Hyperemesis Gravidarum

Obstet Gynecol Clin N Am 35 (2008) 401–417

Hyperemesis Gravidarum T. Murphy Goodwin, MD* Division of Maternal-Fetal Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA

Hyperemesis gravidarum (HG) occurs in 0.3% to 2% of pregnant women, although populations with significantly higher rates have been reported. In most cases, it represents the far end of the spectrum of nausea and vomiting of pregnancy. Nausea and vomiting of pregnancy itself affects approximately 75% of pregnant women, with 25% reporting nausea alone and 50% reporting both nausea and vomiting. In clinical practice, HG is identified by otherwise unexplained intractable vomiting and dehydration.

For the purposes of investigation, a criterion of weight loss, usually more than 5% of prepregnancy weight, confirms the diagnosis.

Until the middle of the twentieth century, about 10% of hyperemesis cases ended in the death of the mother [1]. Although maternal death is uncommon now, it still does occur, related either directly to HG or to interventions. It is the most common cause of hospitalization in the first half of pregnancy, and the cost of care for these cases is estimated to be more than $500M annually for hospitalization alone [2].

Etiology HG is clearly related to a product of placental metabolism because it does not require the presence of the fetus. It occurs commonly with advanced molar gestation and multiple gestations. More than 20 studies of nonthyroidal hormonal changes in nausea and vomiting of pregnancy have been published in the last 30 years. The only differences between subjects who had HG and controls that have been reported in more than one study are in the levels of human chorionic gonadotropin (hCG) and estradiol. Although there is conflicting information, several lines of evidence point toward a role for these two hormones. * Women’s and Children’s Hospital, 1240 North Mission Road, Room 5K-40, Los Angeles, CA 90033.

E-mail address: tgoodwin@usc.edu 0889-8545/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ogc.2008.04.002 obgyn.theclinics.com

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There is a strong temporal association between hCG concentrations and the time of peak symptoms of nausea and vomiting of pregnancy [3,4]. hCG is the thyroid stimulator of pregnancy, and biochemical hyperthyroidism is seen commonly in HG [5]. It has been difficult, however, to link total hCG concentrations directly with the severity of nausea and vomiting of pregnancy and with HG, because concentrations vary widely in the normal and sick population. What commonly is called ‘‘hCG’’ actually is a family of isoforms that differ in half-life and potency at the luteinizing hormone (hCG) and thyroid-stimulating hormone (TSH) receptor, and differences in the isoforms may explain some of the variation in the relationship between total hCG concentrations and thyroid stimulation. Forms lacking the carboxy-terminal portion, for example, are more potent stimulators of the TSH and luteinizing hormone receptor but have shorter half-lives. Hyperglycosylated hCG, on the other hand, has a longer half-life and has a longer duration of action [6].

A link between the action of hCG and estradiol has been suggested by the finding that concentrations of hyperglycosylated hCG correlate with estradiol levels and the severity of nausea and vomiting. It is hypothesized that stimulation of maternal ovarian production (and possibly fetal production of estradiol) increases the estradiol concentration in the mother. Nausea and vomiting in women taking the combined oral contraceptive pill increases in direct correlation with the estradiol dose [7]. A history of nausea and vomiting while taking estrogens is a risk factor for development of HG. At the molecular level, there is evidence that HG is associated with increased activity in the trophoblast cells at the maternal–fetal interface. Increased concentrations of fetal cell free DNA have been identified in maternal serum [8].

This finding is consistent with trophoblast damage caused by a hyperactive maternal immune response in which the normal shift to T-helper cell type 2 over T-helper cell type 1 dominance is more exaggerated in women who have HG [9]. The increase in interleukin 4–secreting cells in this setting favors hCG production, as does the increase in tumor necrosis factor-a (TNFa) that has been reported with HG [10]. Adenosine, which is thought to attenuate the oxidative burst of TNFa in response to a pathologic surge, also is increased in HG [11]; its precursor is catalytic enzyme 5’-nucleotidase [12].

Epidemiologic studies have identified some common factors in women who have HG and other common nausea and vomiting syndromes, namely postoperative nausea and vomiting and chemotherapy-related nausea and vomiting. These factors include younger age, a history of motion sickness, a history of migraines, and symptoms occurring at an early hour of the day. Smoking is associated with decreased concentrations of hCG and estradiol, whereas female gender of the fetus is associated with greater concentrations of hCG [13]. Female gender of the fetus also is associated with more severe HG [14]. Rarely, HG has been reported in association with underlying maternal metabolic disorders, in particular the disorders of fatty acid oxidation.

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Evidence supporting a genetic predisposition to nausea and vomiting of pregnancy includes (1) the concordance in frequency of nausea and vomiting of pregnancy in monozygotic twins [15]; (2) the fact that siblings and mothers of patients affected with nausea and vomiting of pregnancy are more likely to be affected than siblings of unaffected individuals [16]; (3) the variation in the frequency of nausea and vomiting of pregnancy among different ethnic groups [17]; and (4) the occurrence of nausea and vomiting of pregnancy in women who have inherited glycoprotein hormone receptor defects [18]. The role of the paternal genome in HG was suggested by a recent study from Norway [19]. Women who had HG in one pregnancy had a 60% lower rate of recurrence HG in the next pregnancy when the baby had a different father.

Psychologic factors For many years it was presumed that women suffering from HG were predisposed to the disorder by something in their own psychologic make up or in the circumstances of their lives. Numerous competing theories, drawn mostly from psychoanalysis, identified women as rejecting the father of the baby, being ambivalent about the pregnancy, rejecting their own femininity, being either too dependent on their mothers, or, conversely, not dependent enough! None of the many reports and few of the systematic studies offered to support the hypothesis would pass muster by today’s standards.

One of the most influential concluded that women who had HG had a hysteric personality type, even though the only blinded evaluation in the investigation, the Minnesota Multiphasic Personality Inventory, showed no difference [20]. Buckwalter and Simpson [21] reviewed these studies and concluded that there is little support for the concept that HG is caused by a particular psychologic state.

The concept that women are, in a sense, responsible for their own HG persists. In a recent survey study by Munch [22], 93 of 96 women reported their own conviction that the condition had a biologic basis and that psychologic problems were secondary to the severe illness. Nevertheless, most of the same cohort reported that friends, family members, and caregivers constantly implied that they somehow were in control of their disease state.

A behavioral component of nausea and vomiting is well accepted in other areas of medicine. This component does not mean that the subject is responsible for the vomiting; rather, the circumstances of the original stimulus to vomiting exacerbate subsequent vomiting via a behavioral pathway. This concept is supported by the work of Bayley and colleagues [23], who showed that the development of food aversions in pregnancy (present in about 50% of women) is linked closely to the onset of nausea. In 64% of cases, the first occurrence of nausea was reported either in the week preceding the first food aversion or in the same week. These findings are consistent with a taste aversion–learning mechanism, in which foods paired with illness are avoided

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subsequently. The fact that cravings common in pregnancy do not follow this pattern is supportive of the same concept. Anticipatory vomiting associated with chemotherapy is thought to be caused by a similar mechanism; it is refractory to pharmacologic interventions but can be treated by behavioral therapies [24]. Food aversions in pregnancy are similar to those that develop with chemotherapy, in that they generally do not persist after the acute course of the primary stimulus ends; this experience is distinct from conditioned responses, which otherwise may persist for years. Uncontrolled case series have suggested a benefit of behavioral therapy or hypnosis in the treatment of HG. Embryo protection hypothesis A different perspective on nausea and vomiting of pregnancy and HG has come from the filed of evolutionary biology [25]. In this view, nausea and vomiting of pregnancy is a mechanism that has evolved, along with food aversions, to prevent the pregnant mother from ingesting food substances that may be harmful to the developing fetus. According to this theory the harm could come from contamination of the food supply or from substances that in themselves are toxic to the fetus. The common aversion to coffee and highly spiced foods is given as an example of the latter possibility. For the practicing obstetrician, this academic debate has significance, because one consequence is that nausea and vomiting of pregnancy and even, to some extent, HG are treated as normal, protective phenomena. The unfortunate consequence is that many of the 30% or so of pregnant women who suffer some disability from nausea and vomiting of pregnancy and even some cases of HG could be denied treatment. A counter view is that even if nausea and vomiting of pregnancy and HG evolved as a protective phenomenon, this benefit no longer is applicable. Much as thrombophilias are thought to have been preserved in nature as a protection against postpartum hemorrhage but now are understood as a significant health risk, so any perceived benefit of nausea and vomiting of pregnancy would not pertain in societies with modern health care and a safe food supply.

Nausea and vomiting of pregnancy as a syndrome Most of the attempts to understand the cause of nausea and vomiting of pregnancy have been directed at the trigger, which is of placental origin. It is clear, however, that nausea and vomiting of pregnancy is better regarded as a syndrome with the final phenotype arising from different pathways. Thus, for example, the stimulus to HG is affected by placental mass, in that it is more common in multiple gestation, and probably by both mass and aberrant production (perhaps of hCG), as in advanced molar gestation or in pregnancies characterized by trisomy 21. The paternal genotype within the placenta must play a role, as is shown by the effect of different fathers on

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the risk of recurrent HG. Equally important, an individual mother’ response to this stimulus is mediated genetically, as shown by family studies of HG. The susceptibility of the mother varies, depending on a number of factors that are recognized as mediating nausea and vomiting in other settings such as postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting.

Clinical presentation Careful prospective studies show that virtually all women who develop nausea and vomiting of pregnancy have some symptoms by 9 weeks’ gestation. Seven percent of pregnant women have symptoms before the time of the first missed period. Sixty percent are symptomatic by 6 weeks. For the subset of women who have HG, there is a tendency for early onset of symptoms and much greater duration overall. The timing of the cessation of symptoms of nausea and vomiting of pregnancy and HG is shown in Table 1.

In addition to nausea and vomiting, associated complaints include excess salivation (ptyalism) in up to 60% of cases of HG [26]. Although there is a common perception that women who have more severe nausea and vomiting of pregnancy are most sensitive to olfactory stimuli, this belief has not been documented in objective studies. Rather, there is a change in the hedonic rating of odors, somewhat similar to that seen in chemotherapyinduced nausea [27].

The literature has been divided on the relationship between maternal body mass and the risk of HG. Recently, this relationship has been clarified in population-based studies. In a study from Canada, Cedergren and colleagues [28] found a low prepregnancy body mass index was associated with a higher risk of HG. The effect was even stronger for women requiring hospitalization. Obesity seemed to decrease the risk of hospital admission for HG. Table 1 Time to cessation of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG) Estimate (%) Weeks

% of Women

!8 8–9 9–10 10–11 11–12 12–13 13–14 14–15 15–16 O16

8.2 9.2 9.9 15.1 17.5 8.6 11.0 7.2 4.1 9.2

NVP

HG

30

10

30

15

30 10

25 50

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Laboratory abnormalities A wide variety of laboratory abnormalities can be seen with HG, including suppressed TSH and/or elevations in free thyroxine, liver enzymes and bilirubin, amylase, and lipase [29]. These abnormalities resolve with resolution of the HG and do not require specific treatment. There still is insufficient awareness of the spectrum of these transient abnormalities, sometimes resulting in unnecessary antithyroid treatment, cholecystectomy, or even termination of pregnancy. Rare cases of hepatic or renal insufficiency have been reported with HG, but these cases usually are transient or are caused by other underlying disease.

Almost all patients who have transient hyperthyroidism related to HG have a normal TSH level by 20 weeks’ gestation. Such patients have no history of symptoms preceding pregnancy and goiter, other systemic signs of hyperthyroidism (except, occasionally, tachycardia), and thyroid antibodies are absent [30].

Maternal complications Severe maternal complications of HG are categorized as shown in Box 1.

By far the most important serious complication of HG is Wernicke’s encephalopathy [31]. More than 40 cases attributable to HG have been reported in the last 25 years. Patients may present with some of the classic diagnostic triad of ataxia, nystagmus, and dementia, but the most common manifestation described in the literature is simply apathy or confusion. No patient has reported to have developed this complication with less than 4 weeks of persistent vomiting. More than half of women reported have

Box 1. Maternal complications of hyperemesis gravidarum Metabolic/nutritional complications Wernicke’s encephalopathy Beriberi Central pontine myelinolysis Hepatic insufficiency Acute tubular necrosis Peripheral neuropathy Complications caused by the mechanical stress of vomiting Mallory-Weiss tear of the esophagus Esophageal rupture Pneumomediastinum Retinal detachment Splenic avulsion

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died or have had permanent neurologic dysfunction. Reflecting the role of thiamine in glucose metabolism, some cases of Wernicke’s encephalopathy have been precipitated by infusion of dextrose-containing solutions before administration of thiamine.

The problem of Wernicke’s encephalopathy is best addressed by prevention. All patients who have HG should receive at least the recommended dietary allowance of thiamine (3 mg), which is contained in most multivitamins. When a patient’s vomiting is sufficient to require intravenous hydration, thiamine (100 mg) should be administered parenterally on the assumption there is thiamine deficiency. It is the practice of the author and his colleagues to administer this dose of thiamine daily for 3 days if a patient is in hospital for HG. Psychologic burden and long-term health consequences The psychologic burden of severe nausea and vomiting of pregnancy and HG centers around the isolation of having a disease that has a strong subjective component (nausea) for which the cause is not understood. The most extreme manifestation of this burden is termination of an otherwise wanted pregnancy. Poursharif and colleagues [32] reported that 15% of 808 women who had HG had at least one termination of pregnancy resulting specifically from HG. Although women who terminated their pregnancy because of HG did not seem to have more severe disease, they were twice as likely as women who continued the pregnancy despite HG to report that their doctor was uncaring or did not appreciate the severity of the illness.

The long-term health consequences of HG for the women who suffer from it are largely unknown. Two studies suggested an increased risk of breast cancer in these patients, based on a presumed hyperestrogenic milieu, but this suggestion has not been confirmed in recent reports [33]. Reports of posttraumatic stress disorder, depression, and a variety of neurologic complaints are mentioned commonly by women, but there has been no systematic follow-up.

Fetal consequences of hyperemesis The concept that nausea and vomiting of pregnancy is associated with better pregnancy outcomes in general is well supported. The problem arises from applying this principle to cases of HG. It now is clear that the most fetal and maternal complications of HG come from the group of women who have HG and who experience sustained weight loss. Although some degree of weight loss is present in many, if not most, cases of HG, it often is stabilized with supportive therapy and antiemetic therapy. Dodds and colleagues [34] have shown in a recent population-based study that women who have HG who gain less than 7 kg overall during pregnancy are more likely to have low birth weight (relative risk, 2.8) and preterm birth (relative

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risk, 3.0) infants than are women admitted to the hospital for HG who gained more than 7 kg overall. In addition, there is evidence that in this group the rate of fetal death is higher [35].

Major congenital anomalies seem to be less prevalent in women who have nausea and vomiting of pregnancy and HG, although there are some conflicting data. Kulander and Kallen [36] found that hip dysplasia and Down syndrome were more common than expected in a population study of HG in Sweden. Vitamin K deficiency causing fetal coagulopathy or chondrodysplasia has been reported [37]. Apart from these anomalies, which seem to be related to the hormonal milieu in HG, there is an overall lowering of the rate of birth defects [38].

The long-term consequences of HG for the offspring are almost entirely unstudied. There is increasing awareness of the fetal origins of adult disease.

In animal models and in natural experiments such as famine, maternal calorie deprivation, even if limited to a few weeks or months of pregnancy, can have adverse effects on the physical and psychologic well being of the offspring. Several childhood cancers, including testicular cancer and leukemia, have been linked to hyperemesis, although data are conflicting.

Differential diagnosis Many conditions can be confused with HG. Some of those reported in the literature and important diagnostic clues suggesting a diagnosis other than HG are shown in Box 2.

Clinical clues suggesting alternative diagnosis The following findings suggest a cause for nausea and vomiting other than HG: Nausea beginning after 9 weeks’ gestation Nausea and vomiting antedating the pregnancy Abdominal pain Fever Headache Goiter Abnormal neurologic examination Elevated white blood cell count, anemia, or thrombocytopenia Mild elevations of liver enzymes (usually ! 300 the upper limit of normal) and serum bilirubin (!4 mg/dL) are encountered in 20% to 30% of women; serum concentrations of amylase and lipase (up to five times higher than normal levels) are seen in 10% to 15%. Rarely, significant cholestasis and even liver dysfunction (with a prolongation of the prothrombin time) may be seen. Liver enzyme elevations are much higher with primary hepatitis, often in the thousands, and the bilirubin concentration usually is

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Box 2. Differential diagnosis of hyperemesis gravidarum Gastrointestinal conditions Gastroenteritis Gastroparesis Achalasia Biliary tract disease Hepatitis Intestinal obstruction Peptic ulcer disease Pancreatitis Appendicitis Conditions of the genitourinary tract Pyelonephritis Uremia Ovarian torsion Kidney stones Degenerating uterine leiomyoma Metabolic conditions Diabetic ketoacidosis Porphyria Addison’s disease Hyperthyroidism Hyperparathyroidism Neurologic disorders Pseudotumor cerebri Vestibular lesions Migraine headaches Tumors of the central nervous system Lymphocytic hypophysitis Miscellaneous conditions Drug toxicity or intolerance Psychologic conditions Pregnancy-related conditions Acute fatty liver of pregnancy Pre-eclampsia

much higher, as well. Acute pancreatitis may cause vomiting and hyperamylasemia, but serum amylase concentrations are usually 5 to 10 times higher than the elevations associated with nausea and vomiting of pregnancy. Electrolyte abnormalities are found in 15% to 25% of cases. The most common

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are hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis.

With severe volume contraction, a metabolic academia may be seen. All the abnormalities have been reported to regress with adequate volume and nutritional support [29].

Transient hyperthyroidism of hyperemesis is noted in 50% to 70% of women who have hyperemesis. It usually can be distinguished from intrinsic thyroid disease in that there is no history of hyperthyroid symptoms preceding pregnancy, a goiter and thyroid antibodies are absent, and the triiodothyronine level is much less likely to be elevated than the thyroxine level.

There rarely are symptoms of hyperthyroidism except for occasional tachycardia. The condition, which is caused by an effect of hCG on the TSH receptor, is self limited and does not require specific antithyroid therapy.

Because there is an inverse relationship between the severity of nausea and vomiting of pregnancy and the TSH concentration, a nonsuppressed TSH level suggests that the cause of the nausea and vomiting is something other than nausea and vomiting of pregnancy. A TSH level greater than 2.5 mU/mL is rare with severe nausea and vomiting of pregnancy, unless the patient has pre-existing hypothyroidism.

An ultrasound evaluation should be performed in cases of HG, because it may identify a predisposing factor such as multiple gestation or molar gestation.

Management of hyperemesis gravidarum Prevention of HG is a subject that arises naturally in a discussion with the patient who has suffered from HG in the past. Until recently the risk of recurrent HG was not well understood. Two recent studies have shown a recurrence risk of 16% and 19%, the latter a 29-fold increase over the primary rate. This report probably is an underestimate for the most severe cases, because more of these women are unlikely to attempt another pregnancy [19].

For these women in particular, and for women who suffer from HG in general, there is evidence that prevention is possible. Women who are taking a multivitamin at the time of conception and in early pregnancy are less likely to require intervention for HG later in pregnancy [39]. Pre-emptive treatment of HG has been advocated based on the indirect evidence that women who have nausea and vomiting of pregnancy sufficient to interfere with their daily routine (30%–35% of pregnant women) have lower rates of hospital admission for HG [40].

Diet and support There is little evidence to guide one in advising women on dietary adjustments in nausea and vomiting of pregnancy. Commonsense but unsubstantiated advice is to eat small meals when one feels able. Jednak and others [41] found that eating meals with more protein more than carbohydrate

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content and more liquids than solids resulted in less nausea and improved the stomach electrical rhythms associated with nausea. Food aversions and changes in the hedonic effect of smells are linked closely to the development of nausea, probably through a taste aversion–learning mechanism. Besides avoiding offending the senses, there is evidence that behavioral approaches such as relaxation and hypnosis/distracting therapy can diminish nausea and vomiting caused by behaviorally mediated processes.

Pharmacologic and alternative therapy For women who continue to have problematic nausea and vomiting, vitamin B6 (10-25 mg, three times daily) is recommended. Three randomized, controlled trials suggest a benefit of vitamin B6 in reducing nausea in nausea and vomiting of pregnancy, although the effect on vomiting is not clear [42].

Vitamin B6 is safe for mother and fetus in doses up to 100 mg daily. If symptoms persist, an antihistamine may be added. There is evidence that antihistamines have efficacy in treatment of nausea and vomiting of pregnancy, and there is a substantial body of evidence supporting their safety [43].

The combination of vitamin B6 and the first-generation antihistamine doxylamine formed the basis of Bendectin, which was used by approximately 25% of all pregnant women (33 million women) between 1958 and 1982. Several small randomized, controlled trials attest to its efficacy [44].

Questions about its safety, which led to its withdrawal from the market, have not been substantiated. Because of the scrutiny brought on by the litigation, Bendectin has been studied extensively. A meta-analysis of studies of Bendectin with more than 14,000 first-trimester exposures found no increase in anomalies above the background rate [45]. Doxylamine itself is available in the United States only as Unisom sleep tablets, a formulation available over the counter. Twenty-five mg of vitamin B6 plus half a 25-mg Unisom Sleep Tab taken three to four times daily approximates the Bendectin regimen (10 mg vitamin B6 and 10 mg doxylamine). Vitamin B6 is not available in the United States in doses less than 50 mg . The Bendectin formulation also can be obtained from compounding pharmacies and is available in Canada and several other countries under the name Diclectin.

For patients who receive no relief from this regimen or continue to progress in symptoms, the herbal medication ginger may be added. Several randomized, controlled studies attest to its efficacy. The main drawback to its use is that fetal safety data are limited. Nevertheless, problems have not been seen, and theoretic concerns seem to be addressed adequately in a recent review [46]. Other alternative therapies that have been studied extensively in nausea and vomiting of pregnancy are acupuncture and acustimulation. Although there are some conflicting data, the weight of evidence suggests some benefit without significant risks.

Other classes of antiemetics include benzamides, phenothiazines, butyrophenones, type 3 serotonin receptor antagonists, and corticosteroids.

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Box 3. Nausea and vomiting of pregnancy: treatment algorithma,b (If there is no improvement, proceed to next step) Vitamin B6, 10 to 25 mg, three or four times daily (up to 100 mg daily) Alternative therapies may be added at any time during the sequence depending on patient acceptance and the familiarity of the attendant. Consider P6 acupressure or acustimulation or ginger capsules, 250 mg, four times daily Add: Doxylamine, 12.5 mg, three or four times dailyc Adjust schedule and dose according to severity of patient’s symptoms Add: Promethazine, 12.5 to 25 mg taken orally or rectally every 4 hours or Dimenhydrinate, 50 to 100 mg taken orally or rectally every 4 to 6 hours (not to exceed 400 mg/d; not to exceed 200 mg/d if patient also is taking doxylamine) Stop other medications and substitute: Metoclopramide, 5 to 10 mg taken orally every 8 hours For patients not tolerating oral intake Use intravenous fluid replacement and multivitamin and thiamine supplementationd Substitute any of the following (presented in alphabetical order): Dimenhydrinate, 50 mg intraveneously (in 50 mL saline, over 20 minutes), every 4 to 6 hours or Metoclopramide, 5 to 10 mg intraveneously every 8 hours or Promethazine, 12.5 to 25 mg intraveneously every 4 hours or Prochlorperazine, 5 to 10 mg intraveneously every 4 hours (maximum dose, 40 mg/d)

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For persistent vomiting substitute: Ondansetron, 4 to 8 mg orally or intraveneously every 8 hours or Methylprednisolonee, 16 mg orally or intraveneously every 8 hours for 3 days. Taper over 2 weeks to lowest effective dose. If beneficial, limit total duration of use to 6 weeks. a The use of this algorithm assumes that other causes of nausea and vomiting have been ruled out. b At any step, consider parenteral nutrition if dehydration or persistent weight loss is noted. c In the United States, doxylamine is available as the active ingredient in Unisom Sleep Tabs; one half of a scored 25-mg tablet can be used to provide a 12.5-mg dose of doxylamine. d 100 mg thiamine intraveneously daily for 2 to 3 days (followed by intravenous multivitamins) is recommended for every woman who requires intravenous hydration and who has vomited for more than 3 weeks. e Steroids seem to increase risk for oral clefts in first 10 weeks of gestation.

Although randomized trials of agents in most of these classes have shown some efficacy in nausea and vomiting of pregnancy overall, there have been only 10 randomized trials of pharmacologic interventions in HG, six involving steroids. Evidence for efficacy of any agent in HG is inconclusive, perhaps in part because of methodology. Nevertheless, because of their general effectiveness in relieving nausea and vomiting in other states, they have been used commonly. Safety data have been limited as well, although in recent years there is some greater accumulation of data. Corticosteroids seem to be associated with a slight increase in facial clefts when given in the first trimester. Other commonly used tocolytics are not known teratogens, although data on some agents are limited.

Because there is not good evidence for the efficacy of any one of the phenothiazines or benzamides, it is common practice to switch between agents or to combine them. One of the principle dangers of this practice is the confluence of side effects, in particular extrapyramidal symptoms, that may be seen. Several of these agents have similar side effects and adverse reactions. The latter can manifest as anxiety, depression, and even hallucinations. There is evidence that extrapyramidal symptoms commonly are overlooked [47].

Ondansetron and other serotonin receptor antagonists deserve special mention. Most women who have HG report that vitamin and herbal remedies and older antiemetics bring little relief. Although these agents may be effective for less severe nausea and vomiting of pregnancy, more potent interventions seem to be needed for established HG. In this regard, ondansetron has become one of the most widely used antiemetics, largely by analogy to its demonstrated superiority in chemotherapy-related nausea and vomiting. Although the only randomized, controlled trial of ondansetron for HG

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showed that it was not more effective than promethazine , this finding may result from the selection of patients who were likely to improve with most interventions, a point discussed in more detail later. More safety data have accumulated recently [48].

Corticosteroids are potent antiemetics in the setting of chemotherapy-induced nausea and vomiting. They have been studied for their effect in HG with conflicting results. Several series described significant diminution or complete resolution of nausea and vomiting with corticosteroid therapy.

Randomized trials have failed to demonstrate a conclusive benefit, however.

Safari and colleagues [49] found that women discharged on corticosteroids were less likely to be readmitted than those taking promethazine, but Yost and colleagues [50] did not find such a benefit. Moran and Taylor [51] have asserted that the failure to show a benefit from the steroids is caused by patient selection, in that patients who are less ill (those without weight loss in their analysis) are likely to respond to a variety of treatments.

They also review some of the particulars of dose adjustment including the remarkable recrudescence of symptoms with dose lowering which responds immediately to re-institution of therapy.

Nutritional support For patient who does not respond adequately to therapy and is unable to maintain her weight by oral intake, nutritional support is required. This recommendation is based on several points: higher rates of intrauterine growth restriction in this population, the probability of long-term adverse consequences for the fetus because of changes in programming, and rare, lifethreatening vitamin deficiency. Caloric support may be achieved either by enteral or parenteral nutrition. Probably because of a higher rate of patient acceptance, parenteral nutrition for women who have HG as been reported much more often enteral nutrition. Serious complications of parenteral alimentation can occur, however, including infection, thrombophlebitis, and death caused by infection or pericardial tamponade. Peripheral placement of central access was thought to be associated with fewer complications, but many of the same complications reported with central access have been reported with peripheral placement.

Holmgren and colleagues [52] reported on 94 women hospitalized with HG. Forty-two received medication alone, 33 had a peripherally inserted central catheter (PICC) line, and 19 had a nasogastric or nasoduodenal tube. Of those managed with a PICC line, 66.4% required treatment for infection, thromboembolism, or both. In addition, neonatal complications including small size for gestational age, admission to the neonatal ICU, termination of pregnancy because of HG, and fetal loss were increased in the women who had a PICC line.

There is little evidence indicating that the better safety record of enteral feeding and comparable efficacy compared with parenteral feeding via

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a PICC line has led to increased use. In the author and colleagues’ own survey of 792 women who self-reported HG from 2000 to 2004, 16.7% reported receiving parenteral nutrition; only 2.3% reported enteral tube feeding [53].

Although there is no doubt that these techniques are less expensive and are subject to far fewer complications than parenteral nutrition, the reported experience is limited to case reports and small series. It is the author and colleagues’ experience that the nasal tubes frequently are declined by patients; once accepted, they may be difficult to place and are more subject to being vomited up than tubes placed for other reasons. Few disorders requiring enteral nutrition are primarily disorders of vomiting per se. A recurring theme in reports of enteral feeding is the need for a skilled team for replacement and support that is capable of encouraging patients and anticipating their needs.

A schema for an overall approach to prevention and treatment of HG is shown in Box 3.

References [1] Reid DE. The treatment of the nausea and vomiting of pregnancy. N Engl J Med 1938;218: 109–13.

[2] Jiang HG, Elixhauser A, Nicholas J, et al. Care of women in U.S. hospitals, 2000. Rockville (MD): Agency for Healthcare Research and Quality, 2002 HCUP Fact Book No. 3. AHRQ Pub. No. 02-0044.

[3] Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 1993;43:245–8.

[4] Braunstein GD, Hershman JM. Comparison of serum pituitary thyrotropin and chorionic gonadotropin throughout pregnancy. J Clin Endocrinol Metab 1976;42:1123–6.

[5] Yoshimura M, Hershman JM. Thyrotropic action of human chorionic gonadotropin. Thyroid 1995;5:425–34.

[6] Jordan V, Grebe SKG, Cooke RR, et al. Acidic isoforms of chorionic gonadotropin in European and Samoan women are associated with hyperemesis gravidarum and may be thyrotrophic. Clin Endocrinol 1999;50:619–27.

[7] Goldzieher JW, Moses LE, Averkin E, et al. A placebo-controlled double-blind crossover investigation of the side effects attributed to oral contraceptives. Fertil Steril 1971;22:609–23.

[8] Sugito Y, Dekizawa A, Farina A, et al. Relationship between severity of HG and fetal DNA concentration in maternal plasma. Clin Chem 2003;49:1667–9.

[9] Yoneyama Y, Suzuki S, Sawa R, et al. The T-helper 1/T-helper 2 balance in peripheral blood of women with hyperemesis gravidarum. Am J Obstet Gynecol 2002;187:1631–5.

[10] Kaplan PB, Gucer F, Sayin NC, et al. Maternal serum cytokine levels in women with hyperemesis gravidarum in the first trimester of pregnancy. Fertil Steril 1979;2003:498–502.

[11] Yoneyama Y, Shyunji S, Rintaro S, et al. Plasma adenosine concentrations increase in women with hyperemesis gravidarum. Clin Chim Acta 2004;342:99–103.

[12] Yoneyama Y, Suzuki S, Sawa R, et al. Increased plasma adenosine concentrations and the severity of preeclampsia. Obstet Gynecol 2002;101:1266–70.

[13] James WH. The associated offspring sex ratios and cause(s) of hyperemesis gravidarum.

Acta Obstet Gynecol Scand 2001;80:378–9.

[14] Tan P, Jacob R, Quek K, et al. The fetal sex ratio and metabolic, biochemical, haematological and clinical indicators of severity of hyperemesis gravidarum. BJOG 2006;113:733–7.

[15] Corey LA, Berg K, Solaas MH, et al. The epidemiology of pregnancy complications & outcome in a Norwegian twin population. Obstet Gynecol 1992;80:989–94.

416

GOODWIN

[16] Fejzo M, Ingles S, Wilson M, et al. High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. Eur J Obstet Gynecol Reprod Biol, in press.

[17] Matsuo K, Ushioda N, Nagamatsu M, et al. Hyperemesis gravidarum in Eastern Asian population. Gynecol Obstet Invest 2007;64:213–21.

[18] Rodien P, Bremont C, Raffin Sanson M, et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998;339:1823–6.

[19] Trogstad L, Stoltenberg C, Magnus P, et al. Recurrence risk in hyperemesis gravidarum.

BJOG 2005;112:1641–5.

[20] Fairweather DV. Nausea and vomiting in pregnancy. Am J Obstet Gynecol 1968;102(1): 135–75.

[21] Buckwalter JG, Simpson SW. Psychological factor in the etiology and treatment of severe nausea and vomiting in pregnancy. Am J Obstet Gynecol 2002;186:S210–4.

[22] Munch S. Women’s experiences with a pregnancy complication: causal explanations of hyperemesis gravidarum. Soc Work Health Care 2002;36:59–76.

[23] Bayley T, Dye L, Jones S, et al. Food cravings and aversions during pregnancy: relationships with nausea and vomiting. Appetite 2002;38:45–51.

[24] Redd WH, Montgomery GH, DuHamel K. Behavioral intervention for cancer treatment side effects. J Natl Cancer Inst 2001;93:810–23.

[25] Flaxman SM, Sherman PW. Morning sickness: a mechanism for protecting mother and embryo. Q Rev Biol 2000;75:113–48.

[26] Godsey RK, Newman RB. Hyperemesis gravidarum: a comparison of single and multiple admissions. J Reprod Med 1991;36:287–90.

[27] Hummela T, von Meringb T, Huchb R, et al. Olfactory modulation of nausea during early pregnancy? BJOG 2002;109:1394–7.

[28] Cedergren M, Brynhildsen J, Josefsson A, et al. Hyperemesis gravidarum that requires hospitalization and the use of antiemetic drugs in relation to maternal body composition. Am J Obstet Gynecol 2008;198:412, e1–5.

[29] Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992;167:648–52.

[30] Goodwin TM, Hershman JM. Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997;40:32–44.

[31] Togay-Isikay C, Yigit A, Mutluer N. Wernicke’s encephalopathy due to hyperemesis gravidarum: an under-recognised condition. Aust N Z J Obstet Gynaecol 2001;41:453–6.

[32] Poursharif B, Korst L, MacGibbon K, et al. Voluntary termination in a large cohort of women with hyperemesis gravidarum. Contraception 2007;76:451–5.

[33] Erlandsson G, Lambe M, Cnattingius S, et al. Hyperemesis gravidarum and subsequent breast cancer risk. Br J Cancer 2002;87:974–6.

[34] Dodds L, Fell DB, Joseph KS, et al. Outcome of pregnancies complicated by hyperemesis gravidarum. Obstet Gynecol 2006;107:285–92.

[35] Bailit JL. Hyperemesis gravidarum: epidemiologic findings from a large cohort. Am J Obstet Gynecol 2005;193:811–4.

[36] Kallen B. Hyperemesis during pregnancy and delivery outcome: a registry study. Eur J Obstet Gynecol Reprod Biol 1987;26:291–302.

[37] Brunetti-Pierri N, Hunter JV, Boerkoel CF. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency? Am J Med Genet A 2007;143:200–4.

[38] Czeizel AE, Sarkozi A, Wyszynski DF. Effect of hyperemesis gravidarum for nonsyndromic oral clefts. Obstet Gynecol 2003;101:737–44.

[39] Kallen B, Lundberg G, Aberg A. Relationship between vitamin use, smoking, and nausea and vomiting of pregnancy. Acta Obstet Gynecol Scand 2003;82:916–20.

HYPEREMESIS GRAVIDARUM

417

[40] Koren G, Maltepe C. Pre-emptive therapy for severe nausea and vomiting of pregnancy and hyperemesis gravidarum. J Obstet Gynaecol 2004;24:530–3.

[41] Jednak MA, Shadigian EM, et al. Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy. Am J Physiol 1999;277:G855–61.

[42] Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2003;(4):CD000145.

[43] Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14:119–24.

[44] Niebyl JR, Goodwin TM. Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. Am J Obstet Gynecol 2002;186:253–5.

[45] Einarson TR, Leeder JS, Koren G. Method of meta-analysis of epidemiological studies.

Drug Intell Clin Parm 1988;22:813–24.

[46] Borrelli F, Capasso R, Aviello G, et al. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol 2005;105:849–56.

[47] Wright MT. Antiemetics, akathisa and pregnancy. Psychosomatics 2007;48:461–6.

[48] Einarson A, Maltepe C, Navioz Y, et al. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG 2004;111:940–3.

[49] Safari HR, Alsulyman OM, Gherman RB, et al. The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study. Am J Obstet Gynecol 1998;179:921–4.

[50] Yost NP, McIntire DD, Wians FH Jr, et al. A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy. Obstet Gynecol 2003;102:1250–4.

[51] Moran P, Taylor R. Management of hyperemesis gravidarum: the importance of weight loss as a criterion for steroid therapy. QJM 2002;95:153–8.

[52] Holmgren C, Silver RM, Porter TF, et al. Hyperemesis in pregnancy: an evaluation of treatment strategies with maternal and neonatal outcomes. Am J Obstet Gynecol 2008;198:56, e1–4.

[53] Goodwin TM, Poursharif B, Korst LM. Secular trends in the treatment of hyperemesis gravidarum. Am J Perinatol 2008;25:141–7.