyavanich T, Wongtra-ngan S, Ruangsri R: Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial, Am J Obstet Gynecol 173:881–884, 1995. 55. Mazzotta P, Magee LA: A risk-benefit assessment of pharmacological and nonpharmacological treatments for nausea and vomiting of pregnancy, Drugs 59:781–800, 2000. 56. Herrell HE: Nausea and vomiting of pregnancy, Am Fam Physician 89:965–970, 2014. 57. Neutel CI, Johansen HL: Measuring drug effectiveness by default: the case of Bendectin, Can J Public Health 86:66–70, 1995. 58. Natural Medicines Comprehensive Database: Pyridoxine (Vitamin B6): http://naturaldatabase.therapeuticresearch.com, 2011. Accessed 12.09.11. 59. Seto A, Einarson T, Koren G: Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis, Am J Perinatol 14:119–124, 1997. 60. Magee LA, Mazzotta P, Koren G: Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP), Am J Obstet Gynecol 186(Suppl): S256–S261, 2002. 61. Matthews A, Haas DM, O’Mathúna DP, Dowswell T, Doyle M: Interventions for nausea and vomiting in early pregnancy, Cochrane Database Syst Rev 3, 2014. CD007575. 62. Aselton P, Jick H, Milunsky A, et al.: First-trimester drug use and congenital disorders, Obstet Gynecol 65:451–455, 1985. 63. Hurley JD, Eshelman FN: Trimethobenzamide HCl in the treatment of nausea and vomiting associated with antineoplastic chemotherapy, J Clin Pharmacol 20:352–356, 1980. 64. Winters HS: Antiemetics in nausea and vomiting of pregnancy, Obstet Gynecol 18:753–756, 1961. 65. Berkovitch M, Mazzota P, Greenberg R, et al.: Metoclopramide for nausea and vomiting of pregnancy: a prospective multicenter international study, Am J Perinatol 19:311–316, 2002. 66. Matok I, Gorodischer R, Koren G, et al.: The safety of metoclopramide use in the first trimester of pregnancy, N Engl J Med 360, 2528–235, 2009. 67. Tan PC, Khine PP, Vallikkannu N, Omar SZ: Promethazine compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial, Obstet Gynecol 115:975–981, 2010. 68. Lacasse A, Lagoutte A, Ferreira E, Berard A: Metoclopramide and diphenhydramine in the treatment of hyperemesis gravidarum: effectiveness and predictors of rehospitalisation, Eur J Obstet Gynecol Reprod Biol 143:43–49, 2009. 69. Bsat FA, Hoffman DE, Seubert DE: Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy, J Perinatol 23:531–535, 2003. 70. Sullivan CA, Johnson CA, Roach H, et al.: A pilot study of intravenous ondansetron for hyperemesis gravidarum, Am J Obstet Gynecol 174:1565–1568, 1996. 71. Abas MN, Tan PC, Azmmi N, Omar SZ: Ondansetron compared with metoclopramide for hyperemesis gravidarum, Obstet Gynecol 123:1272–1279, 2014.
72. Oliveira LG, Capp SM, You WB, Riffenburgh RH, Carstairs SD: Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial, Obstet Gynecol 124:735–742, 2014. 73. Pasternak B, Svanström H, Hviid A: Ondansetron in pregnancy and risk of adverse fetal outcomes, N Engl J Med 368:814–823, 2013. 74. Danielsson B, Wikner BN, Källén B: Use of ondansetron during pregnancy and congenital malformations in the infant, Reprod Toxicol 50:134–137, 2014. Epub 2014 Oct 31. 75. Andersen JT, Jimenez-Solem E, Andersen NL, et al.: Ondansetron use in early pregnancy and the risk of congenital malformations—a register based nationwide control study, Montreal, Canada, 2013, International Society of Pharmaco-epidemiology. Abstract 25, Pregnancy session 1. 76. Safari HR, Fassett MJ, Souter IC, et al.: The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study, Am J Obstet Gynecol 179:921–924, 1998. 77. Ziaei S, Hosseiney FS, Faghihzadeh S: The efficacy of low dose prednisolone in the treatment of hyperemesis gravidarum, Acta Obstet Gynecol Scand 83:272–275, 2004. 78. Yost NP, McIntire DD, Wians Jr FH, et al.: A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy, Obstet Gynecol 102:1250–1254, 2003. 79. Bondok RS, El Sharnouby NM, Eid HE, Abd Elmaksoud AM: Pulsed steroid therapy is an effective treatment for intractable hyperemesis gravidarum, Crit Care Med 34:2781–2783, 2006. 80. Park-Wyllie L, Mazzotta P, Pastuszak A, et al.: Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies, Teratology 62:385–392, 2000. 81. Tan PC, Norazilah MJ, Omar SZ: Dextrose saline compared with normal saline rehydration of hyperemesis gravidarum: a randomized controlled trial, Obstet Gynecol 121(2 Pt 1):291, 2013. 82. Boyce RA: Enteral nutrition in hyperemesis gravidarum: a new development, J Am Diet Assoc 92:733–736, 1992. 83. Christodoulou DK, Katsanos KH, Makrydimas G, et al.: Peripheral parenteral nutrition in protracted hyperemesis gravidarum: report of two cases and a literature review, Acta Gastroenterol Belg 71:259–262, 2008. 84. Russo-Stieglitz KE, Levine AB, Wagner BA, Armenti VT: Pregnancy outcome in patients requiring parenteral nutrition, J Matern Fetal Med 8:164–167, 1999. 85. Reid DE, Teel HM: The treatment of the vomiting of early pregnancy, N Engl J Med 218:109–113, 1938. 86. Ullman D: Discovering homeopathy: your introduction to the science and art of homeopathic medicine, Berkeley, CA, 1991, North Atlantic Books. 87. Carlston M: Classical homeopathy, St. Louis, 2003, Elsevier. 88. Betts D: Harmonising the penetrating vessel in the treatment of morning sickness, J Chin Med 72:36–41, 2003. 89. National Center for Complementary and Alternative Medicine National Institutes of Health: What is Chinese medicine?: http:// nccam.nih.gov/health/chinesemed/, 2011. Accessed 12.09.11.
Nausea and Vomiting in Pregnancy Andrea Gordon, MD • Abigail Love, MD, MPH
PATHOPHYSIOLOGY Nausea and vomiting in pregnancy (NVP) represent a conundrum for the pregnant woman. On the positive side, NVP are correlated with better fetal outcomes than the absence of these symptoms,1 but at the other extreme, NVP can interfere with nutrition and hydration for the mother and developing fetus. Symptoms may range from occasional mild nausea to multiple episodes of daily vomiting resulting in weight loss and electrolyte abnormalities. This severe manifestation is often referred to as hyperemesis gravidarum. Definitions of hyperemesis gravidarum vary, but commonly accepted criteria include weight loss (often more than 5% of prepregnancy weight), electrolyte disturbances, and ketonuria. Usually appearing before the ninth week of pregnancy, NVP will affect up to 85% of normal pregnancies, with symptoms generally remitting by the fourteenth week. Initial presentation of symptoms after the ninth week should prompt a workup to determine an alternative cause. NVP may be mild, but up to 20% of women find their symptoms so significant that they cannot continue to work.2 The reported incidence of hyperemesis gravidarum, the most severe end of the spectrum, varies from 0.5% to 2%. This severely debilitating condition is the most common reason for hospital admission in the first trimester and the second most common problem for which pregnant women are admitted to the hospital, after preterm labor.3 Even at the milder end of the symptom continuum, NVP can lead to a decreased quality of life and missed time from work. The aptly named Motherisk PregnancyUnique Quantification of Emesis and Nausea (PUQE) index has been shown to demonstrate a significant correlation between the presence and severity of NVP and poorer quality of life.4,5 This effect on quality of life and the economic impact of missed work emphasize the need to control these symptoms. Mild or moderate vomiting does not appear to have any significant effects on the fetus. Among women with severe hyperemesis, the reported incidence of low birth weight is higher, but increased reporting of birth defects has not been noted.6 In fact, several investigators suggested that NVP represent an evolutionary adaptation that helps protect the developing fetus from exposure to foods that may contain potential toxins.7,8 The cause of NVP is unknown. Both biological and psychological factors have been proposed. Human chorionic gonadotropin (HCG) and estrogen have been 542
studied as triggers for these symptoms. Suggestive evidence includes the finding that pregnant women with higher levels of HCG, which occur in molar pregnancies and multiple gestations, have significantly more episodes of vomiting and higher rates of hyperemesis gravidarum. This theory is also supported by the observations that nonpregnant women who experience nausea and vomiting after exposure to estrogens are more likely to experience NVP. Cigarette smoking is known to reduce both estrogen and HCG levels, and pregnant smokers are less likely to experience hyperemesis gravidarum.9 No controlled studies support the theory that NVP comprise a conversion disorder or an inability to respond to life stress.10,11 The association of high levels of HCG and estradiol with increasingly severe episodes of vomiting in pregnancy indicates a physiological origin, as do epidemiological factors. Daughters and sisters of women who had hyperemesis are more likely to have NVP as well. Other risk factors include a previous pregnancy affected by hyperemesis, a female fetus, and a history of motion sickness or migraines.12
INTEGRATIVE THERAPY When treatment is considered, risks and benefits must be clearly explained to the pregnant woman. Minimizing the risks of any treatment is desirable, but the presence of a developing fetus makes it more urgent to decrease any unnecessary exposures. This is an ideal time to use integrative approaches because drugs generally represent more risk than other modalities. In addition, some of the behavior modifications such as exercise are beneficial in and of themselves.
Lifestyle Although the efficacy of lifestyle modifications has not been studied, these interventions are safe and have been anecdotally reported to be useful.13 Avoid Odors Some women report that NVP are triggered by strong odors such as foods, cigarette smoke, or perfume. This is supported by a small study showing that women with congenital anosmia were less likely to develop NVP.14 Avoiding these stimuli may be helpful. Women should be supported in doing so, for example, by passing
54 Nausea and Vomiting in Pregnancy
off cooking duties to someone else, avoiding tasks with strong odors such as feeding the dog, or politely asking coworkers not to wear perfume for a few weeks. Increase Rest Sleep requirements increase in early pregnancy.15 Women frequently report nausea in association with feelings of exhaustion. Caregivers should educate pregnant patients that fatigue is common and support them in trying to obtain the additional rest they need. Exercise Light to moderate aerobic exercise is associated with fewer NVP symptoms. Women who exercised at least three times a week for 20 minutes or more reported fewer symptoms of pregnancy, including nausea.16 Women who have already been exercising can remain active during uncomplicated pregnancies. Previously inactive women may benefit from gentle exercise but should be evaluated on an individual basis before recommendations for physical activity are made.17
Nutrition Low blood glucose levels seem to trigger nausea and subsequently vomiting in many women; thus small, frequent, high-protein, high-fiber meals are often recommended.18 A potentially helpful approach is to decrease simple carbohydrates that rapidly raise blood glucose and thus stimulate insulin secretion, which can cause rapidly falling blood glucose (see Chapter 87). However, this includes foods such as pasta, white rice, potatoes, and white bread, whose blandness seems desirable when patients are nauseated, so education is key. Some patients find that eating something as soon as they wake up and then every 2 hours can suppress nausea. Each pregnant woman may have specific foods she avoids because of a taste or smell that triggers nausea, but it may also be necessary to avoid spicy or fatty foods because they can exacerbate symptoms. Little published evidence exists on the efficacy of dietary changes, but benefit clearly outweighs harm. In one international survey, dietary interventions seemed to help 22% of women with hyperemesis gravidarum.19 Two studies found that taking a multivitamin before pregnancy or before 6 weeks of gestation was associated with a decreased incidence of NVP. Although this approach would not help a woman already suffering with symptoms, it could be helpful for women at risk for symptoms in their next pregnancy.20,21
Botanicals Ginger Root (Zingiber officinale) Historically, ginger has been effectively and safely used to treat nausea, including that of pregnancy. Randomized controlled trials have shown that ginger is effective for treating NVP,22 and it is the most thoroughly studied herb for this indication. Some trials have shown ginger to be not only more effective than placebo23 but also
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comparable to or better than vitamin B624,25 and comparable to dimenhydrinate.26 It will reduce overall nausea symptoms but not the number of vomiting episodes significantly.27 Patients should be advised that it may take longer for ginger to work: up to 3 days, rather than 1 day for dimenhydrinate. The U.S. Food and Drug Administration (FDA) has listed ginger as a food supplement that is generally recognized as safe,28 and studies have not shown any increased incidence of malformations in children of mothers using ginger.29 Ginger seems to work primarily in the gastrointestinal tract on serotonin receptors in the ileum, the same receptors affected by some antiemetics, such as ondansetron. Some evidence indicates that ginger constituents may also have some action in the central nervous system.30 No toxicity has been demonstrated, although ginger can cause abdominal discomfort or heartburn when it is taken in large doses, especially on an empty stomach.
Dosage Most of the studies have used 1000 mg daily, in two or four divided doses.23,26,28,31 A higher dose of 650 mg three times daily has also been used,32 but total doses of less than 1500 mg a day are more effective.34 Ginger is available in a variety of forms, and an evaluation of products purchased in pharmacies and health food stores found a wide variation in the amount of active ingredients and suggested serving sizes.35 Women may prefer one form over another, so approximate equivalents can be calculated. In general, 1 g of standardized extract is equivalent to 1 teaspoon of fresh grated ginger root, two droppers (2 mL) of liquid extract, four 8-oz cups of prepackaged ginger tea, four 8-oz cups of tea made with 0.5 teaspoon of grated ginger steeped for 5–10 minutes, 8 oz of ginger ale (made with real ginger—most commercial ginger ales are not effective), two pieces of crystallized ginger (1 inch square, 0.25 inches thick), or two teaspoons (10 mL) of ginger syrup.36 Capsules of ginger come in various dosages, ranging from 100 to 1000 mg, and chewable tablets may contain 67 to 500 mg, so attention to the dosing of the product used is advisable, with the goal a total of less than 1500 mg a day. Using ginger throughout the day is also helpful. Patients can incorporate ginger into their diet by sprinkling dried or candied ginger in oatmeal, having some ginger tea, and adding fresh ginger to soup or stir-fries. Precautions There is a theoretical risk for bleeding as ginger inhibits thromboxane synthetase and may inhibit platelet function. This has not been demonstrated, but precaution should be taken when ginger is used concomitantly with anticoagulants.
Chamomile (Matricaria chamomilla) Chamomile is a flowering plant that is often used for various types of gastrointestinal upset, including travel sickness, colic, and inflammatory diseases of the bowel. It is commonly used for NVP,37-39 although no research on this application has been published. Chamomile appears to be safe and well tolerated, however, and the FDA labels it as safe.40
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Dosage Prepare it as a tea, allowing it to steep for 5–7 minutes while covered, so it will retain the volatile active constituents, and sip as needed. Precautions Chamomile should be used with caution in patients who are allergic to the Asteraceae/Compositae family, which includes ragweed, daisies, and many other flowers. Some erroneous concern exists about teratogenicity, but that concern is based on a study with alpha-bisabolol at high doses that could not be achieved by someone drinking tea.41
Peppermint Leaf (Mentha piperita) Peppermint is another herb often used in pregnancy.42,43 The active parts are the stems, leaves, and flowers, as well as the peppermint oil that is distilled from these plant parts. Studies have shown peppermint oil to be effective for reducing bowel spasms in irritable bowel syndrome and for patients receiving barium enemas, but peppermint oil has not been studied in pregnancy.44 Its mechanism of action is reduction of spasm in smooth muscle, and it may help with NVP by reducing esophageal dysmotility. However, this effect can also reduce lower esophageal sphincter pressure, resulting in reflux. Theoretical concerns exist with using the essential oil in pregnancy because it may cross the placental barrier, but the amount of peppermint ingested in tea or food seems to be safe.41 Peppermint has been rated as safe by the FDA.40
Dosage The dose is two to three cups of tea daily. Many women find peppermint candies or gum to be effective in squelching nausea. A dose of 0.2 mL in 2 mL of isotonic saline solution used as aromatherapy has been used for postoperative nausea and can be tried if teas or foods containing peppermint are not tolerated.45 Precautions Peppermint can aggravate reflux by decreasing the lower esophageal sphincter tone.
Bioenergetics Acupressure: Stimulation of the P6 Neiguan Point Acupressure of the pericardium 6 (P6) Neiguan (meridian) point, which is located on the inner wrist, may be beneficial. Several small studies have found this to be effective, including a Korean trial, which found significantly less NVP in a group of women with hyperemesis gravidarum,46 and another that demonstrated self-administered nerve stimulation therapy over using a commercial device.47 However, a 2014 Cochrane analysis did not find P6 acupuncture or acupressure wristbands to be significantly more effective than placebo. Other studies using a
crossover design, which were not included in the Cochrane analysis, also showed benefit to using acupressure at the P6 point,46,48 and another trial revealed decreased nausea with P6 stimulation, but no change in the frequency of vomiting.49 Patients should be made aware of this mixed evidence; patients are willing to try acupressure because it is inexpensive and has no significant side effects. Patients can be taught to find the P6 point and treat themselves with either manual pressure or the application of “Sea-Bands” (Fig. 54.1). These elastic bands with attached plastic disks were originally used for motion sickness. Patients can create their own version of such bands by placing a small, round object such as a bead over the point and securing it with tape and then massaging the bead. This therapy has no known negative side effects. To have a patient accurately locate the P6 point, have her lay one hand palm up, with the other hand placed palm down at right angles to the upturned arm. The first three fingers of the palm-down hand are held close together, and the edge of the ring finger is placed at the crease of the wrist closest to the palm in alignment with the middle finger of the upturned hand. The P6 point, between the palmaris longus and flexor radialis tendons, is now readily palpable under the tip of the index finger of the examining hand (see Fig. 54.1A). This point is often tender, a characteristic that aids in its location. Many patients use this acupressure in conjunction with other interventions because it has no known side effects or interactions.
Patients can stimulate the P6 point at any time, but they should be cautioned against using any other acupressure points without consulting a trained practitioner. Some commonly used points, such as the Ho-Ku point that is located between first and second metacarpals (often used for headaches), can stimulate contractions. Patients must be instructed to press on the point when feeling nausea, as just wearing the bands may not provide significant relief.
Mind-Body Therapy Hypnosis Hypnosis has been studied as a treatment for hyperemesis gravidarum. A review of six studies showed encouraging effects, but methodological problems did not allow a definitive recommendation.50 This intervention is safe, however, and some women may want to try it for all levels of NVP. One approach has been to suggest to a woman that the “nausea center” in her brain is very sensitive to the hormones of pregnancy and that she is able to “turn down” that sensitivity as one would a thermostat.51 Another approach is to link the muscle tension in the stomach and throat or the nausea as a hypnotic cue to pleasant imagery.52 This imagery may be helpful for patients to use when nausea strikes. NVP may have an element of conditioned response, as noted with chemotherapy-associated vomiting. Some uncontrolled studies showed that hypnosis can reduce vomiting and anticipatory vomiting in patients
54 Nausea and Vomiting in Pregnancy
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PC6 NEIGUAN P-6
A
B FIG. 54.1 □ A, The P6 Neiguan acupressure point is located on the volar aspect of the forearm by placing the examining hand three fingerbreadths below the wrist crease. The patient’s finger widths should be used for measurement. The P6 point is essentially in the midline between the tendons of the palmaris longus and flexor radialis muscles. B, Location of this point. PC, pericardium
undergoing chemotherapy,10 so the potential exists for hypnosis to work for NVP. Because this treatment may require several sessions of training, the time and expense may be prohibitive for some patients. Counseling and Psychotherapy Although the general consensus is that NVP does not represent a conversion disorder and is not caused by emotional responses to the pregnancy,10 evidence indicates that women with NVP may be under more stress. Two investigators stated that NVP “could subject any normal expectant mother to stress sufficient to trigger adjustment disorders, generalized anxiety, or even depressive episodes.”10 In recognition of this extraordinary stress, counseling or psychotherapy may be helpful in coping with the symptoms and their effects on a woman’s life.
Supplements Vitamin B6 (Pyridoxine) Vitamin B6 is a water-soluble vitamin that is an effective treatment for nausea in pregnancy. The benefit in reducing vomiting episodes is less clear.53,54 The mechanism of action of pyridoxine remains unknown, but extensive analysis for teratogenicity has shown no negative effects on pregnancy outcome.55 Patients can expect a significant reduction of nausea with few side effects if they take vitamin B6, so this should be used as a first-line treatment of NVP.56
A popular medication for nausea and vomiting, known as Bendectin in the United States and Diclectin in Canada, contained pyridoxine and doxylamine. Bendectin was withdrawn from the United States market in 1983 out of safety concerns about teratogenicity, but no studies validated this possibility. Diclectin remains available in Canada and is one of the most widely studied and used medications in pregnancy today. Following removal of Bendectin from the market, no reduction in birth defects was reported, but hospitalization rates for NVP doubled.57 Diclectin, a combination of doxylamine 10 mg and pyridoxine 10 mg, is available in Canada and can be purchased online (www.canadadrugs.com). It is expensive, at more than a dollar a pill. A recommended and less expensive alternative is to combine Unisom (contains 25 mg doxylamine), one-half tablet at bedtime, with 25 mg of pyridoxine, as the combination reduces symptoms by 70%.56 [Category C] Dosage The most effective dosage of B6 appears to be 30–75 mg daily in three divided doses. Studies performed with the higher end of the dosing range have shown effectiveness against vomiting as well as nausea.53,54 When vitamin B6 alone is not effective, it may be combined with doxylamine to obtain relief from NVP. Precautions Pyridoxine can cause sensory neuropathy, which is related to the daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 g or more pose the most risk, so the doses that have been used for NVP appear generally to be safe.58
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Pharmaceuticals Antihistamines Several histamine (H1) receptor antagonists have been studied for the treatment of NVP. The most frequently studied and used is doxylamine (Unisom, an over-the-counter sleep aid). An extensive review of safety data revealed no adverse pregnancy outcomes from the use of doxylamine alone or in combination with pyridoxine.59 Other drugs in this group, which all have shown some evidence of efficacy and safety for controlling NVP, are dimenhydrinate (Dramamine), cetirizine (Zyrtec), meclizine (Antivert), hydroxyzine (Vistaril), and diphenhydramine (Benadryl).60 Dosage Most patients should use 12.5 mg of doxylamine, the amount in one-half of a scored tablet. This is the amount of doxylamine that was present in Bendectin. Indeed, many women try to “make” a form of Bendectin by combining doxylamine with vitamin B6. This safe option can be suggested if vitamin B6 alone or with ginger or P6 point stimulation is not working adequately. Diphenhydramine, given in 25- to 50-mg doses up to every 6 hours, is also safe and easily obtained. Precautions All antihistamines can cause drowsiness.
Phenothiazines The phenothiazines used to treat NVP include promethazine (Phenergan), prochlorperazine (Compazine), chlorpromazine (Thorazine), and perphenazine (Trilafon). Only promethazine has randomized controlled study data supporting its efficacy and safety.60,61 However, some evidence indicates that all medications in this group have some efficacy in the treatment of NVP.55 These medications may be used in the outpatient setting, but therapy is often not started until hospital admission for treatment of dehydration or intractable vomiting. The variable dosing forms are advantageous for NVP: these drugs can be self-administered orally or rectally or given intramuscularly by medical personnel if needed. Dosage For promethazine, begin with 12.5 mg per rectum or by mouth and progress to 25 mg every 4 hours as needed. Precautions Side effects of promethazine include sedation, hypotension, dystonia, and extrapyramidal symptoms. If needed, diphenhydramine 25 mg can be given orally every 6 hours to treat dystonia or extrapyramidal side effects.
Dopamine Antagonists Two dopamine antagonists have been studied for the treatment of NVP: trimethobenzamide (Tigan) and metoclopramide (Reglan). Trimethobenzamide has been shown to be safe,62 but it has been largely studied for
nausea in other settings such as chemotherapy.63 Only one double-blind trial focused on the effectiveness of trimethobenzamide in treating NVP.64 This study showed that trimethobenzamide, alone or in combination with pyridoxine, significantly improved symptoms of nausea and vomiting compared with placebo.64 Metoclopramide is not associated with malformation risk,65,66 and it has been shown to be effective in hyperemesis gravidarum, with or without promethazine.67,68 A combination of vitamin B6 and metoclopramide was shown to be more effective than prochlorperazine or promethazine for NVP.69
Dosage Metoclopramide can be given orally in 5- to 10-mg doses three times daily before meals. Precautions The side effects of metoclopramide are similar to those of the phenothiazines, but occur less frequently.
5-Hydroxytryptamine3 Receptor Agonists Ondansetron (Zofran), a 5-hydroxytryptamine3 receptor agonist, is a potent antiemetic originally used for treatment of chemotherapy-induced nausea and vomiting. Data on NVP are limited, but several small studies have found it to be as effective as promethazine,70 or as effective as metoclopramide in women with hyperemesis gravidarum.71 Another trial, which more accurately reflects what is often used in practice, demonstrated ondansetron to be superior to the combination of pyridoxine and doxylamine.72 Dosage Ondansetron is given orally or intravenously, 4–8 mg up to every 8 hours. Ondansetron is available in an orally disintegrating tablet. This can be useful if one becomes too nauseated to swallow any medication. Precautions Adverse reactions to ondansetron include headache, fever, and bowel dysfunction, although this agent has been reported to be better tolerated by patients than promethazine, with no dystonic or extrapyramidal side effects. Two recent studies found no significant increase in major fetal malformations or outcomes,73,74 and the FDA has labeled ondansetron Pregnancy Category B. However, patients do need to be informed that there is a demonstrated association with an increased risk of cardiac septum defects, mainly atrial septal defect and ventricular septal defect.74,75 In light of this evidence, as well as cost considerations, it is prudent to try the other measures and medications discussed previously prior to considering the use of ondansetron, and then discussing the risks with patients. “No statistically significantly increased risk for a major malformation was found with ondansetron. The risks for a cardiovascular defect and notably a cardiac septum defect were increased and statistically significant (OR = 1.62, 95% CI 1.04–2.14, and RR 2.05, 95% CI 1.19–3.28, respectively). The teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely.”74
54 Nausea and Vomiting in Pregnancy
Corticosteroids Several small studies have evaluated corticosteroids, primarily methylprednisolone, for efficacy in reducing NVP and hyperemesis. Methylprednisolone reduced symptoms of NVP along with hospital readmission rates for hyperemesis.76 Another trial found that promethazine worked more rapidly than prednisolone, but after a week both medications worked equally well, and the prednisolone group had fewer side effects.77 Various oral and intravenous dosages have been studied, but the most common regimen is 16 mg of methylprednisolone 3 times daily, with attempts to taper after 3 days. Most patients respond within 3 days, so if no improvement has been seen by that time, longer treatment is generally not indicated. Methylprednisolone may be continued for up to 6 weeks, but longer use may result in adverse maternal effects related to prolonged steroid exposure.76,78 Evidence also indicates that a shorter course of hydrocortisone is effective for treating intractable hyperemesis.79 A meta-analysis found an increased risk of oral clefts associated with prednisone use.80
Dosage The dose of methylprednisolone is 16 mg orally or intravenously every 8 hours for up to 2 weeks (tapered course to avoid adrenal suppression). The dose of hydrocortisone is 300 mg intravenously daily for 3 days, then tapered over one week. Precautions Avoid corticosteroid use before 10 weeks of gestation if possible. Avoid prolonged use for more than 6 weeks to reduce the risk of maternal side effects.
Intravenous Fluids Intravenous fluids have not been specifically studied for the treatment of hyperemesis, but they are often coadministered with other medications in the hospital setting for the treatment of dehydration. Intravenous fluid is generally recommended when patients fail to tolerate oral fluids for a prolonged period or show electrolyte abnormalities indicating dehydration. Dextrose and intravenous thiamine can be added to fluids when vomiting has been prolonged and persistent.12,81
Extreme Measures for Intractable Nausea and Vomiting in Pregnancy Enteral or Parenteral Feedings Evidence to support enteral or parenteral feedings comes from case reports and small series.82,83 In general, the prudent approach is to start with enteral feedings and move on to peripheral parental nutrition and finally to total parental nutrition if all other methods fail. Serious and even life-threatening complications have been
547
reported with parenteral nutrition, so it is used only as a last resort.84 Therapeutic Abortion With current medical interventions such as intravenous hydration and medications, it is rare for NVP to be so severe as to be life threatening. This was not the case in the early twentieth century, when severe NVP represented an important cause of maternal deaths.85 However, maternal morbidity in the form of Wernicke encephalopathy caused by vitamin B1 deficiency, esophageal rupture, acute tubular necrosis, and splenic avulsion have all been reported to be caused by intractable vomiting of pregnancy.1 When the maternal condition is deteriorating as a consequence of hyperemesis gravidarum despite aggressive medical intervention, pregnancy termination may be indicated (Fig. 54.2). Fortunately, symptoms usually subside rapidly as HCG levels fall. Integrative therapy, Bioenergetics, and Mind-Body Therapy (these are additive methods below)
If dehydration significant can add IV fluids at any point
Vitamin B6 30–75 mg PO divided 3 times per day May concomitantly use ginger, P6 Acupressure
Add: Doxylamine 12.5 mg PO 3 or 4 times per day
Add or substitute: Promethazine 12.5–25 mg PO/PR/IM q 4–6 hrs
Add or substitute: Ondansetron 8 mg IV/PO q 8–12 hrs
Add or substitute: Metoclopramide 5–10 mg PO/IM q 8 hrs
Add or substitute: Methylprednisolone 16 mg PO/IV q 8hrs for 3 days then taper over 2 weeks to lowest effective dose (total duration of therapy not to exceed 6 weeks)
If symptoms persist consider hospitalization along with enteral or parenteral feedings
Consider therapeutic abortion if maternal condition deteriorates despite all measures above FIG. 54.2 □ Integrative therapy, bioenergetics, and mind-body therapy algorithm. IM, intramuscularly; IV, intravenous; PO, orally; PR, per rectum; q, every.
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PART II Integrative Approach to Disease
Therapies to Consider Homeopathy No studies have evaluated the efficacy of homeopathic remedies in the treatment of NVP. Practitioners cite anecdotal evidence of homeopathy use, but choosing the correct remedy can be complex because many subtle differences in symptoms are taken into account. Some of the remedies commonly used include nux vomica, sepia, and ipecac.86 Because homeopathic preparations are extensively diluted, they should be safe for pregnant women and unlikely to have any adverse effects if they are not helpful. Some investigators recommend avoiding any remedies with potencies (dilutions) greater than 12C.87 Traditional Chinese Medicine Practitioners of traditional Chinese medicine (TCM) may recommend acupuncture, acupressure, and herbs,
but they also use certain foods such as umeboshi plums (a very salty preserved fruit) to combat nausea. In addition, these clinicians may use practices such as moxibustion, cupping, or massage. The TCM views of health and the body’s function are different from those in Western medicine, and different patterns of symptoms lead to different treatments,88 so a certified TCM practitioner should advise about the use of these approaches.89 Information about training and accreditation of TCM practitioners can be found at the National Certification Center for Acupuncture and Oriental Medicine (www.nccaom.org). Umeboshi plums can be found in most Asian grocery stores. If the plum itself is too salty, some women obtain relief from nausea by sucking on the pit only. Another option is to use one-fourth to one-half a plum at a time.
PREVENTION PRESCRIPTION • T ake a multivitamin prior to pregnancy or before 6 weeks of gestation.20,21 • Eat frequent, small meals that are high in protein to avoid low blood glucose levels. • Avoid overconsumption of simple carbohydrates such as cakes, candy, and starchy foods because they may lead to rebound low glucose levels, which could stimulate more nausea.
• C onsider trying more salty foods and tart liquids because these are reported by some women to be better tolerated. • Avoid triggers such as pungent odors or unpleasant visual stimuli that may worsen nausea. • Increase rest as needed early in pregnancy. • Do light to moderate exercise for 20 minutes three times a week.
THERAPEUTIC REVIEW Lifestyle, botanical, bioenergetic, and mind-body therapies are additive to all the other methods listed here. If dehydration is significant, add intravenous fluids at any point. BIOENERGETICS • Acupuncture (P6)
B
1
MIND-BODY THERAPY • Hypnotherapy
B
1
A
1
B
1
SUPPLEMENTS • Vitamin B6: 30–75 mg PO divided three times per day • Ginger: 250 mg powdered in capsules four times daily or 500 mg twice daily PHARMACEUTICALS • Doxylamine: 12.5 mg orally three to four times daily
A
2
• Add or substitute promethazine: 12.5–25 mg orally, B 2 rectally, or intramuscularly every 4–6 hours • Add or substitute ondansetron: 8 mg intravenously A 3 or orally every 8–12 hours • Add or substitute metoclopramide: 5–10 mg orally or B 2 intramuscularly every 8 hours • Add methylprednisolone: 16 mg orally or intravenously every 8 hours for 3 days then taper over 2 weeks to the lowest effective dose (total duration of B 2 therapy not to exceed 6 weeks) • If symptoms persist, consider hospitalization along C 3 with enteral or parenteral feedings. SURGERY • Consider therapeutic abortion if the maternal condition deteriorates despite all the measures described here and in Fig. 54.2.
C
3
54 Nausea and Vomiting in Pregnancy
Key Web Resources Motherisk morning sickness information: This website contains a treatment algorithm for hyperemesis gravidarum. Evidence-Based Approaches to Managing Nausea and Vomiting in Early Pregnancy: This article provides an overview of NVP and treatment options. It also contains the PUQE index. Registration is required to access this website. BMJ Clinical Evidence: A systematic review of treatments for NVP. Registration is required to access this website.
REFERENCES References are available online at ExpertConsult.com.
http://www.motherisk.org/prof/morningSickness.jsp http://www.medscape.com/viewarticle/712662_3
http://clinicalevidence.bmj.com/ceweb/conditions/ pac/1405/1405.jsp
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