Hyperemesis Gravidarum Compilation from many E-books

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 pregnantwomen, although populations with significantly higher rates have been re-ported. In most cases, it represents the far end of the spectrum of nauseaand vomiting of pregnancy. Nausea and vomiting of pregnancy itself affectsapproximately 75% of pregnant women, with 25% reporting nausea aloneand 50% reporting both nausea and vomiting. In clinical practice, HG isidentified by otherwise unexplained intractable vomiting and dehydration.For the purposes of investigation, a criterion of weight loss, usually morethan 5% of prepregnancy weight, confirms the diagnosis.

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

Etiology

HG is clearly related to a product of placental metabolism because it doesnot require the presence of the fetus. It occurs commonly with advancedmolar gestation and multiple gestations. More than 20 studies of nonthyroi-dal hormonal changes in nausea and vomiting of pregnancy have been pub-lished in the last 30 years. The only differences between subjects who hadHG and controls that have been reported in more than one study are inthe levels of human chorionic gonadotropin (hCG) and estradiol. Althoughthere is conflicting information, several lines of evidence point toward a rolefor these two hormones.

* Women’s and Children’s Hospital, 1240 North Mission Road, Room 5K-40,

Los Angeles, CA 90033.

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

A link between the action of hCG and estradiol has been suggested by thefinding that concentrations of hyperglycosylated hCG correlate with estra-diol levels and the severity of nausea and vomiting. It is hypothesized thatstimulation of maternal ovarian production (and possibly fetal productionof estradiol) increases the estradiol concentration in the mother. Nauseaand vomiting in women taking the combined oral contraceptive pill in-creases in direct correlation with the estradiol dose [7]. A history of nauseaand vomiting while taking estrogens is a risk factor for development of HG.

At themolecular level, there is evidence thatHG is associatedwith increasedactivity in the trophoblast cells at the maternal–fetal interface. Increased con-centrations of fetal cell free DNA have been identified in maternal serum [8].This finding is consistentwith trophoblast damage causedbyahyperactivema-ternal immune response in which the normal shift to T-helper cell type 2 overT-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 pro-duction, as does the increase in tumor necrosis factor-a (TNFa) that has beenreportedwithHG [10]. Adenosine, which is thought to attenuate the oxidativeburst 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 womenwho have HG and other common nausea and vomiting syndromes, namelypostoperative nausea and vomiting and chemotherapy-related nausea andvomiting. These factors include younger age, a history of motion sickness,a history of migraines, and symptoms occurring at an early hour of theday. Smoking is associated with decreased concentrations of hCG and estra-diol, whereas female gender of the fetus is associated with greater concentra-tions of hCG [13]. Female gender of the fetus also is associated with moresevere HG [14]. Rarely, HG has been reported in association with underly-ing maternal metabolic disorders, in particular the disorders of fatty acidoxidation.

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

Psychologic factors

For many years it was presumed that women suffering from HG werepredisposed to the disorder by something in their own psychologic makeup or in the circumstances of their lives. Numerous competing theories,drawn mostly from psychoanalysis, identified women as rejecting the fatherof the baby, being ambivalent about the pregnancy, rejecting their own fem-ininity, being either too dependent on their mothers, or, conversely, not de-pendent enough! None of the many reports and few of the systematic studiesoffered to support the hypothesis would pass muster by today’s standards.One of the most influential concluded that women who had HG had a hys-teric personality type, even though the only blinded evaluation in the inves-tigation, the Minnesota Multiphasic Personality Inventory, showed nodifference [20]. Buckwalter and Simpson [21] reviewed these studies and con-cluded that there is little support for the concept that HG is caused by a par-ticular psychologic state.

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

A behavioral component of nausea and vomiting is well accepted in otherareas of medicine. This component does not mean that the subject is respon-sible for the vomiting; rather, the circumstances of the original stimulus tovomiting exacerbate subsequent vomiting via a behavioral pathway. Thisconcept is supported by the work of Bayley and colleagues [23], who showedthat 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 firstoccurrence of nausea was reported either in the week preceding the first foodaversion or in the same week. These findings are consistent with a taste aver-sion–learning mechanism, in which foods paired with illness are avoided

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subsequently. The fact that cravings common in pregnancy do not followthis pattern is supportive of the same concept. Anticipatory vomiting asso-ciated with chemotherapy is thought to be caused by a similar mechanism; itis refractory to pharmacologic interventions but can be treated by behav-ioral therapies [24]. Food aversions in pregnancy are similar to those thatdevelop with chemotherapy, in that they generally do not persist after theacute course of the primary stimulus ends; this experience is distinct fromconditioned responses, which otherwise may persist for years. Uncontrolledcase series have suggested a benefit of behavioral therapy or hypnosis in thetreatment of HG.

Embryo protection hypothesis

A different perspective on nausea and vomiting of pregnancy and HG hascome from the filed of evolutionary biology [25]. In this view, nausea andvomiting of pregnancy is a mechanism that has evolved, along with foodaversions, to prevent the pregnant mother from ingesting food substancesthat may be harmful to the developing fetus. According to this theory theharm could come from contamination of the food supply or from substancesthat in themselves are toxic to the fetus. The common aversion to coffee andhighly spiced foods is given as an example of the latter possibility. For thepracticing obstetrician, this academic debate has significance, because oneconsequence is that nausea and vomiting of pregnancy and even, to someextent, HG are treated as normal, protective phenomena. The unfortunateconsequence is that many of the 30% or so of pregnant women who suffersome disability from nausea and vomiting of pregnancy and even some casesof HG could be denied treatment. A counter view is that even if nausea andvomiting of pregnancy and HG evolved as a protective phenomenon, thisbenefit no longer is applicable. Much as thrombophilias are thought tohave been preserved in nature as a protection against postpartum hemor-rhage but now are understood as a significant health risk, so any perceivedbenefit of nausea and vomiting of pregnancy would not pertain in societieswith 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 ofpregnancy have been directed at the trigger, which is of placental origin. It isclear, however, that nausea and vomiting of pregnancy is better regarded asa syndrome with the final phenotype arising from different pathways. Thus,for example, the stimulus to HG is affected by placental mass, in that it ismore common in multiple gestation, and probably by both mass and aber-rant production (perhaps of hCG), as in advanced molar gestation or inpregnancies characterized by trisomy 21. The paternal genotype within theplacenta 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’ responseto this stimulus is mediated genetically, as shown by family studies of HG.The susceptibility of the mother varies, depending on a number of factorsthat are recognized as mediating nausea and vomiting in other settingssuch as postoperative nausea and vomiting and chemotherapy-induced nau-sea and vomiting.

Clinical presentation

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

In addition to nausea and vomiting, associated complaints include excesssalivation (ptyalism) in up to 60% of cases of HG [26]. Although there isa common perception that women who have more severe nausea and vomit-ing of pregnancy are most sensitive to olfactory stimuli, this belief has notbeen documented in objective studies. Rather, there is a change in the he-donic rating of odors, somewhat similar to that seen in chemotherapy-induced nausea [27].

The literature has been divided on the relationship between maternalbody mass and the risk of HG. Recently, this relationship has been clarifiedin population-based studies. In a study from Canada, Cedergren and col-leagues [28] found a low prepregnancy body mass index was associatedwith a higher risk of HG. The effect was even stronger for women requiringhospitalization. Obesity seemed to decrease the risk of hospital admissionfor HG.

Table 1

Time to cessation of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum

(HG)

Weeks % of Women

Estimate (%)

NVP HG

!8 8.2

8–9 9.2

9–10 9.9 30 10

10–11 15.1

11–12 17.5 30 15

12–13 8.6

13–14 11.0

14–15 7.2

15–16 4.1 30 25

O16 9.2 10 50


Laboratory abnormalities

A wide variety of laboratory abnormalities can be seen with HG, includ-ing suppressed TSH and/or elevations in free thyroxine, liver enzymes andbilirubin, amylase, and lipase [29]. These abnormalities resolve with resolu-tion of the HG and do not require specific treatment. There still is insuffi-cient 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 insuffi-ciency have been reported with HG, but these cases usually are transientor are caused by other underlying disease.

Almost all patients who have transient hyperthyroidism related to HGhave a normal TSH level by 20 weeks’ gestation. Such patients have no his-tory of symptoms preceding pregnancy and goiter, other systemic signs ofhyperthyroidism (except, occasionally, tachycardia), and thyroid antibodiesare 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 en-

cephalopathy [31]. More than 40 cases attributable to HG have been re-ported in the last 25 years. Patients may present with some of the classicdiagnostic triad of ataxia, nystagmus, and dementia, but the most commonmanifestation described in the literature is simply apathy or confusion. Nopatient has reported to have developed this complication with less than4 weeks of persistent vomiting. More than half of women reported have

Box 1. Maternal complications of hyperemesis gravidarum

Metabolic/nutritional complicationsWernicke’s encephalopathyBeriberiCentral pontine myelinolysisHepatic insufficiencyAcute tubular necrosisPeripheral neuropathy

Complications caused by the mechanical stress of vomitingMallory-Weiss tear of the esophagusEsophageal rupturePneumomediastinumRetinal detachmentSplenic avulsion

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

The problem of Wernicke’s encephalopathy is best addressed by preven-tion. All patients who have HG should receive at least the recommendeddietary allowance of thiamine (3 mg), which is contained in most multivita-mins. When a patient’s vomiting is sufficient to require intravenous hydra-tion, thiamine (100 mg) should be administered parenterally on theassumption there is thiamine deficiency. It is the practice of the authorand his colleagues to administer this dose of thiamine daily for 3 days if a pa-tient is in hospital for HG.

Psychologic burden and long-term health consequences

The psychologic burden of severe nausea and vomiting of pregnancy andHG centers around the isolation of having a disease that has a strong sub-jective component (nausea) for which the cause is not understood. The mostextreme manifestation of this burden is termination of an otherwise wantedpregnancy. Poursharif and colleagues [32] reported that 15% of 808 womenwho had HG had at least one termination of pregnancy resulting specificallyfrom HG. Although women who terminated their pregnancy because of HGdid not seem to have more severe disease, they were twice as likely as womenwho continued the pregnancy despite HG to report that their doctor was un-caring or did not appreciate the severity of the illness.

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

Fetal consequences of hyperemesis

The concept that nausea and vomiting of pregnancy is associated withbetter pregnancy outcomes in general is well supported. The problem arisesfrom applying this principle to cases of HG. It now is clear that the mostfetal and maternal complications of HG come from the group of womenwho have HG and who experience sustained weight loss. Although some de-gree of weight loss is present in many, if not most, cases of HG, it often isstabilized with supportive therapy and antiemetic therapy. Dodds and col-leagues [34] have shown in a recent population-based study that womenwho have HG who gain less than 7 kg overall during pregnancy are morelikely to have low birth weight (relative risk, 2.8) and preterm birth (relative


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

Major congenital anomalies seem to be less prevalent in women who havenausea and vomiting of pregnancy and HG, although there are someconflicting data. Kulander and Kallen [36] found that hip dysplasia andDown syndrome were more common than expected in a population studyof HG in Sweden. Vitamin K deficiency causing fetal coagulopathy or chon-drodysplasia has been reported [37]. Apart from these anomalies, whichseem to be related to the hormonal milieu in HG, there is an overall lower-ing of the rate of birth defects [38].

The long-term consequences of HG for the offspring are almost entirelyunstudied. There is increasing awareness of the fetal origins of adult disease.In animal models and in natural experiments such as famine, maternal cal-orie deprivation, even if limited to a few weeks or months of pregnancy, canhave adverse effects on the physical and psychologic well being of the off-spring. 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 inthe literature and important diagnostic clues suggesting a diagnosis otherthan HG are shown in Box 2.

Clinical clues suggesting alternative diagnosis

The following findings suggest a cause for nausea and vomiting otherthan HG:

Nausea beginning after 9 weeks’ gestationNausea and vomiting antedating the pregnancyAbdominal painFeverHeadacheGoiterAbnormal neurologic examinationElevated white blood cell count, anemia, or thrombocytopenia

Mild elevations of liver enzymes (usually ! 300 the upper limit of nor-mal) and serum bilirubin (!4 mg/dL) are encountered in 20% to 30% ofwomen; serum concentrations of amylase and lipase (up to five times higherthan normal levels) are seen in 10% to 15%. Rarely, significant cholestasisand even liver dysfunction (with a prolongation of the prothrombin time)may be seen. Liver enzyme elevations are much higher with primary hepa-titis, often in the thousands, and the bilirubin concentration usually is

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

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


are hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis.With severe volume contraction, a metabolic academia may be seen. Allthe abnormalities have been reported to regress with adequate volumeand nutritional support [29].

Transient hyperthyroidism of hyperemesis is noted in 50% to 70% ofwomen who have hyperemesis. It usually can be distinguished from intrinsicthyroid disease in that there is no history of hyperthyroid symptoms preced-ing pregnancy, a goiter and thyroid antibodies are absent, and the triiodo-thyronine level is much less likely to be elevated than the thyroxine level.There rarely are symptoms of hyperthyroidism except for occasional tachy-cardia. The condition, which is caused by an effect of hCG on the TSH re-ceptor, is self limited and does not require specific antithyroid therapy.Because there is an inverse relationship between the severity of nauseaand vomiting of pregnancy and the TSH concentration, a nonsuppressedTSH level suggests that the cause of the nausea and vomiting is somethingother than nausea and vomiting of pregnancy. A TSH level greater than2.5 mU/mL is rare with severe nausea and vomiting of pregnancy, unlessthe patient has pre-existing hypothyroidism.

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

Management of hyperemesis gravidarum

Prevention of HG is a subject that arises naturally in a discussion with thepatient who has suffered from HG in the past. Until recently the risk of re-current HG was not well understood. Two recent studies have shown a re-currence risk of 16% and 19%, the latter a 29-fold increase over the primaryrate. This report probably is an underestimate for the most severe cases, be-cause more of these women are unlikely to attempt another pregnancy [19].

For these women in particular, and for women who suffer from HG ingeneral, there is evidence that prevention is possible. Women who are takinga multivitamin at the time of conception and in early pregnancy are lesslikely to require intervention for HG later in pregnancy [39]. Pre-emptivetreatment of HG has been advocated based on the indirect evidence thatwomen who have nausea and vomiting of pregnancy sufficient to interferewith their daily routine (30%–35% of pregnant women) have lower ratesof hospital admission for HG [40].

Diet and support

There is little evidence to guide one in advising women on dietary adjust-ments in nausea and vomiting of pregnancy. Commonsense but unsubstan-tiated 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 improvedthe stomach electrical rhythms associated with nausea. Food aversionsand changes in the hedonic effect of smells are linked closely to the develop-ment of nausea, probably through a taste aversion–learning mechanism. Be-sides avoiding offending the senses, there is evidence that behavioralapproaches such as relaxation and hypnosis/distracting therapy can dimin-ish nausea and vomiting caused by behaviorally mediated processes.

Pharmacologic and alternative therapy

For women who continue to have problematic nausea and vomiting, vi-tamin B6 (10-25 mg, three times daily) is recommended. Three randomized,controlled trials suggest a benefit of vitamin B6 in reducing nausea in nauseaand 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 symp-toms persist, an antihistamine may be added. There is evidence that antihis-tamines 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 antihistaminedoxylamine formed the basis of Bendectin, which was used by approxi-mately 25% of all pregnant women (33 million women) between 1958 and1982. 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 lit-igation, Bendectin has been studied extensively. A meta-analysis of studiesof Bendectin with more than 14,000 first-trimester exposures found no in-crease in anomalies above the background rate [45]. Doxylamine itself isavailable in the United States only as Unisom sleep tablets, a formulationavailable over the counter. Twenty-five mg of vitamin B6 plus half a 25-mgUnisom Sleep Tab taken three to four times daily approximates the Bend-ectin regimen (10 mg vitamin B6 and 10 mg doxylamine). Vitamin B6 isnot available in the United States in doses less than 50 mg . The Bendectinformulation also can be obtained from compounding pharmacies and isavailable in Canada and several other countries under the name Diclectin.

For patients who receive no relief from this regimen or continue to prog-ress in symptoms, the herbal medication ginger may be added. Several ran-domized, controlled studies attest to its efficacy. The main drawback to itsuse is that fetal safety data are limited. Nevertheless, problems have notbeen seen, and theoretic concerns seem to be addressed adequately in a re-cent review [46]. Other alternative therapies that have been studied exten-sively in nausea and vomiting of pregnancy are acupuncture andacustimulation. Although there are some conflicting data, the weight of ev-idence suggests some benefit without significant risks.

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


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 thefamiliarity of the attendant. Consider P6 acupressure oracustimulation or ginger capsules, 250 mg, four timesdaily

Add:Doxylamine, 12.5 mg, three or four times dailyc

Adjust schedule and dose according to severity of patient’ssymptoms

Add:Promethazine, 12.5 to 25 mg taken orally or rectally every 4

hoursorDimenhydrinate, 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 ifpatient also is taking doxylamine)

Stop other medications and substitute:Metoclopramide, 5 to 10 mg taken orally every

8 hoursFor patients not tolerating oral intake

Use intravenous fluid replacement and multivitamin andthiamine supplementationd

Substitute any of the following (presented in alphabeticalorder):

Dimenhydrinate, 50 mg intraveneously (in 50 mL saline, over20 minutes), every 4 to 6 hours

orMetoclopramide, 5 to 10 mg intraveneously every

8 hoursorPromethazine, 12.5 to 25 mg intraveneously every

4 hoursorProchlorperazine, 5 to 10 mg intraveneously every

4 hours (maximum dose, 40 mg/d)

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Although randomized trials of agents in most of these classes have shownsome efficacy in nausea and vomiting of pregnancy overall, there havebeen only 10 randomized trials of pharmacologic interventions in HG, sixinvolving steroids. Evidence for efficacy of any agent in HG is inconclusive,perhaps in part because of methodology. Nevertheless, because of their gen-eral effectiveness in relieving nausea and vomiting in other states, they havebeen used commonly. Safety data have been limited as well, although in re-cent years there is some greater accumulation of data. Corticosteroids seemto be associated with a slight increase in facial clefts when given in the firsttrimester. Other commonly used tocolytics are not known teratogens, al-though data on some agents are limited.

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

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

For persistent vomiting substitute:Ondansetron, 4 to 8 mg orally or intraveneously every 8 hoursorMethylprednisolonee, 16 mg orally or intraveneously every

8 hours for 3 days. Taper over 2 weeks to lowest effectivedose. If beneficial, limit total duration of use to 6 weeks.

a The use of this algorithm assumes that other causes of nausea and vomitinghave been ruled out.

b At any step, consider parenteral nutrition if dehydration or persistent weightloss is noted.

c In the United States, doxylamine is available as the active ingredient inUnisom Sleep Tabs; one half of a scored 25-mg tablet can be used to providea 12.5-mg dose of doxylamine.

d 100 mg thiamine intraveneously daily for 2 to 3 days (followed byintravenous multivitamins) is recommended for every woman who requiresintravenous 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.


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

Corticosteroids are potent antiemetics in the setting of chemotherapy-in-duced nausea and vomiting. They have been studied for their effect in HGwith conflicting results. Several series described significant diminution orcomplete 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 corticosteroidswere less likely to be readmitted than those taking promethazine, butYost 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 iscaused by patient selection, in that patients who are less ill (those withoutweight loss in their analysis) are likely to respond to a variety of treatments.They also review some of the particulars of dose adjustment including theremarkable recrudescence of symptoms with dose lowering which respondsimmediately to re-institution of therapy.

Nutritional support

For patient who does not respond adequately to therapy and is unable tomaintain her weight by oral intake, nutritional support is required. This rec-ommendation is based on several points: higher rates of intrauterine growthrestriction in this population, the probability of long-term adverse conse-quences for the fetus because of changes in programming, and rare, life-threatening vitamin deficiency. Caloric support may be achieved either byenteral or parenteral nutrition. Probably because of a higher rate of patientacceptance, parenteral nutrition for women who have HG as been reportedmuch more often enteral nutrition. Serious complications of parenteral ali-mentation can occur, however, including infection, thrombophlebitis, anddeath caused by infection or pericardial tamponade. Peripheral placementof central access was thought to be associated with fewer complications,but many of the same complications reported with central access havebeen reported with peripheral placement.

Holmgren and colleagues [52] reported on 94 women hospitalized withHG. Forty-two received medication alone, 33 had a peripherally insertedcentral catheter (PICC) line, and 19 had a nasogastric or nasoduodenaltube. Of those managed with a PICC line, 66.4% required treatment forinfection, thromboembolism, or both. In addition, neonatal complicationsincluding small size for gestational age, admission to the neonatal ICU, ter-mination of pregnancy because of HG, and fetal loss were increased in thewomen who had a PICC line.

There is little evidence indicating that the better safety record of enteralfeeding 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 sur-vey of 792 women who self-reported HG from 2000 to 2004, 16.7% reportedreceiving parenteral nutrition; only 2.3% reported enteral tube feeding [53].

Although there is no doubt that these techniques are less expensive andare subject to far fewer complications than parenteral nutrition, the reportedexperience is limited to case reports and small series. It is the author and col-leagues’ experience that the nasal tubes frequently are declined by patients;once accepted, they may be difficult to place and are more subject to beingvomited up than tubes placed for other reasons. Few disorders requiring en-teral nutrition are primarily disorders of vomiting per se. A recurring themein reports of enteral feeding is the need for a skilled team for replacementand support that is capable of encouraging patients and anticipating theirneeds.

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

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[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] YoneyamaY, Suzuki S, SawaR, 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 hyper-

emesis 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.

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ical and clinical indicators of severity of hyperemesis gravidarum. BJOG 2006;113:733–7.

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come in a Norwegian twin population. Obstet Gynecol 1992;80:989–94.


Diagnosis Ultrasound, maternal blood analysis (Hgb electrophoresis, K-B, IC, serologies for syphilis, toxoplasmosis, CMV, TUBS, parvo) or cordocentesis

Treatment Depends on the cause (see above)

Complications Increased maternal PIH, PTL (50%) due to hydramnios and postpartum hemorrhage due to uterine overdistention and/or retained placenta

HYDROSALPINGES

Watery sterile fl uid in fallopian tube → end stage of pyosalpinx PID – main cause of tubal infertility and ectopic pregnancy Incidence of tubal infertility after one PID 12% two PID 23% three PID 54% Risk of ectopic after PID increases 6–7 x With bilateral hydrosalpinx, IUP is slim at most only about 12%

Diagnosis HSG (hysterosalpingogram) If suspect PID, get sed rate → if elevated → treat with doxycycline 200 mg then 100 mg b.i.d. for 5 days and postpone HSG until sed rate is normal. Water-soluble dye – risk of infection < 1% but 11% with dilated tubes will develop PID from HSG. If tubes are dilated, also give doxycyline as above after the HSG Conception rate within 1 year after using water-soluble agent 27% Use oil dye if there is no history of suspected PID as this causes less spasm and increases the conception rate after HSG Conception rate within 1 year after using oil-based agent 41% Delayed fi lm – crucial to differentiate normal spill from dye that is just distributed through the pelvis Refer for in vitro fertilization if large hydrosalpinges are seen. Distal obstruction is more commonly seen

Treatment Best to remove bilateral hydrosalpinx as it will reduce fl uid and ectopic rate is @ 15%

Ovaries are not to be disturbed and patient to be referred for IVF–ET

Prognosis (After tubal reconstruction) – depends on the damage. If damage is extensive, the chance of conception after tubal reconstruction is almost nil → refer for IVF

HYGROMAS

Cystic hygromas are a malformation of the lymphatic system (occurs in late 6th gestational week) First trimester – consider aneuploidies Second and third trimester – monosomy XO is common Check karyotype – If normal, the prognosis is good Check for septations – if septations present, prognosis is decreased With abnormal karyotype AND septations → this is worse prognosis

HYPEREMESIS

Nausea and vomiting to extent of weight loss, dehydration, ketosis and electrolyte imbalance

Incidence @ what % of women with nausea and vomiting develop hyperemesis gravidarum? 1.3%

Nausea + vomiting 50% Nausea only 25% Neither 25%

Defi nition of hyperemesis Persistent vomiting, weight loss > 5%, ketonuria, electrolytegravidarum abnormalities, dehydration (increased specifi c gravity), usually

requires hospitalization

196 HYDROSALPINGES

When does it occur? Most of the time, the majority between 4–7 weeks’ gestation Usually this % is over by 16 weeks’ gestation 90%

Etiology Vomiting center in medulla is thought to be affected – by unknown. Hormones? Vitamin defi ciency? Psychological infl uences? GI dysmotility of pregnancy? Helicobacter pylori factor? (80% vs 50% H. pylori present in N+V of pregnancy patients)

Differential diagnosis Gastroenteritis, hepatitis, cholelithiasis, pancreatitis, pyelonephritis, appendicitis, peptic ulcer disease, multiple pregnancies, hydatidiform mole

Labs CBC, U/A, lytes, LFTs, amylase, TSH

Test for ketones while NPO after every void, I & Os, weight Specifi c gravity (concentrated) 1.020–1.030

Ketones Acetone, acetoacetate and β-OH butyrate

Management (1) First try

Increase protein and decrease carbohydrate and fatty foods in diet. Vitamin B 6 25 mg t.i.d. (50% stop vomiting). Severe nausea is reduced to mild to moderate nausea. Premesis ® Rx is a prescription tablet containing vitamin B 6 75 mg so it can be given once per day. It also contains vitamin B 12 (12 µg), folic acid (1 mg) and calcium carbonate (200 mg) (2) Second try B 6 and doxylamine (similar to Bendectin ® ) – vitamin B 6 50 mg tablet ½ tablet p.o. t.i.d. with doxylamine (Unisom ® ) 25 mg one tablet p.o. q. h and/or ½ tablet in a.m. and ½ tablet in p.m. (3) Third try And/or add CAM (complementary alternative medicine) Ginger (ginger capsules 250 mg t.i.d. to q.i.d.). Acupressure (wristbands available) Most popular acupoint for nausea and vomiting is Neiguan (P6) point located two cun (approximately three fi nger-breadths) below the distal wrist crease on the anterior surface (palmar side) of the wrist. Acupressure may be more successful than acupuncture for the indication of mild to moderate nausea and vomiting during early pregnancy. Increasing the frequency of treatments may reduce the frequency and severity of vomiting

If still uncomfortable Add doxylamine succinate (Unisom ® ) p.o. 12.5–25 mg daily. Diagnose and treat any Helicobacter pylori infection

Intake and weight Review at each visit IVFs D5NS 250 cc/h x 4 h then 150 cc/h

Give KCl, MVT, folic acid and/or vitamin B6 p.r.n. Total parental nutrition p.r.n. Refer to CNSD (Cert. Nutritional Support Dietician)

Diet Day #1 – NPO, day #2 – clear, day #3 – low fat bland 3 x/day + three snacks

Drug therapy • Ondansetron HCl (Zofran) 32 mg/50 ml premixed bag – best therapy, fi rst choice – category B. Does not cause sedation. Patient can carry out routine activities. Disadvantage is the cost – it is expensive. Zofran also available in tablet and oral disintegrating tablets forms – 4 mg, 8 mg, 24 mg tablets; 4 mg, 8 mg ODT (strawberry fl avor)

• Anticholinergic (scopolamine) • Antihistamines (diphenhydramine/Benadryl) Category B • Serotonin (5-HT3) antagonist (Zofran and others) Category B • Benzamides (metoclopramide/Reglan) Category B • Promethazine (Phenergan) Category C • Phenothiazines (Compazine ® ) Category D • Butyrophenones (droperidol) – has Black Box Warning now

(2001); has caused arrhythmias

Doses (most common therapies) Phenergan 25 mg IV or suppository q. 6 h In doses of 50 mg → 50% patients sleep so titrate doses 12.5 mg →

HYPEREMESIS 197

25 mg → 50 mg Zofran 32 mg IV @ 15 min then 0.15 mg/kg IV q. 4–8 h x 3 dose Zofran 8 mg ODT or p.o. t.i.d. x 14 days → 0% sleepers Reglan 10 mg IV or p.o. t.i.d. ½ hour prior to meals and hs Benadryl 50 mg IV @ 30 min then q. 6 h

Surgical therapy Nasogastric, gastrostomy or jejunostomy feedings

HYPERLIPIDEMIA

Treatment (1) Increased cholesterol

Cholestyramine, colestipol, niacin, atorvastatin, lovastatin, pravastatin, simvastatin

(2) Increased triglycerides Gemfi brozil, niacin (3) Combined hyperlipids Niacin, atorvastatin, lovastatin, pravastatin, omega-3 fatty acid,

vitamin E and vitamin C

HYPERPLASIA

Diagnosis Endometrial biopsy

Histology Nuclear enlargement, hyperchromasia, irregularity of nuclei, signifi cant crowding but with some intervening stroma Most important prognosticator of malignant potential ATYPIA

Treatment If patient over 40 – HYSTERECTOMY is treatment of choice but if patient at increased risk – progestins x 3–6 months with repeat endometrial biopsies or D & C and/or hysteroscopy. Hysterectomy if indicated

If patient under 40 – progestin 10 mg daily x 10 days or Provera 20 mg daily day 16–25 or DMPA 200 mg IM q. 2 months x 3 doses or OCP or ovulation induction with FOLLOW-UP in 3 months Endometrial evaluation 3–6 month follow-up is effective 62% Discuss risks and informed consent @ hysterectomy p.r.n.

Figure 7 Ultrasound of hyperstimulation syndrome

198 HYPERLIPIDEMIA

HYPEREMESIS GRAVIDARUMHyperemesis gravidarum is persistent, otherwise unexplained vomiting in early pregnancy associated with ketonuria weight loss. It affects 1–2% of pregnantwomen and is the second most common cause of antenatal hospitalization in the United States. Elevated levels of transaminases, bilirubin, amylase, lipase,and various electrolytes are seen in 15–40% of patients. Biochemical evidence of hyperthyroidism due to the effect of human chorionic gonadotropin on thethyroid-stimulating hormone receptor is seen in 60–70% of patients. The differential diagnosis includes a wide variety of conditions capable of causingpersistent nausea and vomiting and must be considered carefully in each patient.The etiology is not understood. The spectrum of maternal susceptibility to an unknown emetogenic stimulus from the placenta accounts for the variability inthe condition and the difficulty in identifying a single etiologic factor. The recurrence rate is approximately 20% in prospective studies but this value probablyis an underestimation because the sickest women often limit family size.Treatment of hyperemesis gravidarum begins with supportive measures including hydration and vitamin supplementation, in particular vitamin B1, which isneeded to prevent Wernicke's encephalopathy. Nonpharmacologic measures, such as vitamin B6, ginger, and acupressure, appear to be effective withlesser degrees of, vomiting but their role in hyperemesis gravidarum is uncertain. Antihistamines as a class have some efficacy and the best record for fetalsafety. Other conventional antiemetics can be used in an algorithm that balances safety and efficacy (Fig 23–1).

Figure 23–1.

Nausea and vomiting of pregnancy/hyperemesis gravidarum treatment sequence at the University of Southern California. PO = by mouth; PR = by rectum.

Fetal status is generally not adversely affected by vomiting until persistent maternal weight loss occurs. In this setting, the rate of intrauterine growthretardation (IUGR) increases and fetal death appears to increase. Long-term effects of hyperemesis gravidarum on offspring are unknown. If weight losspersists despite therapy, nutritional supplementation by enteral tube feeding or parenteral feeding is necessary.REFERENCESRenal Disorders

Armenti VT et al: Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. In: Cecka JM,Terasaki PI (editors): Clinical Transplants. UCLA Immunogenetics Center, 2002, p. 97.

Bar J et al: Prediction of pregnancy outcome in subgroups of women with renal disease. Clin Nephrol 2000;53:437. [PMID: 10879663]

Cohen RA, Brown RS: Microscopic hematuria. N Engl J Med 2003;348:2330. [PMID: 12788998]

Cunningham FG, Lucas MJ: Urinary tract infections complicating pregnancy. Baillieres Clin Obstet Gynaecol 1994;8:353. [PMID: 7924012]

Hill JB et al: Acute pyelonephritis in pregnancy. Obstet Gynecol 2005;105:18. [PMID: 15625136]

Lindheimer MD, Davison JM, Katz AL: The kidney and hypertension in pregnancy: twenty exciting years. Semin Nephrol 2001;21:173. [PMID: 11245779]

Schrier RW et al: Acute renal failure: Definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 2004;114:5. [PMID: 15232604]

Selcuk NY et al: Outcome of pregnancies with HELLP syndrome complicated by acute renal failure (1989–1999). Ren Fail 2000;22:319. [PMID: 10843242]

Teichman JM: Acute renal colic from ureteral calculus. N Engl J Med 2004;350:684. [PMID: 14960744]

Gastrointestinal Disorders

Alsulyman OM et al: Intrahepatic cholestasis of pregnancy: Perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996;175:957.[PMID: 8885754]

Castro MA et al: Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28consecutive cases. Am J Obstet Gynecol 1999;181:389. [PMID: 10454689]

Connell W, Miller A: Treating inflammatory bowel disease during pregnancy: Risks and safety of drug therapy. Drug Saf 1999;21:311. [PMID: 10514022]

European Paediatric Hepatitis C Virus Network: A significant sex—but nor elective cesarean section—effect on mother-to-child transmission of hepatitis Cvirus infection. J Infect Dis 2005;192:1872.

Goodwin TM: Hyperemesis gravidarum. Prog Obstet Gynecol 2006; In press.

Ibdah JA: Role of genetic screening in identifying susceptibility to acute fatty liver of pregnancy. Nat Clin Pract Gastroenterol Hepatol 2005;21:494.

Sloan D et al: Prevention of perinatal transmission of hep B to babies at high risk: An evaluation. Vaccine 2005;23:5500. [PMID: 16112253]

Strader D et al: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147. [PMID: 15057920]

Williamson C et al: Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111:676. [PMID:15198757]

Current Diagnosis and Treatments in Obstetrics and Gynecology

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be D negative, antepartum prophylaxis is notnecessary.

F. Postpartum D immunoglobulin1. D immunoglobulin is given to the D negative

mother as soon after delivery as cord bloodfindings indicate that the baby is Rh positive.

2. A woman at risk who is inadvertently not given Dimmunoglobulin within 72 hours after deliveryshould still receive prophylaxis at any time upuntil two weeks after delivery. If prophylaxis isdelayed, it may not be effective.

3. A quantitative Kleihauer-Betke analysis shouldbe performed in situations in which significantmaternal bleeding may have occurred (eg, aftermaternal abdominal trauma, abruptio placentae,external cephalic version). If the quantitativedetermination is thought to be more than 30 mL,D immune globulin should be given to the motherin multiples of one vial (300 mcg) for each 30 mLof estimated fetal whole blood in her circulation,unless the father of the baby is known to be Dnegative.

G. Abruptio placentae, placenta previa, cesareandelivery, intrauterine manipulation, or manualremoval of the placenta may cause more than 30mL of fetal-to-maternal bleeding. In these condi-tions, testing for excessive bleeding (Kleihauer-Betke test) or inadequate D immunoglobulin dos-age (indirect Coombs test) is necessary.

References: See page 184.

Complications of Preg-nancy

Nausea and Vomiting of Preg-nancy and HyperemesisGravidarumNausea and vomiting to affects about 70% to 85% ofpregnant women. Symptoms of nausea and vomiting ofpregnancy (NVP) are most common during the firsttrimester; however, some women have persistent nauseafor their entire pregnancy. Hyperemesis often occurs inassociation with high levels of human chorionic gonado-tropin (hCG), such as with multiple pregnancies,trophoblastic disease, and fetal anomalies such astriploidy.

Conditions that Predispose to Excessive Nau-sea and Vomiting

Viral gastroenteritisGestational trophoblastic diseaseHepatitisUrinary tract infectionMultifetal gestationGallbladder diseaseMigraine

I. Treatment of nausea and vomiting of pregnancyA. Patients should avoid odors or foods that seem to

be aggravating the nausea. Useful dietary modifica-tions include avoiding fatty or spicy foods, andstopping iron supplements. Frequent small mealsalso may improve symptoms. Recommendationsinclude bland and dry foods, high-protein snacks,and crackers at the bedside to be taken first thing inthe morning.

B. Cholecystitis, peptic ulcer disease, or hepatitis cancause nausea and vomiting and should be ex-cluded. Gastroenteritis, appendicitis, pyelonephritis,and pancreatitis also should be excluded. Obstetricexplanations for nausea and vomiting may includemultiple pregnancies or a hydatidiform mole.

C. Non-pharmacologic remedies are adequate for upto 90% of patients with NVP. However, about 10%will require medication and about 1% have severeenough vomiting that they require hospitalization.

D. Vitamin therapy. Pyridoxine is effective as first-linetherapy and is recommended up to 25 mg threetimes daily. Pyridoxine serum levels do not appearto correlate with the prevalence or degree of nauseaand vomiting. Multivitamins also are effective forprevention of NVP. Premesis Rx is a prescriptiontablet with controlled-release vitamin B6, 75 mg, soit can be given once a day. It also contains vitaminB12 (12 mcg), folic acid (1 mg), and calcium car-bonate (200 mg).

E. Over-the-Counter Therapy. If pyridoxine alone isnot efficacious, an alternative is to combine over-the-counter doxylamine 25 mg (Unisom) andpyridoxine 25 mg. One could combine the 25 mg ofpyridoxine three times daily with doxylamine 25 mg,1 tablet every bedtime, and ½ tablet morning andafternoon. There is no evidence that doxylamine isa teratogen.

Drug Therapy for Nausea and Vomiting of Preg-nancy

Generic name (tradename)

Dosage

Antihistamines

Doxylamine (Unisom) 25 mg 1/2 tab BID, 1 tabqhs

Dimenhydrinate (Drama-mine)

25 to 100 mg po/im/iv every4 to 6 hr

Diphenhydramine (Bena-dryl)

25 to 50 mg po/im/iv every4 to 6 hr

Trimethobenzamide (Tigan) 250 mg po every 6 to 8 hror200 mg im/pr every 6 to 8hr

Meclizine (Antivert) 12.5 to 25 mg BID/TID

Phenothiazines

Promethazine (Phenergan) 12.5 to 25 mg po/iv/pr ev-ery 4 to 6 hr

Prochlorperazine(Compazine)

5 to 10 mg po/iv every 6 to8 hr or25 mg pr every 6 to 8 hr

Prokinetic agents

Metoclopramide (Reglan) 10 to 20 mg po/iv every 6hr

Serotonin (5-HT3) antagonists

Ondansetron (Zofran) 8 mg po/iv every 8 hr

Corticosteroids

Methylprednisolone(Medrol)

16 mg po TID for 3 daysthen 1/2 dose every 3 daysfor 2 wks

F. Pharmacologic Therapy1. Prescribed medication is the next step if dietary

modifications and vitamin B6 therapy withdoxylamine are ineffective. The phenothiazinesare safe and effective, and promethazine(Phenergan) often is tried first. One of the dis-advantages of the phenothiazines is theirpotential for dystonic effects.

2. Metoclopramide (Reglan) is the antiemeticdrug of choice in pregnancy in several Euro-pean countries. There was no increased risk ofbirth defects.

3. Ondansetron (Zofran) has been comparedwith promethazine (Phenergan), and the twodrugs are equally effective, but ondansetron ismuch more expensive. No data have beenpublished on first trimester teratogenic risk withondansetron.

II. Hyperemesis gravidarumA. Hyperemesis gravidarum occurs in the extreme

0.5% to 1% of patients who have intractable vomit-ing. Patients with hyperemesis have abnormalelectrolytes, dehydration with high urine-specificgravity, ketosis and acetonuria, and untreatedhave weight loss >5% of body weight. Intravenoushydration is the first line of therapy for patients withsevere nausea and vomiting. Administration ofvitamin B1 supplements may be necessary toprevent Wernicke's encephalopathy.

References: See page 184.

Spontaneous AbortionAbortion is defined as termination of pregnancy resultingin expulsion of an immature, nonviable fetus. A fetus of<20 weeks gestation or a fetus weighing <500 gm isconsidered an abortus. Spontaneous abortion occurs in15% of all pregnancies.

I. Threatened abortion is defined as vaginal bleedingoccurring in the first 20 weeks of pregnancy, without thepassage of tissue or rupture of membranes.A. Symptoms of pregnancy (nausea, vomiting, fatigue,

breast tenderness, urinary frequency) are usuallypresent.

B. Speculum exam reveals blood coming from thecervical os without amniotic fluid or tissue in theendocervical canal.

C. The internal cervical os is closed, and the uterus issoft and enlarged appropriate for gestational age.

D. Differential diagnosis1. Benign and malignant lesions. The cervix often

bleeds from an ectropion of friable tissue.Hemostasis can be accomplished by applyingpressure for several minutes with a large swab or

Editors: Hillard, Paula J. AdamsTitle: 5-Minute Obstetrics & Gynecology Consult, The, 1st Edition

Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > Section V - Pregnancy-Related Conditions > Hyperemesis Gravidarum

Hyperemesis Gravidarum

Alice Stek MD

Basics

DescriptionHyperemesis represents the extreme end of the continuum of nausea and vomiting of pregnancy.

No single accepted definition for hyperemesis gravidarum, but generally includes:

Persistent vomiting without other etiology

Measure of acute starvation, such as large ketonuria

Weight loss, usually at least 5% of prepregnancy weight

EpidemiologyNausea and vomiting of pregnancy affects 70–85% of pregnant women

Hyperemesis gravidarum in ~0.5–2% of pregnant women

Risk FactorsIncreased placental mass (e.g., molar gestation, multiple gestation)

Family history

History of hyperemesis in previous pregnancy

Women with history of nausea and vomiting after estrogen exposure (such as OCPs)

History of motion sickness or migraine

Female fetus

GeneticsWomen whose mothers or sisters had hyperemesis are more likely to experience hyperemesis themselves.

PathophysiologyEtiology is poorly understood.

Higher hCG and estrogen levels correlate with hyperemesis.

Associated ConditionshCG is a thyroid stimulator; up to 70% of women with hyperemesis have elevated free thyroxine and low TSH.

Rarely, Wernicke encephalopathy due to vitamin B1 deficiency, esophageal rupture, or pneumothorax

Depression

Diagnosis

Signs and Symptoms

History

Nausea and vomiting, typically starting before 9 weeks' gestation

Clinical diagnosis of exclusion

Typically no pain, fever, or headache

Physical Exam

Clinically diagnosis of exclusion

No fever, no tenderness, no neurologic findings, no goiter

Tests

Labs

Liver enzymes:

May be slightly elevated (<300 U/L)

Serum bilirubin:

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May be slightly elevated (<4 mg/dL)

Amylase and lipase:

May be slightly elevated (<5 times ULN)

Electrolytes, chemistry:

Hypochloremic metabolic alkalosis is possible

UA:

Elevated specific gravity, ketonuria

If hyperthyroidism suspected:

TSH, free thyroxine, free triiodothyronine

ImagingObstetric US for GA, evaluate for multiple gestation, molar gestation

Differential DiagnosisIf patient experiences nausea and vomiting for 1st time after 9 weeks' gestation, consider alternate diagnosis.

Infection

Gastroenteritis

Pyelonephritis

Appendicitis

Hepatitis

Metabolic/Endocrine

Diabetic ketoacidosis

Hyperthyroidism

Addison's disease

Tumor/Malignancy

CNS tumors

Ovarian torsion

DrugsDrug toxicity or substance abuse

Other/Miscellaneous

GI conditions:

Peptic ulcer disease, gastroparesis, pancreatitis, obstruction, hepatitis, appendicitis

GU tract:

Nephrolithiasis, pyelonephritis

Neurologic:

Pseudotumor cerebri, migraines, CNS tumor

Psychologic

Acute fatty liver of pregnancy

Treatment

General MeasuresExclude other etiologies.

Treat early manifestations to reduce need for hospitalization.

Pregnancy-Specific Issues

Risks for Fetus

The drugs listed below are generally considered safe, with the exception of corticosteroids, which may be associated with oral clefts.

Little safety data on ondansetron in pregnancy

Increased risk for prematurity and low birth weight if poor maternal weight gain

Special Therapy

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Complementary and Alternative Therapies

Ginger 250 mg powder capsules 4/d or fresh: In randomized trials, powdered ginger was more effective for relieving the severity of nausea andvomiting of pregnancy than placebo and of comparable efficacy to vitamin B6.

High-protein, low-carbohydrate, low-fat meals

Hypnosis has possible efficacy.

Often recommended, but no proven efficacy: Rest; frequent small meals; bland, low-fat foods; acupressure to wrist

Medication (Drugs)Start with 1st listed, and if no response, continue to next treatment:

Vitamin B6 10–25 mg t.i.d./q.i.d.

Vitamin B6 + doxylamine 10–12.5 mg t.i.d./q.i.d.

Vitamin B6 + doxylamine + promethazine 12.5–25 mg q4h PO or rectal

Add metoclopramide 5–10 mg q8h, IM or PO, or promethazine 12.5–25 mg q4h IM, PO, or rectal, or trimethobenzamide 200 mg q6–8h rectal

If dehydrated:

IV fluids with correction of ketosis and vitamin deficiencies, thiamine

Dimenhydrinate 50 mg IV q4–6h, or metoclopramide 5–10 mg IV q8h, or promethazine 12.5–25 mg IV q4h

Add methylprednisolone 16 mg q8h for 3 days; taper to stop or to lowest effective dose over 2 weeks, or ondansetron 8 mg IV q12h

If unable take food PO and losing weight:

Peripheral parenteral nutrition with high-lipid formula for several days only

TPN for longer-term needs. Consider PICC line.

Followup

Disposition

Issues for ReferralHospitalization if IV hydration and therapy needed

PrognosisPrognosis for resolution of symptoms and normal pregnancy outcome is good. However, there is a risk for recurrence with subsequent pregnancy.

ComplicationsDepression

Wernicke encephalopathy

Complications of hospitalization/intravenous treatments/TPN

Transient hyperthyroidism

Patient MonitoringHydration status

Weight gain

Electrolytes

Evaluate for anemia

Monitor for preterm labor

Bibliography

ACOG Practice Bulletin No. 52: Nausea and Vomiting of Pregnancy. Washington, DC: ACOG; April 2004.

Borrelli F, et al. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol. 2005;105:849–856.

Dodds L, et al. Outcomes of pregnancies complicated by hyperemesis gravidarum. Obstet Gynecol. 2006;107:285–292.

Safari HR, et al. The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: A randomized, double-blind, controlled study. AmJ Obstet Gynecol. 1998;179:921–924.

Smith C, et al. A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy. Obstet Gynecol. 2004;103:639–645.

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Vutyavanich T, et al. Ginger for nausea and vomiting of pregnancy: Randomized, double-masked, placebo-controlled trial. Obstet Gynecol.2001;97:577–582.

Vutyavanich T, et al. Pyridoxine for nausea and vomiting of pregnancy: A randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol.1995;173:881–884.

Miscellaneous

Clinical Pearls• Nausea and vomiting of pregnancy is very common and may progress to hyperemesis.

• Early treatment is beneficial.

• Effective treatment, thought to be safe for the fetus, is available and prognosis is good.

Abbreviations• GA—Gestational age

• hCG—Human chorionic gonadotropin

• OCPs—Oral contraceptive pills

• PICC line—Peripherally inserted central catheter

• TPN—Total parenteral nutrition

• TSH—Thyroid-stimulating hormone

Codes

ICD9-CM• 643.0 Mild hyperemesis gravidarum

• 643.1 Hyperemesis gravidarum with metabolic disturbance

• 643 Excessive vomiting in pregnancy

Patient Teaching• Reassurance about favorable pregnancy outcome

• Dietary advice

• Ginger

• Possible acupressure

Prevention• Daily multivitamin: Women taking daily multivitamin at the time of conception had less severe hyperemesis.

• Small, high-protein meals

• Evaluate and treat nausea and vomiting of pregnancy early.

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165

Introduction

Nausea and vomiting of pregnancy (NVP) affects about 75% of pregnant women, with 25% reporting nausea alone and 50% reporting both nausea and vomiting. Hyperemesis gravidarum (HG) occurs in 0.3–2% although popula-tions with significantly higher rates have been reported. It is identified by otherwise unexplained intractable vomiting and dehydration. Significant weight loss, usually � 5% of pre-pregnancy weight, confirms the diagnosis.

Maternal mortality was about 10% until the middle of the 20th century. Maternal death is now uncommon but it still does occur, either related directly to HG or to therapeutic interventions. It is the most common cause of hospitalization in the first half of pregnancy and the cost of hospitalization alone is estimated to be more than $500 million annually.

Etiology

Hyperemesis gravidarum is clearly related to a product of placental metabolism since it does not require the presence of the fetus and it occurs commonly in molar gestation. More than 20 studies about hormonal changes in NVP have been published in the last 30 years and despite some conflicting information, the evidence points towards hCG and estradiol as having a role.

There is a strong temporal association between hCG concentrations and the time of peak symptomatology. hCG is also a thyroid stimulator and biochemical hyper-thyroidism is commonly seen in HG. It has been difficult, however, to directly link total hCG concentrations with

the severity of NVP because its concentrations vary widely in the normal and NVP populations. This occurs because hCG is actually a family of isoforms which differ in their half-life and in their binding potency to the hCG, LH and TSH receptors. Isoforms lacking the carboxyl-terminal portion, for example, are more potent stimulators of the TSH and LH receptor but have shorter half-lives. Hyperglycosylated hCG, on the other hand, has a longer half-life and a longer duration of action.

A link between the action of hCG and estradiol has been suggested because concentrations of hypergly-cosylated hCG correlate with estradiol and the severity of nausea and vomiting (NV). It is hypothesized that stimulation of maternal ovarian production of estra-diol (and possibly fetal production as well) increases maternal estradiol concentration. NV in women taking the combined oral contraceptive pill increases in direct correlation with the estradiol dose and a history of NV while taking estrogens is a risk factor for the develop-ment of HG.

Epidemiologic studies have in general identified some common threads between women with HG and other common NV syndromes such as postoperative and chemotherapy-related NV and include younger age, a history of motion sickness, history of migraines and earlier hour of the day. Of interest is that smoking is associated with decreased concentrations of hCG and estradiol and with less NVP while fetal female gender is associated with greater concentrations of hCG and more severe HG.

Evidence in support of a genetic predisposition to NVP includes the concordance in frequency of nausea and vomiting of pregnancy in monozygotic twins; that siblings and mothers of patients with NVP are more likely to be affected; the variation in the frequency of NVP among different ethnic groups; and the occurrence of NVP in women with inherited glycoprotein hormone receptor defects. The paternal genome may have a role as well since women with HG in one pregnancy for whom there was a different father in the next pregnancy had a 60% lower rate of recurrence HG.

Chapter 36Nausea and Vomiting of Pregnancy Including Hyperemesis Gravidarum

T. Murphy Goodwin and Martin N. MontoroDepartment of Medicine and Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, CA, USA

Management of Common Problems in Obstetrics and Gynecology, 5th edition. Edited by T.M. Goodwin, M.N. Montoro, L. Muderspach, R. Paulson and S. Roy. © 2010 Blackwell Publishing Ltd.

166 Chapter 36

fetuses. The paternal genotype within the placenta must play a role, as is shown by the effect of changing fathers on the recurrence risk of HG. Equally important, the way an individual mother responds to this stimulus is geneti-cally mediated, as is shown by family studies of HG. The susceptibility of the mother varies depending on a number of factors that are recognized as mediating NV in other settings such as postoperative NV and chemo-therapy-induced NV.


Prospective studies show that virtually all women who develop NVP will have some symptoms by 9 weeks’ gestation; 7% have symptoms before the time of the first missed period and 60% are symptomatic by 6 weeks. For the subset of women with HG, there is a tendency for early onset of symptoms and much greater overall dura-tion. The timing of end of symptoms for NVP and HG is shown in Table 36.1.

In addition to NV, associated complaints include excess salivation (ptyalism) in up to 60%. There is a com-mon perception that women with more severe NVP are very sensitive to olfactory stimuli, but it has not been documented in objective studies. Rather, there is a change in the pleasurable (or, rather, lack of pleasurable) rating of odors, something similar to what is seen during chemotherapy-induced nausea.

Recent population-based studies have found that low pre-pregnancy BMI was associated with a higher risk of HG and that the effect was even stronger for women requiring hospitalization. Obesity appeared to decrease the risk of hospital admission for HG.

Laboratory abnormalitiesA wide variety of laboratory abnormalities can be seen with HG, including suppressed TSH and/or elevations in free T4, elevated liver enzymes as well as bilirubin,

Psychologic factors

For many years it was presumed that women suffering from HG were predisposed by something in their own psychologic make-up or by the circumstances of their lives. Numerous theories, drawn mostly from psychoa-nalysis, identified these women as rejecting the father of the baby, ambivalent about the pregnancy, reject-ing their own feminity and either being too dependent on their mothers … or not dependent enough! One of the most influential studies concluded that women with HG had a hysterical personality type. At present, HG is not believed to be due to any particular psychologic state. In a recent survey, 93 of 96 women believed that HG had a biologic basis and that psychologic problems were sec-ondary to the severe illness. Nevertheless, most of them also reported that friends, family members and caregiv-ers implied that they were somehow in control of their disease state.

The development of food aversions in pregnancy (present in about 50% of women) is closely linked 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 con-sistent with a taste aversion learning mechanism, where foods paired with illness are subsequently avoided. 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 have a similar mechanism. Interestingly, the food aver-sions in pregnancy are similar to those that develop with chemotherapy in that they do not generally persist after the acute course of the primary stimulus ends; this is distinct from other conditioned responses which may persist for years. Uncontrolled case series have suggested a benefit of behavioral therapy or hypnosis in treatment of HG.

Embryo protection hypothesisIn the view of evolutionary biology, NVP is a mechanism that has evolved, along with food aversions, to prevent pregnant mothers from ingesting substances that may be harmful to the developing fetus such as infections in the food supply or other toxins. However, even if NVP and HG evolved as a protective phenomenon, this fetal benefit is no longer applicable.

Nausea and vomiting of pregnancy as a syndromeNausea and vomiting of pregnancy is better thought of as a syndrome with the final phenotype arising from dif-ferent pathways. Thus, for example, the stimulus to HG is affected by placental mass (more common in multiple gestation) as well as by aberrant hCG production as in advanced molar gestation or in carriers of trisomy 21

Table 36.1 Time to cessation of NVP and HG

Weeks Women (%) Estimate NVP

(%)HG

<8 8.28–9 9.29–10 9.9 30 1010–11 15.111–12 17.5 30 1512–13 8.613–14 11.014–15 7.215–16 4.1 30 2016+ 9.2 10 50

Nausea and vomiting of pregnancy including hyperemesis gravidarum 167

The most extreme manifestation of this is termination of an otherwise wanted pregnancy. In one study, 15% of 808 women with HG had at least one termination of preg-nancy due specifically to HG. Although women who terminated their pregnancy due to HG did not appear to have more severe disease, they were twice as likely 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 stud-ies suggested an increased risk of breast cancer based on a presumed hyperestrogenic milieu but this has not been confirmed. Post-traumatic stress disorder, depression and a variety of neurologic complaints are commonly reported by these women but there has been no systematic follow-up.

Fetal consequences of hyperemesis

Nausea and vomiting of pregnancy is generally associated with good pregnancy outcome. The problem arises from applying this principle to cases of HG. It is now clear that the vast majority of fetal and maternal complications come from the group of HG women who have sustained weight loss. Although some degree of weight loss is present in many, if not most cases of HG, it is often stabilized with supportive therapy and antiemetic therapy. Women with HG who gain less than 7 kg overall in pregnancy are more likely to have low birthweight and preterm birth than women who gained more than 7 kg. The rate of fetal death is higher in the group with the most weight loss.

Major congenital anomalies appear to be less prevalent in women with NVP and HG, although the data are con-flicting. A Swedish population study found that hip dys-plasia and Down’s syndrome were higher than expected in HG women. Vitamin K deficiency causing fetal coag-ulopathy or chondrodysplasia has been reported. But apart from these possible anomalies, there is no overall increased rate of birth defects.

The long-term consequences of HG for the offspring are almost entirely unstudied but there is increasing awareness of the fetal origins of many adult diseases (Barker hypothesis). 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 psycho-logic well-being of the offspring. Several childhood cancers including testicular cancer and leukemia have been linked to hyperemesis although there are con-flicting data.

Differential diagnosis

Gastrointestinal conditions that could be confused with HG include gastroenteritis, gastroparesis, achalasia, biliary

amylase and lipase. These abnormalities resolve when the vomiting stops and do not require specific treatment. There is still insufficient awareness of the spectrum of these tran-sient 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 are usually transient as well or due to other underlying disease.

Virtually all patients with transient hyperthyroidism related to HG will have a normal TSH after the vomiting stops. In such patients there is no history of symptoms preceding pregnancy, no goiter, no other systemic signs of hyperthyroidism (except occasionally tachycardia) and negative thyroid antibodies.

Maternal complications

Severe metabolic/nutritional maternal complications of HG may include Werrnicke’s encephalopathy, beriberi, central pontine myelinolysis, hepatic insufficiency, acute tubular necrosis and peripheral neuropathy. Complications due to the mechanical stress of vomiting may include Mallory–Weiss tear of the esophagus, esophageal rupture, pneumomediastinum, retinal detachment and splenic avulsion.

One of the most serious complications of HG is Wernicke’s encephalopathy and more than 40 cases have been reported in the last 25 years. Presenting symptoms may include the classic diagnostic triad of ataxia, nystag-mus and dementia but the most common manifestation described in the literature is simply apathy or confusion. No patient has developed this complication with less than 4 weeks of persistent vomiting. More than half of the women reported have died or had permanent neu-rologic dysfunction. Reflecting the role of thiamine in glucose metabolism, some cases of Wernicke’s encepha-lopathy have been precipitated by infusion of solutions containing dextrose prior to administration of thiamine.

The problem of Wernicke’s encephalopathy is best addressed by prevention. All patients with HG should receive the minimum RDA for thiamine (3 mg/day) that is contained in most multivitamins or more. If the vom-iting is severe enough to require intravenous hydration, 100 mg thiamine should be administered parenterally on the presumption of thiamine deficiency. It is our practice to administer this daily for 3 days if a patient is in hospital for HG.

Psychologic burden and long-term health consequences

The psychologic burden of severe NVP and HG results from having a disease that has a strong subjective com-ponent (nausea) for which the cause is not understood.

168 Chapter 36

tract disease, hepatitis, intestinal obstruction, peptic ulcer disease, pancreatitis and appendicitis. Genitourinary tract conditions include pyelonephritis, ovarian torsion, nephrolithiasis, and degenerating uterine leiomyoma. Metabolic conditions include uremia, diabetic ketoaci-dosis, porphyria, Addison’s disease, severe hyperthy-roidism and hyperparathyroidism. Neurologic disorders may include pseudotumor cerebri, vestibular lesions, migraines, intracranial tumors and lymphocytic hypo-physitis. Pregnancy-related conditions include acute fatty liver of pregnancy and pre-eclampsia. Other possible causes include drug toxicity or intolerance.

Clinical clues suggesting alternative diagnosisThese include NV antedating pregnancy, nausea begin-ning after 9 weeks’ gestation, abdominal pain, fever, headache, goiter, abnormal neurologic exam, elevated WBC, anemia or thrombocytopenia.

Mild elevations of liver enzymes (usually � 300 U/L) and serum bilirubin (� 4 mg/dL) are encountered in 20–30% of women; serum concentrations of amylase and lipase (up to five times greater than normal levels) are seen in 10–15%. 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, and the bilirubin con-centration is generally much higher as well. Acute pan-creatitis may cause vomiting and hyperamylasemia, but serum amylase concentrations are usually 5–10 times higher than the elevations associated with NVP. Electrolyte abnormalities are found in 15–25% of cases. The most common are hypokalemia, hyponatremia and hypochloremic metabolic alkalosis. With severe volume contraction, a metabolic acidemia may be seen. All the abnormalities have been reported to regress with adequate volume replacement and nutritional support.

Elevated thyroxine and suppressed TSH (see Chapter 24) is noted in 50–70% of women with hyperemesis. It can usually be distinguished from intrinsic thyroid dis-ease in that there is no history of hyperthyroid symptoms preceding pregnancy, no goiter, negative thyroid anti-bodies, and the tri-iodothyronine is either not elevated or proportionally much less elevated than thyroxine. There are rarely symptoms of hyperthyroidism except occasional tachycardia. The condition, which is due to 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 NVP and the TSH concentration, a nonsuppressed TSH level suggests that the cause of the NV is something other than NVP. A TSH level greater than 2.5 µU/mL is rare with severe NVP, unless the patient has pre-existing hypothyroidism.

An ultrasound should be performed in cases of HG as 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 recurrence risk of HG was not well understood. Two recent studies have shown recurrence risks of 16% and 19%, a 29-fold increase over the primary rate. This is probably an underestimate for the most severe cases since more of these women are unlikely to attempt another pregnancy.

For these women in particular and for 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 interven-tion for HG later in pregnancy. Pre-emptive treatment of HG has been advocated based on the indirect evidence that in women who have NVP sufficient to interfere with their daily routine (30–35% of pregnant women), such treatment is associated with lower rates of hospital admission for HG.

Diet and supportLittle is known about what dietary adjustments should be made. Commonsense but unsubstantiated advice is to eat small meals when one feels able. Protein meals rather than carbohydrate, and liquids rather than solids, resulted in less nausea and improved stomach electri-cal rhythms associated with nausea. Food aversions and changes in the effect of smells are closely linked to the development of nausea, probably through a taste aver-sion learning mechanism. Besides avoiding the offend-ing foods and odors, there is evidence that behavioral approaches such as relaxation and hypnosis/distracting therapy can diminish nausea and vomiting.

Pharmacologic and alternative therapyFor women who continue to have problematic NV, vitamin B6, 25 mg three times daily, is recommended. Several randomized studies suggest a benefit of B6 in NVP in reducing nausea although the effect on vomiting is less clear. B6 is safe for mother and fetus in doses up to 100 mg daily. If symptoms persist, an antihistamine may be added; antihistamines have proven to be effective and safe.

The combination of B6 and the first-generation anti-histamine doxylamine formed the basis of Bendectin which was used by approximately 25% of all pregnant women (33 million) between 1958 and 1982. Several, although small, randomized controlled studies attested


to its efficacy but questions about its safety led to its withdrawal from the market, even though the risks have not been substantiated. Because of the scrutiny brought on by the ensuing litigation, Bendectin has been stud-ied 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. Doxylamine itself is only available in the US in the form of Unisom sleep tablets and available over the counter; 25 mg of B6 plus half of a 25 mg Unisom Sleep Tab 3–4 times daily approximates the Bendectin regimen (10 mg B6 and 10 mg doxylamine; B6 is not available in less than 50 mg doses in the United States). The Bendectin formulation can also be obtained from compounding pharmacies, and is available in Canada and several other countries as Diclectin.

For patients who receive no relief from this regimen, the herbal medication Ginger may be added and sev-eral randomized controlled studies attest to its efficacy. However, the fetal safety data are limited. Nevertheless, problems have not been seen and theoretical concerns seem adequately addressed in a recent review. Another alternative therapy which has been studied extensively in NVP is acupuncture and acoustic stimulation. Although there are some conflicting data, the weight of evidence suggests some benefit without significant risks.

Other classes of antiemetics include benzamides, phe-nothiazines, butyrophenones, 5-HT3 receptor antagonists and corticosteroids. While randomized trials of agents in most of these classes have shown some efficacy in NVP overall, there have only been 10 randomized trials of pharmacologic interventions in HG, six involving ster-oids. Because of their general effectiveness in relieving NV in other states, they have been commonly employed in NVP. Safety data have been limited although in recent years more information has accumulated. Corticosteroids appear to be associated with a slight increase in facial clefts when given in the first trimester.

Since there is not good evidence for the efficacy of any one of the agents among the phenothiazines or benzamides, it is common practice to switch between agents or combine them. One of the main dangers in this regard is the confluence of side effects, in particular extrapyramidal symptoms. Several of these agents have similar side effects and adverse reactions, particularly anxiety, depression and even hallucinations; there is evi-dence that the extrapyramidal symptoms are commonly overlooked.

Ondansetron and other 5-HT3 receptor antagonists deserve special mention. Most women with HG report that vitamin and herbal remedies and older antiemetics bring little relief. Although these agents may be effective for less severe NVP, more potent interventions appear to be needed for established HG. In this regard, ondanset-ron has become one of the most widely used antiemetics,

largely by analogy to its demonstrated superiority in chemotherapy-related NV. Although the only rand-omized controlled study of ondansetron for HG showed that it was not more effective than phenergan, this may be due to selection of patients who were likely to improve with most interventions, a point discussed fur-ther below. More safety data have accumulated recently.

Corticosteroids are potent antiemetics in the setting of chemotherapy-induced NV. They have been studied for their effect in HG with conflicting results. Several series described significant diminution or complete resolution of NV with corticosteroid therapy but randomized tri-als have failed to demonstrate a conclusive benefit. In one study, women discharged on corticosteroids were less likely to be readmitted than those on phenergan but another study did not find such a benefit. There may be a remarkable recrudescence of symptoms with steroid dose lowering which responds immediately to reinstitution of therapy. It has been suggested that the failure to show a benefit from steroids is due to patient selection bias in that less ill patients (those without weight loss in this analysis) are likely to respond to a variety of treatments.

Nutritional supportFor a patient who does not respond adequately to ther-apy and is unable to maintain her weight by oral intake, nutritional support is required. This recommendation is based on several points: higher rates of IUGR in this population, the probability of long-term adverse conse-quences for the fetus due to changes in programming and, rarely, life-threatening vitamin deficiency. Caloric support may be achieved by either enteral or parenteral nutrition. Probably because of a higher rate of patient acceptance, parenteral nutrition for women with HG has been reported much more often than enteral nutri-tion. Serious complications of parenteral alimentation can occur, however, including infection, thrombophlebi-tis, and death due to 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 also occurred.

In a study of 94 women hospitalized with HG, 42 received medication alone, 33 a peripherally inserted cen-tral catheter (PICC) line, and 19 a nasogastric or nasodu-odenal tube. Of those managed with a PICC line, 66.4% required treatment for infection, thromboembolism or both. In addition, neonatal complications including small for gestational age, admission to neonatal intensive care, 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 com-pared with parenteral feeding via a PICC line has led to increased usage. In our own survey of 792 women who

170 Chapter 36

Figure 36.1 Nausea and vomiting of pregnancy: treatment algorithm.

Nausea and vomiting of pregnancy: treatment algorithm**,†

(If no improvement, proceed to next step)

Vitamin B6 10 mg – 25 mg, TID or QID (up to 100 mg daily)

Add:

Doxylamine 12.5 mg, TID or QID1

Adjust schedule and dose according to severity of patient's symptoms

Add:

Promethazine (Phenergan®) 12.5 – 25 mg q4h PO/PROr

Dimenhydrinate (Dramamine® Oral) 50 – 100 mg q4 – 6h PO/PR(not to exceed 400 mg per day; not to exceed 200 mg per day if patient is also

taking doxylamine)

Stop other medications and substitute:

Metoclopramide (Reglan®) 5 – 10 mg q8h POor

Trimethobenzamide (Tigan®) 200 mg q6h – 8h PRor

Prochlorperzine 25 mg q12h PR

Alternative therapies may be added at any time during the sequence depending on patient acceptance and the familiarity of the attendant: consider P6 acccupressure with Sea

Bands® or accustimulation with Relief Band® or Ginger capsules 250 mg 4 times daily

Not tolerating PO

IV fluid replacement and multivitamin and thiamine supplementation2

Substitute any of the following (presented here in alphabetical order):Dimenhydrinate (Dramamine® Injection) 50 mg

(in 50 mL saline, over 20 min) q4–6h IVor

Metoclopramide (Reglan®) 5–10 mg q8h IVor

Promethazine (Phenergan®) 12.5–25 mg q4h IVor

Prochlorperazine 5–10 mg q4h IV (max dose 40 mg/day)

Persistent Vomiting: Substitute:

Ondansetron3 (Zofran®) 4–8 mg q8h PO/IV.or

Methylprednisolone4 (Medrol®) 16 mg q8h PO/IV for 3 days.Taper over 2 weeks to lowest effective dose.

If beneficial, limit total duration of use to 6 weeks.

1In the US, 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.2100 mg thiamine IV daily for 2–3 days (followed by IV multivitamins) is recommended for every woman who requires IV hydration and has vomited for more than 3 weeks.3Less effect on nausea.4Steroids appear to increase risk for oral clefts in first 10 weeks of gestation.** The use of this algorithm assumes that other causes of nausea and vomiting have been ruled out.†At any step, consider parenteral nutrition, if dehydration or persistent weight loss is noted.


self-reported HG from 2000 to 2004, 16.7% reported parenteral nutrition, but only 2.3% reported enteral tube feeding.

While there is no doubt that these techniques are less expensive and subject to far fewer complications than parenteral nutrition, the experience is limited to case reports and small series. It is our experience that the nasal tubes are frequently 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. This may be because few disorders requiring enteral nutrition are primarily disorders of vomiting per se. A recurring theme in reports of usage of enteral feeding is the presence of 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 Figure 36.1.

Suggested reading

Borrelli F, Capasso R, Aviello G, et al. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vom-iting. Obstet Gynecol 2005; 105: 849–856.

Brunetti-Pierri N, Hunter JV, Boerkoel CF. Gray matter heteroto-pias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency? Am J Med Genet A 2007; 143: 200–204.

Buckwalter JG, Simpson SW. Psychological factor in the etiology and treatment of severe nausea and vomiting in pregnancy. Am J Obstet Gynecol 2002; 186: S210–214.

Dodds L, Fell DB, Joseph KS, Allen V, Butler B. Outcome of pregnancies complicated by hyperemesis gravidarum. Obstet Gynecol 2006; 107: 285–292.

Einarson A, Maltepe C, Navioz Y, et al. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective compara-tive study. BJOG 2004; 111: 940–943.

Flaxman SM, Sherman PW. Morning sickness: a mechanism for protecting mother and embryo. Quart Rev Biol 2000; 75: 113–148.

Goodwin TM, Hershman JM. Hyperthyroidism due to inappropri-ate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997; 40: 32–44.

Goodwin TM, Montoro M, Mestman JH. Transient hyperthy-roidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992; 167: 648–652.

Goodwin TM, Poursharif B, Korst LM, MacGibbon KW, Romero R, Fez MS. Secular trends in the treatment of hyperemesis gravidarum. Am J Perinatol 2008; 25(3): 141–147.

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

Hummela T, von Meringb T, Huchb R, et al. Olfactory modulation of nausea during early pregnancy? BJOG 2002; 109: 1394–1397.

Kallen B, Lundberg G, Aberg A. Relationship between vitamin use, smoking, and nausea and vomiting of pregnancy. Acta Obstet Gynecol Scand 2003; 82: 916–920.

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

Poursharif B, Korst L, MacGibbon K, Fejzo MS, Romero R, Goodwin TM. Voluntary termination in a large cohort of women with hyperemesis gravidarum. Contraception 2007; 76: 451–455.

Safari HR, Alsulyman OM, Gherman RB, et al. The efficacy of methylprednisolone in the treatment of hyperemesis gravi-darum: a randomized, double-blind, controlled study. Am J Obstet Gynecol 1998; 179: 921–924.

Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997; 14: 119–124.

Trogstad L, Stoltenberg C, Magnus P, Skjærven R, Irgens L. Recurrence risk in hyperemesis gravidarum. BJOG 2005; 112: 1641–1645.

Yoshimura M, Hershman JM. Thyrotropic action of human chori-onic gonadotropin. Thyroid 1995; 5: 425–434.

1050 Medical and Surgical Complications

SECTION

8

■ Laparotomy and LaparoscopySurgery is lifesaving for certain gastrointestinal conditions—perforative appendicitis being the most common example. In thefirst study using the Swedish Registry database through 1981,Mazze and Källén (1989) reported that abdominal exploration bylaparotomy or laparoscopy was performed in 1331 of 720,000pregnancies—approximately 1 in every 500. Kort and associates(1993) reported a similar incidence of 1 in 635 in nearly 50,000pregnancies. In both studies, the most common indications forsurgery were appendicitis, an adnexal mass, and cholecystitis.

Laparoscopic procedures have replaced traditional surgicaltechniques for many abdominal disorders during pregnancy(Carter and Soper, 2004). In the updated report from theSwedish Registry database, Reedy and associates (1997) de-scribed 2181 pregnant women who underwent laparoscopy and1522 who had laparotomy for nonobstetrical indications. Theincidence for all procedures was similar to their first study—approximately 1 in every 800 pregnancies. Both were mostlyperformed before 20 weeks, and they were found to be safe.Finally, long-term surveillance studies suggest no deleterious ef-fects for either mother or child (Rizzo, 2003).

The most common nongynecological procedures performedduring pregnancy are cholecystectomy and appendectomy(Fatum and Rojansky, 2001; Rollins and associates, 2004). Formore details and for descriptions of surgical technique, seeChapter 41 (p. 913) as well as Operative Obstetrics, 2nd edition(Gilstrap and colleagues, 2002). Guidelines for diagnosis, treat-ment, and use of laparoscopy for surgical problems duringpregnancy have been provided by the Society of American Gas-trointestinal and Endoscopic Surgeons (2008).

■ Nutritional SupportSpecialized nutritional support can be delivered enterally, usu-ally via nasogastric tube feedings, or intravenously with periph-eral or central venous access. When possible, enteral alimentation is preferable because it has fewer serious complica-tions (Hamaoui and Hamaoui, 2003; Vaisman and co-workers,2004). In obstetrical patients, very few conditions prohibit en-teral nutrition as a first effort to prevent catabolism.

The purpose of parenteral feeding, or hyperalimentation, is toprovide nutrition when the intestinal tract must be kept quiescent.Peripheral venous access may be adequate for short-term supple-mental nutrition, which derives calories from isotonic fat solutions.Central venous access is necessary for total parenteral nutritionbecause its hyperosmolarity requires rapid dilution in a high-flowvascular system. These solutions provide 24 to 40 kcal/kg/day,principally as a hypertonic glucose solution. Heyland and col-leagues (1998) reviewed 26 randomized trials involving more than2200 critically ill nonpregnant patients and reported that overallmortality rates were not influenced by parenteral nutrition.

Parenteral Nutrition During PregnancyThere have been a variety of conditions for which total par-enteral nutrition was employed during pregnancy (Table 49-1).Gastrointestinal disorders are the most common indication, andin the many studies cited, duration of feeding averaged 33 days.It is imperative to emphasize that complications of par-

enteral nutrition are frequent and they may be severe. Themyriad gastrointestinal complications were recently reviewed byGuglielmi and colleagues (2006). And Russo-Stieglitz and asso-ciates (1999) described 26 pregnancies with a 50-percent rate ofcomplications, which include pneumothorax, hemothorax, andbrachial plexus injury. The most frequent serious complication iscatheter sepsis, and Folk and co-workers (2004) described a 25-percent incidence in 27 women with hyperemesis gravidarum.Although bacterial sepsis is most common, Candida septicemiahas been described (Paranyuk and associates, 2006). The Centersfor Disease Control and Prevention (2002) has published de-tailed guidelines for management to prevent catheter-relatedsepsis. Perinatal complications are uncommon, however, fetalsubdural hematoma caused by maternal vitamin K deficiencywas described by Sakai and colleagues (2003).

There is also appreciable morbidity from a peripherally in-serted central catheter (PICC). Ogura and colleagues (2003) re-ported infection with long-term access in 31 of 52 pregnantwomen. Holmgren and co-workers (2008) reported complica-tions in 21 of 33 women in whom a PICC line was placed forhyperemesis. Infections were the most common, and half ofinfected women also had bacteremia. From their review of48 reports of nonpregnant adults, Turcotte and associates(2006) concluded that there were no advantages to peripherallyplaced catheters compared with centrally placed ones.

DISORDERS OF THE UPPER GASTROINTESTINALTRACT

■ Hyperemesis GravidarumIn most women, mild to moderate nausea and vomiting areespecially common until approximately 16 weeks (see Chap. 8,p. 210). In some women, however, it is severe and unresponsiveto simple dietary modification and antiemetics. In an attempt toquantify the severity of nausea and vomiting, Lacasse and col-leagues (2008) have proposed a PUQE scoring index—Preg-nancy-Unique Quantification of Emesis and Nausea. Hypereme-sis gravidarum is defined variably as vomiting sufficiently severeto produce weight loss, dehydration, alkalosis from loss of hy-drochloric acid, and hypokalemia. Acidosis develops from partial

TABLE 49-1. Some Conditions Treated with ParenteralNutrition During Pregnancy

Anorexia nervosa Jejunoileal bypassAppendiceal rupture MalignanciesBowel obstruction PancreatitisBurns Preeclampsia syndromeCholecystitis Preterm labor/rupturedCrohn disease membranesDiabetic gastropathy Short bowel syndromeEsophageal injury Small bowel obstructionHyperemesis gravidarum Stroke

From Kirby (1988), Ogura (2003), and Russo-Stieglitz(1999), and all their colleagues.

1051Gastrointestinal Disorders

CHA

PTER

49

starvation (Chihara and co-workers, 2003). In some women,transient hepatic dysfunction develops (see Chap. 50, p. 1063).

Population incidences vary, and there appears to be an ethnicor familial predilection (Grjibovski and co-workers, 2008). Inpopulation-based studies from California and Nova Scotia, thehospitalization rate for hyperemesis was 0.5 to 0.8 percent(Bailit, 2005; Fell and co-workers, 2006). Hospitalization is lesscommon in obese women (Cedergren and associates, 2008). Inwomen hospitalized in a previous pregnancy for hyperemesis, upto 20 percent require hospitalization in a subsequent pregnancy(Dodds and associates, 2006; Trogstad and co-workers, 2005).

Hyperemesis appears to be related to high or rapidly risingserum levels of pregnancy-related hormones. Although the ex-act stimulus is unknown, putative culprits include humanchorionic gonadotropin (hCG), estrogens, progesterone, leptin,placental growth hormone, prolactin, thyroxine, and adreno-cortical hormones (Verberg and associates, 2005). Studies byGoodwin and co-workers (2008) implicate the vestibular sys-tem. There seems to be no doubt that in some but not nearly allsevere cases, there are interrelated psychological components(Buckwalter and Simpson, 2002). In some, hyperemesis is givenas a reason for elective termination (Poursharif and colleagues,2007). Other factors that increase the risk for admission includehyperthyroidism, previous molar pregnancy, diabetes, gastroin-testinal illnesses, and asthma (Fell and co-workers, 2006). Andfor unknown reasons, a female fetus increases the risk by 1.5-fold (Schiff and colleagues, 2004; Tan and co-workers, 2006).

Helicobacter pylori InfectionAn association of H. pylori infection has been proposed, but evi-dence is not conclusive. Goldberg and colleagues (2007) performeda scholarly systematic review of 14 case-control studies. Althoughthe analysis indicated an association between H. pylori and hyper-emesis, heterogenicity between study groups was extensive. At thistime, we do not test for or treat for gastric infection in women withhyperemesis. Certainly, the “cocktail(s)” required for eradicationwould most likely cause vomiting in most pregnant women.

Somewhat unrelated, Ponzetto and colleagues (2006) re-ported that H. pylori seropositivity was linked to an increasedrisk for preeclampsia. In the population-based California studyby Dodds and associates (2006), however, the incidence of ges-tational hypertension was not different from that in controlwomen. H. pylori infection has also been linked to iron defi-ciency in pregnancy (Weyermann and associates, 2005).

ComplicationsVomiting may be prolonged, frequent, and severe. Plasma zinclevels are increased, copper levels decreased, and magnesiumlevels unchanged (Dokmeci and associates, 2004). Preliminaryfindings are that a third of women with hyperemesis have anabnormal electroencephalogram (EEG) (Vaknin and colleagues,2006). A list of potentially fatal complications is given inTable 49-2. Various degrees of acute renal failure from dehy-dration are encountered, and we have cared for a number ofwomen with markedly impaired renal function. The extremeexample, which was described by Hill and colleagues (2002), isa woman who required 5 days of dialysis when her serum crea-

tinine level rose to 10.7 mg/dL. Life-threatening complicationsof continuous retching include Mallory-Weiss tears, such asshown in Figure 49-1. Others are esophageal rupture, pneu-mothorax, and pneumomediastinum (Schwartz and Rossoff,1994; Yamamoto and colleagues, 2001).

At least two serious vitamin deficiencies have been reportedwith hyperemesis in pregnancy. Wernicke encephalopathy fromthiamine deficiency is not uncommon. Chiossi and colleagues(2006) reviewed 49 cases and reported that only half had thetriad of confusion, ocular findings, and ataxia. Usually, there areMR imaging findings. At least three maternal deaths have beendescribed, and long-term sequelae are common and includeblindness, convulsions, and coma (Selitsky and co-workers,2006). Vitamin K deficiency has been reported causing maternalcoagulopathy and fetal intracranial hemorrhage (Kawamura,2008; Robinson, 1998; Sakai, 2003, and all their colleagues).

ManagementMethods to control nausea and vomiting of early pregnancy arediscussed in Chapter 8 (see p. 210). A Cochrane Database re-view by Jewell and Young (2000) confirmed a salutary effectfrom a number of antiemetics given orally or by rectal supposi-tory as first-line agents. When simple measures fail, intravenous

TABLE 49-2. Some Life-Threatening Complications ofRecalcitrant Hyperemesis Gravidarum

Depression—cause versus effect?Esophageal rupture—Boerhaave syndromeHypoprothrombinemia—vitamin KHyperalimentation complicationsMallory-Weiss tears—bleeding, pneumothorax,

pneumomediastinum, pneumopericardiumRenal failure—may require dialysis Wernicke encephalopathy—thiamine deficiency

FIGURE 49-1 Endoscopic view of Mallory-Weiss tear. (From Micheland co-workers, 2008, with permission.)

1052 Medical and Surgical Complications

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8

crystalloid solutions are given to correct dehydration, ketonemia,electrolyte deficits, and acid-base imbalances. Thiamine, 100 mg,is given to prevent Wernicke encephalopathy previously discussed.

If vomiting persists after rehydration and failed outpatientmanagement, hospitalization is recommended (American Col-lege of Obstetricians and Gynecologists, 2004). Antiemeticssuch as promethazine, prochlorperazine, chlorpromazine, ormetoclopramide are given parenterally. There is little evidencethat treatment with glucocorticosteroids is effective. Two smalltrials found no benefits of methylprednisolone compared withplacebo, but the steroid-treated group had significantly fewerreadmissions (Duggar and Carlan, 2001; Safari and co-workers,1998). In a study of 110 women at Parkland Hospital, Yost andcolleagues (2003) compared placebo with intravenous methyl-prednisolone plus tapered oral steroids. A third in each grouprequired readmission. In a study by Bondok and co-workers(2006), pulsed hydrocortisone therapy was superior to metoclo-pramide to reduce vomiting and readmissions. Serotonin antag-onists are the most effective agents for controlling chemother-apy-induced nausea and vomiting (Hesketh, 2008). When usedin one trial for hyperemesis gravidarum, however, ondansetronwas not superior to promethazine (Sullivan and associates,1996). Reports of serotonin antagonist use in pregnancy arelimited, but there is no evidence of teratogenicity (Briggs andassociates, 2005; Mahadevan and Kane, 2006).

With persistent vomiting after hospitalization, appropriatesteps should be taken to exclude possible underlying diseases asa cause of hyperemesis. Endoscopy did not change managementin 49 women reported by Debby and co-workers (2008). Ex-amples include gastroenteritis, cholecystitis, pancreatitis, hepati-tis, peptic ulcer, and pyelonephritis. In addition, severepreeclampsia and fatty liver are considerations after midpreg-nancy. And although clinical thyrotoxicosis has been implicatedas a cause of hyperemesis, it is more likely that abnormally ele-vated serum thyroxine levels are a surrogate for higher-than-aver-age serum hCG levels (see Chap. 3, p. 63). Tan and colleagues(2002) have described this as “chemical hyperthyroidism.” Andof interest, Panesar and associates (2006) showed that a cohort ofwomen with hyperemesis had lower serum thyrotropin levels. Inour experiences, serum free thyroxine levels normalize quicklywith hydration.

Following treatment, most women have had a salutary re-sponse and may be sent home with antiemetic therapy. Theirreadmission rate is 25 to 35 percent in most prospective studies.

If associated psychiatric and social factors contribute to theillness, the woman usually improves remarkably while hospital-ized, but may relapse after discharge. In these women, assistancewith psychosocial problems is beneficial (Swallow and co-workers, 2004).

Nutritional SupportIn the small percentage of women who continue to have recal-citrant vomiting, consideration is given for enteral nutrition asdiscussed on page 1050. Vaisman and co-workers (2004) de-scribed successful use of nasojejunal feeding for up to 21 days in11 such women. Percutaneous endoscopic gastrostomy with a jejunalport—PEG (J) tube—was described by Schrag and co-workers(2007).

In our experiences, only a very few women will requireparenteral nutrition. In their study of 166 women, Folk andcolleagues (2004) reported that in 16 percent, central venousaccess was established for nutrition. The litany of complicationsincluded line sepsis in 25 percent and thrombosis and infectiveendocarditis in one woman each.

■ Reflux EsophagitisHeartburn, or pyrosis, is common in late pregnancy. The ret-rosternal burning sensation is caused by esophagitis from gas-troesophageal reflux related to relaxation of the loweresophageal sphincter (Hytten, 1991). Common folklore hasheld that women with excessive heartburn give birth to infantswith more hair. And although this may seem strange, Costiganand associates (2006) recently confirmed this! They proposed ashared biological mechanism. Pregnancy hormones caused bothrelaxation of the esophageal sphincter—thus more reflux, moreheartburn, and they also modulated hair growth.

Symptoms usually respond to raising the head of the bed andtreatment with oral antacids. If severe symptoms persist, an H2-receptor antagonist such as cimetidine or ranitidine is pre-scribed. These are considered safe, but misoprostol is contraindi-cated because it may stimulate labor (see Chap. 22, p. 503). Thecommonly used proton-pump inhibitor, omeprazole, is also safefor use in pregnancy (Diav-Citrin and associates, 2005; Ma-hadevan and Kane, 2006). If there still is no relief, then en-doscopy should be considered.

Biertho and associates (2006) described 25 women who hadundergone laparoscopic Nissen fundoplication for reflux priorto pregnancy. Only 20 percent had reflux symptoms requiringantacids during pregnancy.

■ Hiatal HerniaThe older literature is informative here. Rigler and Eneboe (1935)performed upper gastrointestinal radiographs in 195 women inlate pregnancy. Almost 20 percent of 116 multiparas and 5 percentof 79 nulliparas had a hiatal hernia. Notably, in only three of 10women, a hernia persisted for 1 to 18 months postpartum.

The relationship of hiatal hernia with reflux esophagitis, andthus symptoms, is not clear. Cohen and Harris (1971) demon-strated no relationship between reflux and hernia and showed thatthe lower esophageal sphincter functioned effectively even whendisplaced intrathoracically. Nevertheless, during pregnancy, thesehiatal hernias may cause vomiting, epigastric pain, and bleedingfrom ulceration. Curran and colleagues (1999) described a 30-week pregnancy complicated by gastric outlet obstruction from aparaesophageal hernia, which they subsequently successfullyrepaired. Biertho and associates (2006) reported a woman with aprior Nissen fundoplication whose pregnancy was complicated bygastric herniation into the thoracic cavity. Emergency surgicalintervention was followed by spontaneous abortion.

■ Diaphragmatic HerniaThese are caused by herniations of abdominal contents througheither the foramen of Bochdalek or foramen of Morgagni. For-tunately, they rarely complicate pregnancy. Kurzel and associates

742

Background and epidemiology

Hyperemesis gravidarum (HG) is a condition of severe nausea and vomiting during pregnancy leading to fluid, electrolyte and acid–base imbalance, nutritional deficiency and weight loss [1]. Ketonuria and weight loss of greater than 5% pre-pregnancy bodyweight, which cannot be attributed to other causes, distinguishes HG from the more common nausea and vomiting of pregnancy [2]. Although the prognosis is gener-ally favorable, severe, untreated disease may lead to signifi-cant maternal and fetal morbidity.

While up to 50% of all pregnant patients will experience some nausea and vomiting of pregnancy (NVP), HG occurs in only 0.3–2% of all pregnancies [3]. The incidence appears to vary with ethnicity [4]. Symptoms usually begin at 4–5 weeks gestation and improve by 14–16 weeks. However, in up to 20% of patients, symptoms persist throughout pregnancy [5].

Hyperemesis gravidarum places a significant financial bur-den on the healthcare system and on society in general by leading to time loss from work, frequent hospitalizations and frequent visits to healthcare professionals. A study from 2002 estimated the cost of treating a single patient with HG in the United States could be as high as $17,000 [6].

Reported risk factors include personal or family history of hyperemesis, female sex of the offspring, multiple gestation, ges-tational trophoblastic disease, trisomy 21, hydrops fetalis and Helicobacter pylori (H. pylori) infection [7,8]. Maternal age greater than 30 and cigarette smoking may be protective [9].

Pathophysiology

The exact etiology of HG is unknown. Whether HG is an extreme form of gestational vomiting or a distinct entity has

also not been determined. Many possible causes have been investigated including hormonal changes, thyroid dysfunc-tion, gastrointestinal tract dysmotility, H. pylori infection and psychologic factors.

The pregnancy-related hormones, specifically human chori-onic gonadotropin (HCG) and estrogen, have been suggested to be the stimulus for nausea and vomiting of pregnancy [10]. It is well recognized that the peak symptoms of HG occur during periods of peak HCG concentration.

States of high estrogen concentration such as low parity and high maternal Body Mass Index have also been associ-ated with higher incidence of HG [11]. Estrogen is thought to contribute to HG by slowing gastric intestinal transit time and gastric emptying. Among the estrogens, estradiol has been found in some studies to correlate with nausea and vomiting of pregnancy and higher rates of HG, whereas estriol has not [12,13]. It is unlikely that estrogens are the sole cause of HG, especially considering that estrogen levels peak in the third trimester of pregnancy while HG tends to improve during late pregnancy [1].

Nonpregnancy-related hormones implicated in the pathogen-esis of HG include the thyroid hormones (thyroid- stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thy-roxine (FT4)) and leptin. Abnormal results on thyroid func-tion tests are common in HG, occurring in two-thirds of women [14]. “Biochemical thyrotoxicosis” characterized by suppressed TSH and slightly elevated FT4 may be seen due to the mild thyroid-stimulating activity of HCG. Despite these laboratory abnormalities, women with HG are generally euthyroid with no history of prior thyroid diseases, absent goiter and negative antithyroid antibodies [7]. Treatment is generally not necessary as the thyroid function tests normalize in most patients by 18 weeks [15].

Recently, a relationship between the hormone leptin and HG has been proposed. Increased serum leptin levels dur-ing pregnancy, possibly the result of increased total fat mass and placental production have been found to be significantly

Approach to hyperemesis gravidarumSumona Saha1, Catherine Williamson2, Niharika Mehta1, Edward K.S. Chien3 and Silvia Degli Esposti11 Department of Medicine, Warren Alpert Medical School of Brown University, Women &Infants’ Hospital of Rhode Island, Providence, RI, USA

2 Institute of Reproductive and Developmental Biology, Imperial College London, London, UK3 Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women & Infants’ Hospital of Rhode Island, Providence, RI, USA

de Swiet’s Medical Disorders in Obstetric Practice, 5th edition. Edited by R. O. Powrie, M. F. Greene, W. Camann. © 2010 Blackwell Publishing.

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APPROACH TO HYPEREMESIS GRAVIDARUM

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higher in patients with HG when compared to healthy pregnant controls [16,17].

The role of the gram-negative spiral bacterium H. pylori in HG remains controversial. Several studies have found H. pylori seropositivity to be significantly associated with HG [8,18], whereas others could not determine any relationship between the two conditions [19]. In the single study which used endoscopy with gastric mucosal biopsies to identify active H. pylori infection, 95% of women with HG were pos-itive for H. pylori infection compared with 50% of healthy pregnant controls [20]. A small case series of the effect of treatment of H. pylori infection in patients with HG reported dramatic improvement in symptoms after eradication [21]. Currently, there are no guidelines regarding whom or how to check for H. pylori infection in pregnancy; however, in severe cases of HG, H. pylori infection should be considered a contributing cause and should be treated.

Early studies proposed that HG may be a psychosomatic illness [1]. Recent studies, however, have not found definite psychogenic causes of HG [22,23]. It is likely that sociocul-tural factors rather than scientific evidence have led to the labeling of HG as a psychologically based condition and that psychologic disturbances are the result rather than the cause of HG [24].


Hyperemesis gravidarum presents in the first trimester of pregnancy, usually starting at 4–5 weeks gestation. In addition to severe nausea and vomiting, patients may report ptyalism, spitting and retching. Patients may also complain of gastro-esophageal reflux symptoms such as retrosternal discomfort and heartburn. The initial evaluation of patients with HG is reviewed in Box 48.1. A pregnancy unique quantification of emesis and nausea (PUQE) score that is calculated using the number of hours of nausea per day, number of episodes of emesis per day and number of episodes of retching per day can be used to track the severity of symptoms [25] (Box 48.2).

On physical exam, patients may have evidence of volume depletion with dry mucous membranes, tachycardia and postural hypotension. Weight loss of greater than 5% of pre-pregnancy bodyweight or inadequate weight gain are viewed by many experts to be the features that distinguish HG from nausea and vomiting of pregnancy. Severely affected patients may have muscle wasting and weakness.

Laboratory studies that are useful in diagnosing and managing patients with HG include urinalysis to assess for specific gravity, ketonuria and infection. Electrolytes and renal function should also be assessed to evaluate for hyponatremia, hypokalemia, and metabolic alkalosis from severe dehydration. Complete blood count testing may reveal an elevated hemoglobin due to hemoconcentration and volume depletion. Prealbumin (plasma transthyretin) levels may be

Box 48.1 Initial approach to hyperemesis gravidarum

History and physical exam

Assess duration and severity of symptoms Assess for weight lossAssess for dehydrationElicit presence of other symptoms (e.g. fever, abdominal pain, etc.)Calculate PUQE score

Laboratory studies

UrinalysisElectrolytesLiver function testsTSH and free T4Serum lipasePrealbumin

Imaging

Consider abdominal ultrasoundConsider obstetric ultrasound

Endoscopy

EsophagoGastroDuodenoscopy (EGD) if nausea is accompanied by hematemesis, odynophagia and dysphagia

••••

•

••••••

••

•

Box 48.2 Motherisk-PUQE score system

1. In the last 12 hours, for how long have you felt nauseated or sick to your stomach? a. Not at all (1 point) b. 1 hour or less (2 points)c. 2–3 hours (3 points)d. 4–6 hours (4 points)e. More than 6 hours (5 points)

2. In the last 13 hours have you vomited or thrown up? a. I did not throw up (1 point) b. 1–2 times (2 points)c. 3–4 times (3 points)d. 5–6 times (4 points)e. 7 or more times (5 points)

3. In the past 12 hours how often have you had retching or dry heaves without bringing any-thing up? a. At no time (1 point)b. 1–2 times (2 points)c. 3–4 times (3 points)

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Thyroid stimulating hormone levels may be low in HG, as mentioned above, due to cross-reaction between the alpha-subunit of HCG with the TSH receptor. In the majority of cases, this biochemical thyrotoxicosis is not clinically relevant as patients are euthyroid. Thyroid hormone levels generally normalize without treatment by 18 weeks gestation. In cases where it is hard to exclude thyrotoxicosis, thyroid autoanti-bodies (TSH receptor antibodies suggestive of Graves’ disease and thyroid peroxidase and thyroglobulin antibodies most commonly seen in Hashimoto’s thyroiditis) may be of value. In HG the raised liver transaminases and abnormal thyroid function tests should improve as the disease resolves and if they do not, further investigation should be undertaken to exclude other liver disease or hyperthyroidism.

Diagnosis

Hyperemesis gravidarum is a clinical diagnosis based on symptoms and the exclusion of other conditions. No clear delineation exists between HG and nausea and vomiting of pregnancy which may complicate making the diagnosis. No specific testing is needed to diagnose HG; however, ultra-sound of the abdomen and/or obstetric ultrasound may be helpful to exclude other causes such as gallbladder disease, hydatidiform mole and multiple gestation. The differential diagnosis is reviewed in Table 48.1 and includes nausea and vomiting of pregnancy, acute thyroiditis, eating disorders, viral gastroenteritis, biliary tract disease, pancreatitis, hepatitis, gastroesophageal reflux disease and less commonly, intracere-bral neoplasm and Addison’s disease.

low, reflecting poor protein nutrition status in the mother and possibly predicting lower fetal birthweights [26].

Liver function tests may be abnormal in up to 50% of hospitalized patients [27]. Mild hyperbilirubinemia (bilirubin �4 mg/dL) and/or a rise in alkaline phosphatase to twice the upper limit of normal may be seen [28]. A moderate transamin-itis is the most common liver function test abnormality, with alanine aminotransferase (ALT) levels generally greater than aspartate aminotranferase (AST) levels. The transaminase ele-vation is usually 2–3 times the upper limit of normal; however, levels greater than 1000 U/mL have been reported [29]. The abnormal liver tests are likely related to starvation and resolve promptly upon resolution of the vomiting.

Hyperamylasemia is common in HG. One study found elevated amylase levels in 24% of patients with HG [30]. This is likely due to excessive salivary gland production of amylase rather than pancreatic secretion and a result rather than a cause of HG [1].

d. 5–6 times (4 points)e. 7 or more times (5 points)

Calculate total score and categorize patient’s symp-toms as follows: 1–3 no symptoms; 4–6 mild; 7–12 moderate symptoms; �13 severe.

Adapted from Koren G, Baskovic R, Hard M, et al. Motherisk-PUQE (pregnancy unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol 2002;186:S228–31.

Table 48.1 Differential diagnosis of hyperemesis gravidarum

System Diagnosis Investigation/initial assessment

Genitourinary Urinary tract infection Mid-stream urine specimen for culture Uremia Urinalysis, electrolytes, BUN and creatinineMolar pregnancy Ultrasound of the uterus

Gastrointestinal Gastritis/peptic ulceration Helicobacter pylori antibodiesGastroesophageal reflux and ulcerative esophagitis Endoscopy or empirical proton pump inhibitor therapyPancreatitis Amylase, blood glucose, calciumBowel obstruction Plain supine abdominal X-ray

Endocrine Addison’s disease Urinalysis and electrolytes, early morning cortisol, a cosyntropin (a synthetic peptide with similar activity to ACTH that is known as tetracosactrin in the UK) stimulation test

Hyperthyroidism Surveillance for symptoms and signs of hyperthyroidism, thyroid function tests, thyroid autoantibodies (especially TSH receptor antibodies)

Diabetic ketoacidosis Blood glucose, urinary dipstick for ketones, glucose tolerance testRenal tubular acidosis Urinalysis (with urinary pH), electrolytes, BUN and creatinine

CNS Intracranial tumor Neurologic examination, brain imaging Vestibular disease History (vertigo should be a prominent feature) and neurologic examination

(sudden movements of the head may precipitate symptoms and nystagmus)

Respiratory Asthma Chest examination, peak expiratory flow rate (asthma can be associated with vomiting especially if there are large amounts of swallowed respiratory secretions)


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Complications

Mild-to-moderate nausea and vomiting of pregnancy is not associated with adverse fetal outcomes and may, in fact, be associated with reduced risks for miscarriage, preterm deliv-ery and stillbirth [31]. In contrast, severe, refractory HG has been associated with adverse maternal and fetal outcomes. In a study of more than 150,000 singleton pregnancies, infants born to women with hyperemesis and low pregnancy weight gain (less than 7 kg) were more likely to be low birthweight, born before 37 weeks of gestation and have a 5-minute Apgar score of less than 7 [3]. If the mother develops Wernicke’s encephalopathy the fetal outcome is worse; of 45 cases in the published literature, only 44% were reported as having been born alive [32].

Common maternal complications include weight loss, dehydration, micronutrient deficiency, and muscle weakness. More severe, albeit rare, complications of intractable vomiting or retching that have been reported include Mallory–Weiss tears (tears of the lower esophageal mucosa with subsequent gastrointestinal bleeding), esophageal perfo-ration, retinal hemorrhage and spontaneous pneumomediasti-num with or without subcutaneous emphysema [7]. Central pontine myelinolysis and Wernicke’s encephalopathy with or without Korsakoff’s psychosis are catastrophic but prevent-able complications of HG. Central pontine myelinolysis is seen in cases of HG where severe hyponatremia is corrected too rapidly. It is a symmetric destruction of myelin at the center of the basal pons. It can cause pyramidal tract signs, spastic quadraparesis, pseudobulbar palsy and impaired con-sciousness. Wernicke’s encephalopathy is seen in cases of HG with untreated thiamine deficiency, especially if these patients are given glucose or fed before thiamine has been replaced. A review of 45 reported cases established that the most com-mon presenting symptoms are ocular signs (diplopia, sixth nerve palsy or nystagmus, 82%), confusion (71%) and ataxia (69%) [32]. If untreated, Wernicke’s encephalopathy may lead to Korsakoff’s psychosis (amnesia, impaired ability to learn) or death. Lastly, severe depression with elective ter-mination of pregnancy has also been reported in association with HG [33].

Management

Given the potential for adverse outcomes, HG should be aggres-sively treated with the goals of maintaining fluid and electrolyte balance, maintaining adequate caloric intake and controlling symptoms. Patients able to maintain some oral intake benefit from nutritional counseling. Women are advised to eat several small meals throughout the day and to avoid an empty stom-ach as this may precipitate nausea. Avoiding offensive odors, separating solids and liquids and eating high-carbohydrate foods may also be helpful [34].

Complementary therapies such as acupressure, hypnosis, and herbal remedies have been variably effective in treating nausea and vomiting of pregnancy [35]. Recently, tactile massage [36] and acupressure have been found to be effective in HG [37]; other literature suggests that hypnosis as an adjunctive therapy may also be helpful [38]. Regarding herbal therapy, ginger was found to be more effective than placebo in a randomized con-trolled trial for treatment of HG [39]. And in a retrospective Canadian study, medicinal cannabis obtained through a com-passion society was found to be over 90% effective in treating nausea and vomiting of pregnancy [40].

Pharmacologic therapy with antiemetics and antireflux medications constitute first-line treatment for outpatients who fail dietary changes. An evidence-based algorithm for the treatment of nausea and vomiting of pregnancy is detailed below (Figure 48.1). Although there is often anxiety and reluctance to prescribe antiemetics in pregnancy, extensive data show lack of teratogenesis and good fetal safety for many of these medications [41,42]. Patients may, however, not tolerate oral therapy and a trial of treatment with rectal, sublingual or intravenous formulations should be attempted in these cases.

Promethazine (12.5–25 mg PO/4 h), the phenothiazines (chlorpromazine 10–25 mg PO/6 h and prochlorperazine 5–10 mg PO or 2.5–10 IV/6 h), the dopamine antagonist meto-clopramide (10 mg PO or IV/6 h), and pyridoxine (vitamin B6 typically as 10–25 mg PO three to four times daily) by itself or in combination with doxylamine (where available; typically given as 10–12.5 mg PO three or four times a day) are often used as first-line therapy for nausea and vomiting of pregnancy [43]. In patients who fail or cannot tolerate these medications due to severe side effects (e.g. extreme sedation and extrapyramidal symptoms in the case of the phenothi-azines or extrapyramidal symptoms in the case of metoclopra-mide), treatment with newer antiemetics such as ondansetron can be considered.

A 5-hydroxytryptamine (5-HT) receptor antagonist, ondansetron is widely used for the treatment of postoperative and chemotherapy-induced nausea and vomiting [44]. Its safety in pregnancy was suggested in a recent study which showed no significant increase in the number of miscarriages, major malformations or birthweight between infants exposed to ondansetron and unexposed controls [45]. It is categorized as a category B drug (“No evidence of risk in humans”) in the US Food and Drug Administration (FDA) Pregnancy Risk Classification (see Chapter 30 on prescribing in pregnancy). A pilot study of 30 pregnant women with hyperemesis did not find any benefit of ondansetron 10 mg given intravenously every 8 hours as needed over promethazine 50 mg given intra-venously every 8 hours in terms of nausea, weight gain, days of hospitalization or total doses of medicine [46]. However, the entry criteria for this study were not stringent and so the repro-ducibility of its findings remains in question. Both case reports and widespread clinical experience support the superior efficacy

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increased sense of well-being, improved appetite and increased weight gain in women treated with steroids compared with pla-cebo, although no statistically significant improvement in actual nausea and vomiting was seen [49]. In another study 40 women with hyperemesis were randomized to receive either oral meth-ylprednisolone (16 mg three times a day for 3 days and then tapered over 2 weeks) or oral promethazine (25 mg three times a day for 2 weeks). There was a similar response to both drugs after 2 days, but no woman who received methylprednisolone

Give doxyalamine 10 mg PO � pyridoxine (B6) 10 to 40 mg in divided doses.Adjust dose and schedule to severity of symptoms

Add dimenhydrate 50 to 100 mg every 4 to 6 h PO or PR to 200 mg/d when taking40 mg of pyridoxine (if vomiting frequently, take 30 to 45 min before taking

pyridoxine); or add promethazine 12.5 to 25 mg every 4 to 6 h PO or PR.

NO DEHYDRATION DEHYDRATION

Add any of the following:(listed in alphabetical order)

• chlorpromazine 10 to 25 mg every 4 to 6 h PO or IM or 50 to 100 mg every 6 to 8 h PR• metoclopramide 5 to 10 mg every 8 h IM or PO • ondansetron 4 to 8 mg every 6 to 8 h PO • prochlorperazine 5 to 10 mg every 6 to 8 h IM or PO • promethazine 12.5 to 25 mg every 4 to 6 h IM, PO, or PR

Note:

Use of this algorithm assumes other causes of nauseaand vomiting of pregnancy have been ruled out.

At any step, when nutritional support is indicated,consider enteral or parenteral nutrition

*No study has compared various fluid replacementsfor nausea and vomiting of pregnancy

Start rehydration treatment:

• IV fluid replacement (per local protocol*)• multivitamin IV supplementation• dimenhydrinate 50 mg (in 50 ml of saline over 20 min) every 4 to 6 h IV

Add any of the following:(listed in alphabetical order)

• chlorpromazine 25 to 50 mg every 4 to 6 h IV• metoclopramide 5 to 10 mg every 8 h IV• prochlorperazine 5 to 10 mg every 6 to 8 h IV• promethazine 12.5 to 25 mg every 4 to 6 h IV

Add 1 of the following:• methylprednisolone 15 to 20 mg every 8 h IV or 1 mg/h continuously up to 24 h• ondansetron 8 mg over 15 min every 12 h IV or 1 mg/hr continuously up to 24 h

Figure 48.1 Algorithm for the treatment of hyperemesis gravidarum. From Levichek Z, Atanackovic G, Oepkes D, et al. Motherisk Update. Nausea and vomiting of pregnancy: evidence-based treatment algorithm. Can Fam Physician 2002;48:267–8,277.

of ondansetron 8 mg every 8 hours for the treatment of HG and its better tolerability over older antiemetics [47,48].

5-HT4 receptor antagonists (cisapride) may also be used as an alternative to standard treatment of hyperemesis but cisapride is no longer marketed in the US because of its association with cardiac arrhythmia.

Oral and intravenous corticosteroids have been used for refractory cases of HG with variable results. One randomized placebo-controlled trial of 25 women with HG found an


747

was readmitted within 2 weeks of discharge while five women who received promethazine were readmitted with hyperem-esis [50]. Other randomized controlled trials, however, have reported less optimistic results with the same rates of rehospi-talization found in women treated with steroids compared with conventional therapy [51]. Direct comparison of these studies is limited, however, by differences in the type of corticosteroid used and differences in the doses and durations of steroid use. If corticosteroids are used for longer than 4 weeks to treat HG, they should be reduced gradually because of the possibility of adrenal suppression and stress-dose steroids should be consid-ered for labor and delivery (see Chapter 47). A cosyntropin (a synthetic peptide with similar activity as ACTH known as tetracosactrin in the UK) stimulation test should be considered before corticosteroids are stopped.

Patients who are ketotic and not able to maintain hydra-tion by oral intake require intravenous hydration. Normal saline (NaCl 0.9%, 150 mmol/L Na), lactated Ringer’s solu-tion (130 mmol/L Na) or Hartmann’s solution (NaCl 0.6%; 131 mmol/L Na) are preferred since fluids containing dex-trose may precipitate Wernicke’s encephalopathy if given before thiamine. In addition, these three solutions are more effective at preventing or correcting hyponatremia than fluids containing dextrose [52]. Hypertonic saline is never required and may precipitate central pontine myelinosis by the overly rapid correction of serum sodium levels.

Potassium supplements should be added to the intravenous fluid replacement therapy as required. Thiamine should be given to prevent Wernicke’s encephalopathy, as a daily dose of either 50–150 mg orally or 100 mg diluted in 100 mL normal saline as an intravenous infusion.

Intravenous hydration is often started during hospitalization. In severely affected patients, this may need to be continued after discharge [53]. Patients may be treated with fluid boluses or with continuous fluid infusions at home via peripheral IV, mid-line catheters or peripherally inserted central catheters (PICC).

In addition to hydration, patients with refractory HG may also require nutritional support. Both parenteral and enteral nutrition have been described in HG. Total parenteral nutri-tion (TPN) given via central catheters or PICC lines requires close supervision and monitoring. Hyperglycemia and abnor-mal liver function tests due to cholestatic liver disease are common complications of TPN. Other serious complications of parenteral nutrition in pregnancy, reported to be as high as 50% in one study, are sepsis, pneumothorax, and thrombosis [54]. Immunosuppression and the hypercoagulable state associated with pregnancy dramatically increase the risks of indwelling catheters in the pregnant population and reduce the safety of TPN. Other disadvantages to parenteral nutrition are its attendant care and expense.

Enteral feeding in HG has been described via nasoen-teric tubes [55], percutaneous gastrostomy (PEG) [56] and jejunostomy [57,58]. Although relatively easy and safe to place, nasoenteric tube use in clinical practice has been limited

by tube dislodgment, occlusion and poor patient tolerance. Altered anatomy in pregnancy poses risks with respect to PEG placement although in small case series both feeding gas-trostomy and jejunostomy have been reported to be safe and efficacious in the treatment of HG.

Patients who are hospitalized with HG should be considered for thromboprophylaxis with either heparin or intermittent compression stockings. Immobilization, dehydration and preg-nancy may predispose these patients to thromboembolism.

Women who have had HG in a previous pregnancy have a 20-fold increased risk of developing it in a subsequent preg-nancy compared to women with previous uncomplicated pregnancies [58]. The risk is slightly lower with a different partner. It is important to exclude associated conditions (Figure 48.1) and to optimize their management. For exam-ple, “triple therapy” (typically a proton pump inhibitor, amoxicillin and clarithromycin) can be used for Helicobacter pylori infection before conception and women with thyroid dysfunction can have their treatment optimized.

References

1. Verberg MFG, Gillott DJ, Al-Fardan N, et al. Hyperemesis gravidarum, a literature review. Human Reprod Update 2005;11:527–39.

2. Goodwin TM. Hyperemesis gravidarum. Clin Obstet Gynecol 1998;41:597–605.

3. Dodds, L, Fell DB, Joseph KS, et al. Outcomes of pregnan-cies complicated by hyperemesis gravidarum. Obset Gynecol 2006;107:285–92.

4. Bashiri A, Neumann L, Maymon E, et al. Hyperemesis gravi-darum: epidemiologic features, complications and outcome. Eur J Obstet Gynecol Reprod Biol 1995;63:138–8.

5. Kelly CK, Degli-Esposti S. Hyperemesis gravidarum. In: McGarry K, Tong IL (eds) 5-Minute clinical consult com-panion to women’s health. Lippincott, Williams and Wilkins, Philadelphia, 2007:238–40.

6. Attard CL, Kholi MA, Coleman S, et al. The burden of illness of severe nausea and vomiting of pregnancy in the United States. Am J Obstet Gynecol 2002;186:S220–7.

7. Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and management. Postgrad Med J 2002;78:76–9.

8. Frigo P, Lang C, Reisenberger K, et al. Hyperemesis gravidarum assoicated with Helicobacter pylori seropositivity. Obstet Gynecol 1998;91:615–17.

9. Fell DB, Dodds L, Joseph KS, et al. Risk factors for hyperemesis gravidarum requiring hospital admission during pregnancy. Obstet Gynecol 2006;107:277–84.

10. Goodwin TM. Nausea and vomiting of pregnancy: an obstetric syndrome. Am J Obstet Gynecol 2002;186:S184–9.

11. Depue RH, Bernstein L, Ross RK, et al. Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol 1987;156:1137–41.

12. Goodwin TM, Montoro M, Mestman JH, et al. The role of chorionic gonadotropin in transient hyperthyroidism of hyper-emesis gravidarum. J Clin Endocrinol Metab 1992;75:1333–7.

13. Lagiou P, Tamimi R, Mucci LA, et al. Nausea and vomiting in pregnancy in relation to prolactin, estrogens, and progesterone: a prospective study. Obstet Gynecol 2003;101:639–44.

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C. Cirrhosis. Women with ci rrhosis have an extremely high r isk of spontaneous abort ion, fetal death, and neonatal death. T heseveri ty of hepat ic dysfunct ion, rather than the cause of the ci rrhosis, is predict ive of maternal and fetal prognosis. T he mostcommon compl icat ion of ci rrhosis is esophageal var ices. Other compl icat ions include postpartum hemorrhage, asci tes,per i toni t is, splenic artery aneurysm, portal vein thrombosis, portal vein hypertension, coma, and death. Maternal mortal i ty isest imated to be 10% to 18%. Vaginal del ivery in these pat ients is preferred to cesarean del ivery due to the high rate ofpostoperat ive compl icat ions. A prolonged second labor stage should be avoided, and early intervent ion with forceps isencouraged.

D. Budd-Chiari sy ndrome is a veno-occlusive disease of the hepat ic veins, resul t ing in hepat ic congest ion and necrosis. T hedisease is marked by abdominal pain wi th an abrupt onset of asci tes and hepatomegaly. Diagnosis is made by Dopplerul t rasonographic imaging of the l iver to determine venous patency as wel l as direct ion and ampl i tude of blood f low. Maternal andfetal prognoses are poor. Abdominal asci tes occurs rapidly and is f requent ly resistant to medical management. T he r isk ofthrombosis remains high, even with therapeut ic ant icoagulat ion therapy.

Gallbladder DiseaseI. Cholelithiasis and Cholecystitis in PregnancySilent cholel i thiasis requires no treatment dur ing pregnancy. Acute cholecyst i t is, however, can happen i f cyst ic duct is obstructed bystones, accompanied by bacter ial infect ion. Present ing symptoms of cholecyst i t is include r ight upper quadrant pain, nausea, andvomit ing, low-grade fever, and mi ld leukocytosis. Diagnosis is usual ly made by ul t rasonography,

but endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepat ic cholecystography may be performedsafely wi th proper shielding of the fetus. Medical management includes bed rest, bowel rest, IV hydrat ion, and ant ibiot ic therapy.T herefore, some surgeons advocate surgical t reatment of cholecyst i t is as soon as possible. Dissolut ion of stones with bi le acids andl i thotr ipsy is contraindicated in pregnancy.

II. CholecystectomyChole cy ste ctomy is second only to appendectomy as the most common nonobstetr ic surgery performed in pregnant women.Cholecystectomy, i f necessary, is opt imal ly performed in the second tr imester.

Gastrointestinal DiseaseI. GastroenteritisViral enter i t is caused by the Norwalk agent is the most common infect ious disease of the GI tract dur ing pregnancy. Pat ients usual lypresent wi th nausea, cramping, vomit ing, diarrhea, headache, and myalgia. Low-grade fever is common. T he symptoms last 48 to 72hours, and treatment is support ive.

Hyperemesis gravidarumHy pe re me sis grav idarum is def ined as nausea and vomit ing causing dehydrat ion, weight loss, and metabol ic abnormal i t ies. Itaf fects 0.5 to 10 of 1,000 pregnancies and peaks between the 8th and 12th weeks of pregnancy.

A. T he e tiology of hyperemesis gravidarum is unknown but is bel ieved to involve hormonal, neurologic, metabol ic, toxic, andpsychosocial factors. Laboratory f indings include ketonuria, increased ur ine speci f ic gravi ty, elevated hematocr i t and BUN level ,hyponatremia, hypokalemia, hypochloremia, and metabol ic alkalosis. A sonogram and thyroid funct ion tests are usual lyperformed because molar pregnancy and hyperthyroidism can cause hyperemesis. Some pat ients wi th hyperemesis gravidarumhave transient hyperthyroidism that usual ly resolves spontaneously as pregnancy cont inues.

B. Tre atme nt should be tai lored to the severi ty of symptoms. T herapy usual ly includes IV hydrat ion and ant iemetic therapy.Pat ients may need to be hospi tal ized for intracTable emesis, correct ion of any electrolyte abnormal i t ies, and hypovolemia. Insevere cases in which prolonged IV hydrat ion is ant icipated, parenteral nutr i t ion and vi tamin supplementat ion may be inst i tuted;this should include thiamine supplementat ion (100 mg qd intramuscular ly or intravenously) to avoid Wernicke's encephalopathy.Oral feedings should be introduced slowly when tolerated. Fatty and spicy foods should be avoided. If pregnant women do notrespond to medical and support ive care, a psychiatr ic consul tat ion is advisable.

C. Medicines shown to be effect ive include the fol lowing: (T he U.S. Food and Drug Administrat ion has approved no drugs fortreatment of nausea and vomit ing in pregnancy.)

1. Pyr idoxine (vi tamin B6) 10 to 50 mg by mouth (po) three t imes dai ly ( t id)

2. Phosphorylated carbohydrate solut ion (Emetrol) 15 to 30 mL every 15 minutes for a maximum of f ive doses

3. Doxylamine succinate (hal f of Unisom tablet) 12.5 mg three t imes dai ly wi th pyr idoxine 10 to 50 mg

4. Metoclopramide hydrochlor ide (Reglan) 5 to 10 mg po or IV t id

5. Promethazine hydrochlor ide (Phenergan) 12.5 to 25 mg four t imes dai ly (qid) po, IV, IM, or PR

6. Prochlorperazine (T horazine) 10 to 25 mg po qid; 25 to 50 mg IV or IM qid; 50 to 100 mg PR t id

7. Ondansetron hydrochlor ide (Zofran) 4 to 8 mg po t id

8. Methylprednisolone (Medrol) 48 mg po for 3 days, fol lowed by a taper, as out l ined in Table 16.3.

9. Glucocort icoid administrat ion should be accompanied by assessment of glucose metabol ism.

Table 16.3 Methylprednisone Taper Dosage in Milligrams

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Day # Morning Midday Be dtime

1 16 16 16

2 16 16 16

3 16 16 16

4 16 8 16

5 16 8 8

6 8 8 8

7 8 4 8

8 8 4 4

9 8 4

10 8 4

11 8

12 8

13 4

14 4

II. Gastroesophageal reflux diseaseGastroe sophage al re flux dise ase, wi th resul tant heartburn, is very common during pregnancy. Treatment consists pr imari ly ofneutral izing or decreasing the acid mater ial that is being regurgi tated. Symptomatic rel ief may be achieved by elevat ion of the headof the bed, consumption of smal l meals, reduct ion in dietary fats, avoidance of ingest ing meals or l iquids wi thin 3 hours of bedt ime,smoking cessat ion, and avoidance of chocolate and caffeine. Treatment wi th over-the-counter antacids after meals and at bedt ime orthe use of sucral fate (1 g t id) may be considered. In refractory cases, an H2 blocker, such as cimet idine or rani t idine, should beadministered. Data are l imi ted on the safety of the proton pump inhibi tors lansoprazole and omeprazole in pregnancy.Metoclopramide hydrochlor ide (Reglan) can be helpful in reducing ref lux. Endoscopy should be considered i f therapeut ic measuresdo not rel ieve symptoms.

III. Peptic ulcer disease (PUD)Pe ptic ulce r dise ase (PUD) dur ing pregnancy is uncommon. Pat ients who develop PUD before pregnancy frequent ly experiencefewer symptoms during pregnancy and may even become asymptomatic, because gastr ic secret ion and mobi l i ty is decreased duringpregnancy. Treatment dur ing pregnancy consists of taking antacids after meals and at bedt ime; avoiding fat ty foods, caffeine,alcohol , chocolate, and nicot ine, which may tr igger gastr ic retent ion; avoiding aspir in and other nonsteroidal ant i - inf lammatory drugs(NSAIDs); and taking an H2-receptor antagonist , such as cimet idine or rani t idine. Indomethacin should be avoided as a tocolyt icagent in pat ients wi th a history of PUD. Current ly, no guidel ines exist for t reatment of this condi t ion in pregnancy, and the need formult iple therapeut ic agents poses addi t ional r isks. Symptoms may be adequately t reated with acid-reduct ion therapy. Diagnosis andtreatment of Hel i cobacter pyl ori infect ion is usual ly deferred to the postpartum period.

IV. Inflammatory Bowel Disease (IBD)Ulcerat ive col i t is and Crohn's disease often present dur ing chi ldbearing years. Women with IBD are at increased r isk for pretermbirths and low bir th weight. Disease act ivi ty at concept ion seems to determine the degree of disease act ivi ty dur ing pregnancy.

A. Tre atme nt. T he medical management of IBD in pregnant pat ients is simi lar to that of nonpregnant pat ients. T he mainstay ofmedical therapy for IBD is sul fasalazine and cort icosteroids. Because sul fasalazine may interfere wi th the absorpt ion of folate,supplemental folate should be prescr ibed to pregnant women. Immunosuppressive agents, such as azathiopr ine or 6-mercaptopurine, are occasional ly used in IBD. T he r isk of miscarr iage and congeni tal anomal ies are decreased

i f these immunosuppressive medicat ions are stopped 3 months before concept ion. Limited experience has shown that thesemedicat ions are safe dur ing pregnancy and are reasonable to use i f the disease is not control led by other medicat ions, such assul fasalazine. Ant ibiot ics, part icular ly metronidazole hydrochlor ide and ciprof loxacin, are useful for t reat ing per i rectal abscessesand f istulas that compl icate IBD. Long-term use of metronidazole is controversial . Ciprof loxacin is not recommended duringpregnancy because i t af fects cart i lage growth. When cort icosteroids are indicated for IBD, they should be given duringpregnancy in the usual nonpregnant doses. Cort icosteroids are excreted in breast mi lk and therefore breast- feeding should be

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122

Hyperemesis gravidarum

IncidenceLess than 1 :1000 pregnancies in UK; a rare condi-

tion in the endogenous population.

Aetiology• Hormonal —rapid increase in hCG and proges-

terone; hypothyroidism.

• Reflex —a chemosensitive trigger zone which

stimulates the vomiting centre.

• Ketosis—after excess vomiting, build up of ketones

exacerbates the vomiting and a vicious circle develops.

• Hydatidiform mole —very high hCG levels.

ProgressCan lead to:

• Dehydration.

• Hypovolaemia.

• Electrolyte depletion.

• Vitamin deficiency, particularly thiamine.

• Death from liver failure or the end processes of

the above.

Presentation• Cannot retain food or fluid.

• Weight loss because of loss of body fluid and

burning up of fat.

• Haemoconcentration and unstable acid–base

balance.

• Ketosis.

Management1 Exclude other diseases:

• Urinary infection.

• Hiatus hernia and gall bladder disease.

• Obstructive gut lesions.

• Central nervous system (CNS)-expanding

lesions.

2 Exclude obstetric cause:

• Multiple pregnancy.

• Hydatidiform mole.

• Acute yellow atrophy of the liver.

3 Restore fluid and electrolyte balance intra-

venously (i.v.).

4 Specific anti-vomiting drugs, e.g. cyclizine or

Maxolon.

5 Thiamine to prevent Wernicke’s encephal-

opathy.

6 Steroid therapy —being assessed.

7 Psychological treatment —most respond to sug-

gestion. If not, formal psychotherapy is needed.

8 Therapeutic abortion —very rarely required.

Hypertensive disorders of pregnancy

Hypertension has these risks:

• In the mother.

• Cerebrovascular accident.

• Renal failure.

• Heart failure.

• Coagulation failure.

Chapter 10

Diseases of pregnancy

AMI10 6/9/04 4:58 PM Page 122

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Editors: Ev ans, Arthur T.Tit le : Manual of Obstetrics, 7th Edition

Copyright ©2007 Lippincott Wi l l iams & Wilkins

> Table of Contents > III - Maternal Compl icat ions > 16 - Gastrointest inal Compl icat ions

16Gastrointestinal ComplicationsDav id F. Le wisMark Carl Wil l iams

Key PointsMost pregnant women complain of mult iple gastrointest inal problems during their pregnancy.

T he major i ty of these pat ients experience nausea, vomit ing, and const ipat ion dur ing pregnancy.

Many pregnant women wi l l develop gastroesophageal ref lux.

St i l l others develop or have more ser ious gastrointest inal (GI) problems.

Health-care providers must become fami l iar wi th treatment opt ions for the minor complaints and be able to diagnose pat ientswith ser ious pathological condi t ions in order to opt imize maternal and perinatal outcomes.

Nausea and VomitingBackgroundMost pat ients complain of mi ld to severe nausea and vomit ing dur ing the f i rst and early second tr imesters of pregnancy. Al though theet iology remains obscure, rapidly r ising human chorionic gonadotropin (hCG) and estrogen levels have been impl icated.

EpidemiologyAs many as 85% of pregnancies are accompanied by nausea and vomit ing. T he major i ty of these cases are sel f- l imi t ing.

EvaluationPhysical assessment should include a complete abdominal examinat ion.

Laboratory Tests

A chemistry panel is needed to detect and correct any electrolyte imbalances. T he potassium concentrat ion is especial lyimportant to note.

T hyroid funct ion tests (Free T3, Free T4, and T SH) are obtained to exclude thyroid disease.

A hepat i t is panel is needed to rule out these condi t ions, which many t imes present wi th vomit ing.

Human chorionic gonadotropin is ordered to screen for possible molar pregnancy.

Ultrasound is ordered to determine whether a molar or part ial -molar pregnancy exists.

DiagnosisDifferential DiagnosisNumerous i l lnesses present wi th nausea and vomit ing (see Table 16-1).

Clinical ManifestationsIn severe or refractory cases, i t is extremely important to rule out possible pathologic processes.

TreatmentDietEncourage pat ients to eat f requent, smal l meals that are r ich in simple carbohydrates (e.g., dry toast, crackers).

MedicationsResults f rom the Cochrane database (1) concluded that most drugs used for t reat ing nausea and vomit ing dur ing pregnancy are moreeffect ive than placebo.

Bendect in contains both vi tamin B6 (FDA class A) and Doxylamine (FDA class A). Al though i t is not avai lable in the United Statesdue to medical- legal concerns, evidence indicates that both drug components appear safe and effect ive.

Promethazine (Phenergan, FDA class C) and prochlorperazine (Compazine, FDA class C): Oral or rectal use has become verypopular in the United States. Ini t ial t reatment favors rectal supposi tor ies due to l imi ted gastr ic absorpt ion caused by emesis (2).

Droperidol ( Inapsine, FDA class C) represents a dopamine antagonist that is unresponsive to f i rst- l ine therapy. Cont inuous

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infusion seems more effect ive in refractory cases (3).

Mecl izine (Ant ivert , FDA class B) and cycl inine (Marezine, FDA class B): T hese ant ihistamines are effect ive when given alone orin combinat ion with vi tamin B6 in 80% to 90% of pat ients.

T he promoting agent metoclopramide (Reglan, FDA class B) accelerates gastr ic emptying.

TABLE 16-1 Differential Diagnosis for Nausea and Vomiting in Pregnancy

Acute appendici t is

Bowel obstruct ion

Food poisoning

Hepat i t is

Hiatal hernia

Hyperthyroidism

Molar pregnancy

Pancreat i t is

Pept ic ulcer disease

Pyelonephri t is

Renal col ic

Alternative Therapies

Ginger (FDA class C): Some evidence suggests that ginger decreases nausea. No adverse effects have been reported (4).

Acupressure: Pressure st imulates the PC-6 si te. Large studies have fai led to conf i rm the eff icacy of acupressure.

Sensory afferent st imulat ion: Transcutaneous nerve st imulat ion (T ENS) of P6 on the wrist has been effect ive (5).

ComplicationsElectrolyte imbalance, especial ly hypokalemia, may induce cardiac arrhythmias.

Hypovolemia (severe) may lead to uteroplacental insuff iciency.

Weight loss accompanied by negat ive ni t rogen balance can resul t in ketone product ion.

Hyperemesis GravidarumBackgroundT his manifests as severe nausea and vomit ing wi th signi f icant metabol ic disturbances (6).

EtiologyAlthough the speci f ic et iology is uncertain, hCG, estrogen, psychological factors, and certain personal i ty t rai ts are associated withhyperemesis gravidarum. Other suggested et iologies include thyrotoxicosis, serotonin anomal ies, nutr i t ional dysfunct ion, andHel i cobacter pyl ori infect ions (7).

EpidemiologyT he incidence of hyperemesis gravidarum is 1 in 200 pregnancies (0.5%).

EvaluationLaboratory

Urinalysis: Speci f ic gravi ty and bi l i rubin evaluat ions. T he speci f ic gravi ty access f luid status of the pat ient and bi l i rubin are usedto evaluate for hepat i t is and hemolysis.

Serum electrolytes: Potassium and creat inine are especial ly needed.

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Hepat ic funct ions: T hese tests evaluate for severe dehydrat ion, and they are also elevated with hepat i t is.

T hyroid funct ion tests help rule out thyrotoxicosis.

Fetal ul t rasound: T his is used to exclude molar or part ial molar pregnancy.

DiagnosisDifferential Diagnosis

Please see Table 16-2.

Clinical ManifestationsHyperemesis gravidarum usual ly manifests between four and ten weeks of gestat ion and is resolved by 20 weeks of gestat ion. It isusual ly wel l tolerated at i ts incept ion, but leads to weight loss, dehydrat ion, electrolyte abnormal i t ies, and ketosis.

TreatmentIf hospi tal izat ion is required, pat ients should remain NPO for 24 to 48 hours and have intravenous replacement of isotonic f luidscontaining dextrose. After 48 hours, their diet can be slowly advanced from clear l iquids to abundant undersized meals r ich in simplecarbohydrates, such as dry toast and crackers.

MedicationsData from the Cochrane database (1) indicated that most drugs used for t reat ing nausea and vomit ing dur ing pregnancy were moreeffect ive than placebo.

Bendect in is a combinat ion of vi tamin B6 (FDA class A) and doxylamine (FDA class A). Al though i t is not avai lable in the UnitedStates due to medical- legal concerns, evidence indicates that i t is safe and effect ive.

Promethazine (Phenergan, FDA class C) and Prochlorperazine (Compazine, FDA class C) are used oral ly or rectal ly and are verypopular in the United States. Rectal supposi tor ies are recommended for ini t ial t reatment because of the lack of gastr icabsorpt ion resul t ing from emesis.

TABLE 16-2 Commonly Used Anti-Emetics in Pregnancy

Class Ge ne ric name Proprie taryname

FDArating

Dose

Piperazine ant ihistamine Bucl izine Bucladin Ca 50 mg po q12h

Derivat ives Cycl izine Marezine B IM only: 50 mg q6h, prn

Mecl izine Ant ivert Ba 25–50 mg po q24h

Phenothiazine ant ihistaminederivat ives

Chlorpromazine T horazine C PO: 10–25 mg q6hIM: 25 mg q4–6hSupposi tory: 50–100 mg q8h

Prochlorperazine Compazine C PO: 5-10 mg q8hIM: 5-10 mg q4h, max 40 mg/24 hrSupposi tory: 25 mg q12h

Promethazine Phenergan Cb PO: 25 mg q6h

Antihistamine Diphenhydramine Benadryl Bb PO: 25–50 mg q6h

Dolasctron Anzemt B 12.5 mg IV

SHT 3 Antagonist ic Ondansetron Zofran B PO: 8 mg PO BID—T ID IV: 4–8 mg IVq8h

Doxylamine Unisom A Manufacturer recommends against usein pregnancy

Benzoquinol izine ant ihistamine Benzoquinamide Emete-con Manufacturer recommends against usein pregnancy

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Dopamine antagonist Metoclopramide Reglan Ba PO: 10–15 mg q6hIM: 10 mg q6hIV: 10 mg q6h, given slowly over 1–2minutes

Apomorphine antagonist Droperidol Inapsine Cb IM or slow IV: 2.5–5 mg; use inintractable vomit ing

aManufacturer recommends against use in ear ly pregnancy. See Chapter 24 for detai ls of FDA rat ing categories.bManufacturer recommends use only i f potent ial benef i t just i f ies potent ial r isk to fetus.FDA, Food and Drug Administrat ion.

Droperidol ( Inapsine, FDA class C) represents a dopamine antagonist that is unresponsive as f i rst- l ine therapy. However,cont inuous infusion is ef fect ive for refractory cases.

T hecl izine (Ant ivert , FDA class B) and cycl inine (Marezine, FDA class B) are ant ihistamines that are effect ive alone or incombinat ion with vi tamin B6 in 80% to 90% of pat ients.

Promoting agents: Metoclopramide (Reglan, FDA class B) accelerates gastr ic emptying.

Al ternat ive therapies

Ginger (FDA class C): Some evidence suggests that ginger decreases nausea. Adverse associat ions have not beenreported.

Acupressure: T his treatment st imulates the PC-6 si te wi th pressure, but numerous studies have not conf i rmed i ts ef f icacy.

Sensory afferent st imulat ion: Transcutaneous nerve st imulat ion (T ENS) of P6 on the wrist has been effect ive (5).

Ondansetron (Zofran, FDA class B): T his agent is ef fect ive for refractory cases.

Steroids: In some tr ials, l imi ted courses of methylprednisolone have been effect ive.

T his therapy remains controversial (6).

Refractory Cases

Enteral feedings: T his opt ion should be considered for enabl ing normal funct ion of the intest ines.

Hyperal imentat ion: T his may be necessary in certain cases to help maintain volume requirements and al low weight gain.T his treatment requires placement of a central venous l ine, which increases the r isk of infect ion.

ComplicationsMallory-Weiss tear of esophagus.

Vi tamin def iciency, including Wernicke encephalopathy (vi tamin B def iciency).

Renal damage resul t ing from hypovolemia.

Intrauter ine growth restr ict ion and fetal death have been associated with these disorders.

Gastroesophageal Reflux DiseaseBackgroundDefinitionReflux esophagit is or dyspepsia resul ts in ref lux of gastr ic contents into the esophagus.

Pathophysiology and EtiologyRelaxat ion of the esophageal sphincter due to elevated progesterone t i ters and increased intra-abdominal pressure from the uterusare reasons that this condi t ion compl icates a large percentage of pregnancies.

EpidemiologyAs many as 80% of Caucasian and 10% of Afr ican-American women complain of this condi t ion at some point dur ing pregnancy.

EvaluationA history and physical should include careful examinat ion of the chest and the abdomen. Symptoms include classical substernalburning or pain that usual ly occurs after meals or when supine.

DiagnosisDifferent ial diagnosis includes: cardiovascular pain (angina), pulmonary causes (pneumonia or pleur i t ic chest pain), and abdominalpain (cholecyst i t is, appendici t is, or other intra-abdominal processes). In the second and third tr imesters, hemolysis, elevated l iverenzymes, and low platelets (HELLP) syndrome or hepat ic hematoma must also be considered.

Treatment

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When reviewed in the obstetric medicine clinic at 5 weeks postpar-

tum, she was well and normotensive (110/70 mmHg), and urinalysis

was clear. Her serum creatinine was 87 �mol/l. Atenolol was discon-

tinued and GP follow-up was arranged. Urodynamic follow-up was

organized by the urology department.

Discussion

With improvements in antenatal care and both improved recognition

and earlier diagnosis of pre-eclampsia, in addition to earlier delivery

for those with severe pre-eclampsia, there seems to have been a shift

in the timing of eclampsia towards the postpartum period, perhaps

increasingly �48 hours post-delivery. Of eclamptic convulsions, 44%

occur postpartum.

More than one-third of women experience their first convulsion

before the development of hypertension and proteinuria. In the vast

majority of patients, at least one prodromal symptom is experienced.

In a recent study, 87% had headache, 44% had visual symptoms, 22%

had nausea or vomiting and 9% had epigastric pain [16].

Fortuitously, this woman remained an in-patient because she devel-

oped a paralytic ileus; she would otherwise have been discharged and

had the convulsion at home.

Her blood pressure was elevated both in the immediate postpar-

tum period and between her convulsions, but it remained untreated;

this was probably owing, in part, to the focus on her paralytic ileus

and, in part, because of being falsely reassured by the normal blood

profile on day 2 [17].

Her headache, severe enough to require opiate analgesia, should

have prompted further examination and investigation because it

heralded her first convulsion.

Her blood pressure was markedly elevated before her second

convulsion, although there were no prodromal symptoms.

MgSO4 had been discontinued after 24 hours (as per protocol),

and it is difficult to predict which patients will develop recurrent con-

vulsions and require additional therapy [18].

Beware of the routine use of nonsteroidal anti-inflammatory

drugs (NSAIDs) following Caesarean section. This patient received

two doses of voltarol despite deteriorating renal function.

5.6 HYPEREMESIS GRAVIDARUM

Ms F was a 35 year old woman in her third pregnancy. In her first preg-

nancy, she had been admitted on four occasions with severe hyperemesis

5. CASE STUDIES 109

and needed prolonged periods of hospitalization, in addition to regular

antiemetics until 33 weeks’ gestation. She terminated her second preg-

nancy because she could not face such severe hyperemesis again.

She was previously fit and well, but in the index pregnancy, she

experienced nausea and vomiting from her first missed period and pre-

sented to the hospital at 8 weeks’ gestation. On examination, she was

tachycardiac and had postural hypotension and ketonuria. Ms F was

admitted and treated with intravenous fluids and metoclopramide,

10 mg intramuscularly three times daily. A viable intrauterine preg-

nancy was confirmed on ultrasound scan; she improved on the above

therapy and was discharged 2 days later. In the subsequent 2 weeks, she

had three further admissions with hyperemesis gravidarum (HG). On

the third occasion, she was severely dehydrated, had lost 7 kg in weight

and was ketotic. She was admitted, rehydrated and given regular

cyclizine, 50 mg intravenously three times daily. Over the following

week, she improved and was sent home with oral antiemetics, folic acid

(5 mg) and thiamine hydrochloride (25 mg three times daily).

Her next admission was at 12 weeks’ gestation despite regular use

of oral cyclizine. She had lost a further 3 kg in weight and, again, had

4� ketones in her urine. Investigations revealed a raised free thyrox-

ine (fT4) level, undetectable thyroid-stimulating hormone (TSH),

abnormal liver function with an alanine aminotransferase (ALT)

level of 70 iu/l and hypokalaemia (serum potassium, 3.1 mmol/l).

She was once again rehydrated with normal saline and potassium

chloride (40 mmol/l in each 1 l bag) and given domperidone, 60 mg

per rectum three times daily, cyclizine, 50 mg intravenously three

times daily and oral metoclopramide. Enoxaparin (40 mg) was given

daily for thromboprophylaxis. This time she was maintained on

intravenous fluids and parenteral anitemetics for 1 week. After 1 week,

she was still vomiting up to three times daily and was unable to drink

enough to avoid intravenous fluids. She was noted to be very

depressed by her husband and the nurses caring for her and was

requesting a termination of pregnancy.

The decision was made to undertake a trial of corticosteroid ther-

apy. This was begun as hydrocortisone, 100 mg intravenously twice

daily. After the first two doses, Ms F was able to tolerate oral fluids

and the intravenous fluids and antiemetics were discontinued.

Therapy was changed to prednisolone, 20 mg oral twice daily and she

was discharged. On review in clinic 1 week later, she had had no fur-

ther vomiting or nausea but still complained of “spitting”. Serum

electrolytes were normal, repeat liver function tests showed a normal

ALT level and a repeat thyroid function test showed resolving bio-

chemical thyrotoxicosis, with a free T4 level just above the normal

range. The prednisolone dose was decreased to 15 mg twice daily.

110 OBSTETRIC MEDICINE: A PROBLEM-BASED APPROACH

The dose was gradually weaned over the next month to 10 mg

twice daily. Ptyalism had resolved by 19 weeks’ gestation. An anomaly

scan of the baby was normal. Several times over the next 2 months

she attempted decreasing the steroid dose but would not tolerate

doses below 20 mg/day. If she reduced the dose to 15 mg/day, the

vomiting returned. She was thus maintained on a dose of 20 mg/day.

A glucose tolerance test at 28 weeks’ gestation was normal. At 30 weeks’

gestation, the prednisolone dose was successfully reduced to

15 mg/day and thereafter reduced by 5 mg every 2 weeks, such that

she was weaned off steroids by 36 weeks’ gestation.

At 39 weeks’ gestation, she presented in spontaneous labour

having ruptures her membranes. She vaginally delivered a healthy

female infant weighing 6 lbs 3 ozs. Postnatally, she was counselled

regarding the likely recurrence of hyperemesis in future pregnancies

and a plan was made to use corticosteroids at the first admission for

HG.

Discussion

This was a case of severe HG causing associated abnormal liver and

thyroid function. In her first pregnancy, symptoms had lasted until

the third trimester and, therefore, it was likely that this would happen

in any future pregnancy.

Nausea and vomiting occur commonly in pregnancy, usually

between the 6th and 16th week. In 20% of cases, it persists into the

second and third trimesters. Management involves reassurance, small,

frequent high-carbohydrate food and avoidance of large-volume drinks.

Acupunture, ginger and vitamin B6 might relieve symptoms. Other

causes of vomiting in pregnancy include the following:

Ear, nose and throat diseases, for example, labyrinthitis or Meniere’s

disease.

Acute fatty liver of pregnancy (AFLP; in the third trimester).

HELLP syndrome.

Gastrointestinal causes, for example, cholecystitis, pancreatitis, pep-

tic ulceration and, rarely, gastric cancer.

Metabolic/endocrine, for example, hypercalcaemia, Addison’s disease

and hyperparathyroidism.

Drugs, for example, opioids, iron therapy and antibiotics.

Psychological, for example, eating disorders.

If abdominal pain and tenderness is a marked feature, consideration

should be given to further investigation with endoscopy.

HG is defined as vomiting occurring before the 20th week of

pregnancy that is sufficient to cause dehydration, acidosis and a

5. CASE STUDIES 111

minimum weight loss of 5%. Some definitions include the inability

to maintain the fluid and electrolyte balance without hospital admis-

sion. It occurs in about 0.5–1.5% of pregnancies and remains the

third most common cause for admission to hospital during preg-

nancy. Before the introduction of intravenous fluids, mortality from

HG was 159 deaths/1 million pregnancies. Complications of HG

include Wernicke’s encephalopathy, central pontine myelinosis

and peripheral neuropathy. Pneumomediastinum and oesophageal

rupture secondary to the mechanical forces of vomiting have been

described.

Meta-analysis of the available data showed a small reduction in the

risk of spontaneous miscarriage, stillbirth and preterm delivery in

women who experience HG. However, when HG is severe and asso-

ciated with maternal weight loss and repeated hospital admissions,

there is a slight increase in the incidence of IUGR. There is no

known increase in rate of congenital defects in vomiting pregnancies

compared with nonvomiting pregnancies.

The aetiology of HG remains elusive. It is believed that the

genetic variation in incidence is related to the presence of specific iso-

forms of human chorionic gonadotrophin (HCG) that cause HG

[19]. Elevated levels of oestrogen and progesterone have also been

implicated. Although high levels of oestrogen do cause slower intes-

tinal transit times, there are no studies showing a relationship

between severity of HG and oestrogen levels. Prospective cohort

studies have not shown any consistent relationship between proges-

terone levels and HG.

Thyroid hormone values deviate from the normal range in early

pregnancy, leading to gestational transient thyrotoxicosis [20].

Although evidence supports a relationship between HCG and gesta-

tional transient thyrotoxicosis, the exact role of this in HG is obscure.

Overactivity of the adrenal cortex is also associated with HG, but it

is uncertain whether it has a role in its pathogenesis. Helicobacterpylori infection was found in a significant number of patients with

HG in 11 prospective, case-controlled studies [21]. Liver function

abnormalities have been reported in about 67% of women with HG.

Elevations of aspartate aminotransferase (AST) or ALT levels can be

very dramatic, but return to normal with the cessation of vomiting

and the end of starvation.

Clinical assessment should include measurement of the pulse, lying

and standing blood pressures, urinalysis and weight, in addition to a

complete examination to exclude other causes of vomiting,

particularly infection. Further investigations should include urea and

electrolytes, liver function tests, thyroid function tests, and serum

phosphate, magnesium and calcium levels. A full blood count,

112 OBSTETRIC MEDICINE: A PROBLEM-BASED APPROACH

midstream urine sample and blood glucose level should also be

determined.

Management of HG involves rehydration with intravenous fluids,

replacement of electrolytes, vitamins, antiemetics and cessation of oral

nutrition and fluids. Fluid replacement can be with either sodium

chloride (plus potassium, 20 mmol or 40 mmol) or Hartmann’s solu-

tion. Protracted vomiting is associated with Mallory-Weiss oesophageal

tears, Mendelson’s syndrome and jaundice. The neurological distur-

bances are a result of vitamin B1 deficiency. It is imperative that

thiamine hydrochloride (25–50 mg orally three times daily or as Pabrinex

intravenous weekly supplements) is prescribed in these cases, to avoid

Wernicke’s encephalopathy and Korsakov’s psychosis.

Antiemetic therapy is a mainstay of treatment, although no antiemetic

treatment is specifically licensed for use in pregnancy. Pyridoxine

hydrochloride (vitamin B6) and ginger have been shown to relieve

symptoms in severe HG.

Dopamine receptor antagonists can be used, including the

following: metoclopramide, domperidone, and phenothiazines.

These drugs are safe but can cause extrapyramidal side effects. Other

antiemetics that can be used include the following: cyclizine,

prochlorperazine, and chlorpromazine.

Ondansetron, a potent and highly selective type 3 serotonin

(5-hydroxytryptamine; 5-HT)receptor (5-HT3) antagonist can be

used if all other antiemetics have failed. The safety of this drug has

not been sufficiently evaluated in large-scale trials. If management

has been optimal and there is no improvement, consideration might

be given to starting steroids (prednisolone, 20 mg twice daily or

hydrocortisone, 100 mg intravenously twice daily) [22,23]. The

response is usually dramatic, but if there is no response, steroids

should be discontinued after 2–3 days. For those who respond to

steroids, it is important to continue the therapy after discharge and

wean the dose slowly. Usually, steroids will need to be continued in

reduced doses until such time as nausea and vomiting have abated.

With prolonged use of steroids in pregnancy, it is important to

monitor blood glucose levels.

Parenteral nutrition is only recommended if there is maternal

protein-calorie malnutrition and all other therapy has failed. Total

parenteral nutrition (TPN) is safe, with expert advice and monitor-

ing of maternal levels of nutrition. The fetus must be monitored with

serial growth scans, and there must be facilities to accommodate

preterm delivery available.

HG can be mild or severe, but most cases improve with optimal

management and termination is rarely required for medical reasons.

Early treatment of a recurrence is advised.

5. CASE STUDIES 113

Obstetrics 18 MCCQE 2000 Review Notes and Lecture Series

NotesMEDICAL CONDITIONS IN PREGANCY. . . CONT.

Management of Eclampsia❏ airway, breathing, circulation❏ seizure control and prevention (see Neurology Notes)

• do not attempt to shorten or abolish the initial convulsion• prevent maternal injury and maintain adequate oxygenation• minimize risk of aspiration, auscultate lungs after every seizure• give adequate magnesium sulphate as soon as convulsion has

ended• correct maternal acidemia (obtain post-ictal blood gases)• some use valium for seizure control

Chronic Hypertension❏ features

• history of hypertension (> 140/90) before gestation• detection of hypertension prior to 20 weeks gestation

(unless there is a GTN)• persistence of hypertension postpartum• strong family history of hypertension• most gravidas have essential hypertension, associated with

an increased risk of preeclampsia or eclampsia, abruptioplacenta, IUGR and IUD

❏ management• methyldopa and/or labetalol• no ACE inhibitors, diuretics, propranolol

Chronic Hypertension with Superimposed Preeclampsia/ Eclampsia ❏ 2-7 fold increased likelihood of developing preeclampsia/

eclampsia if pre-existing maternal hypertension ❏ tends to recur❏ occurs early in pregnancy, tends to be severe, often with IUGR

Transient or Gestational Hypertension ❏ hypertension alone that develops during the latter half of

pregnancy or during the first 24 hours after delivery and disappearswithin 10 days following parturition

❏ monitor for signs of preeclampsia/eclampsia

HYPEREMESIS GRAVIDARUM

Definition ❏ intractable nausea and vomiting to extent of weight loss, dehydration

and electrolyte imbalance, acid-base disturbance and if severe, hepatic and renal damage

❏ usually present in T1 then diminishes; persists throughout pregnancyin a minority

Etiology ❏ presently thought to be multifactorial with hormonal, immunologic

and psychologic components❏ high or rapidly rising ßhCG or estrogen levels are implicated

Maternal Complications❏ Mallory Weiss tears❏ Wernicke's encephalopathy, if protracted course❏ death

Fetal Complications ❏ usually none ❏ IUGR is 15x more common in women losing > 5% of prepregnant weight

Differential Diagnosis of Nausea and Vomiting❏ hyperemesis is a diagnosis of exclusion❏ GI inflammation/infection

• appendicitis• cholecystitis• hepatitis

MCCQE 2000 Review Notes and Lecture Series Obstetrics 19

NotesMEDICAL CONDITIONS IN PREGANCY. . . CONT.

• gastroenteritis• pancreatitis • PUD• fatty liver of pregnancy

❏ pyelonephritis ❏ thyrotoxicosis ❏ multiple gestation ❏ GTN (see Gynecology Notes) ❏ HELLP syndrome

Investigations❏ labs (CBC, lytes, BUN and creatinine, urinalysis, LFTs)❏ ultrasound (to R/O molar pregnancy, multiple pregnancy and to assess

liver, pancreas, gallbladder, etc...)

Treatment❏ general

• early recognition is important• if severe, admit to hospital• NPO initially, then small frequent meals of appealing foods • correct hypovolemia, electrolyte imbalance and ketosis• thiamine, if indicated• TPN if severe to reverse catabolic state• consider emotional support, dietary and psychologic counselling

❏ pharmacological options• dimenhydrinate (Gravol) • vitamin B6 and doxylamine succinate (Diclectin)

❏ non-pharmacological options• accupressure at inner aspect of the wrists, just proximal to the

flexor crease has been shown to significantly reduce symptomsof nausea and vomiting

• avoid triggers (i.e. certain smells)

ISOIMMUNIZATION❏ antibodies produced against a specific RBC antigen as a result of

antigenic stimulation with RBC of another individual❏ most common is anti-Rh Ab produced by a sensitized Rh-negative mother❏ other antibodies can lead to fetal red blood cell hemolysis

• much less common and no prophylaxis is available

Pathogenesis❏ maternal-fetal circulation normally separated by placental barrier❏ upon first exposure, initially IgM and then IgG antibodies are produced;

IgG antibodies cross the placental barrier❏ sensitization routes

• incompatible blood transfusion• previous fetal-maternal transplacental hemorrhage• invasive procedure while pregnant• therapeutic abortion, D&C, amniocentesis

❏ complications• anti-Rh Ab can cross the placenta and cause fetal hemolysis

resulting in fetal anemia, CHF, edema, and ascites• severe cases can lead to fetal hydrops (total body edema), or

erythroblastosis fetalis

Diagnosis❏ routine screening at first visit for blood group, Rh status, antibodies❏ Ab titres < 1:16 considered benign❏ Ab titres > 1:16 necessitates amniocentesis (correlation exists

between amount of biliary pigment in amniotic fluid and severityof fetal anemia) from 24 weeks onwards

❏ Liley curve is used to determine bilirubin level and appropriate management (see below)

❏ Kleihauer-Betke test can be used to determine extent of fetomaternalhemorrhage

• fetal red blood cells are identified on a slide treated with citratephosphate buffer

• adult hemoglobin is more readily eluted through cell membranein presence of acid

DISEASES OF PREGNANCY

VOMITING IN PREGNANCY

Nausea and retching are common in the early weeks of pregnancy, sufficiently so almost tobe recognised as evidence of being pregnant. Although often described as morning sickness,symptoms can occur at any time of the day. Most women cope with this readily and theproblem disappears spontaneously by the end of the first trimester. Sometimes, however,drug treatment may be necessary and antihistamines such as cyclizine or a phenothiazine canbe prescribed safely.

HYPEREMESIS GRAVIDARUMOccasionally there is a progression from ordinary nausea and vomiting to the rejection of allfood and drink. Unchecked this may lead to dehydration and starvation with ketosis, liverdamage, jaundice, neuropathies and even death.

102

DISEASES OF PREGNANCY

VOMITING IN PREGNANCY

The cause of vomiting in pregnancy is not clear. Alterations in serum hormone levels areoften blamed but social and psychological factors also appear to play a role. Support for thefirst explanation comes from the fact that the condition is commoner in multiple pregnanciesand in hydatidiform mole, and for the latter two, by the improvement in symptoms withhospitalisation alone.

High levels of Human Chorionic Gonadotrophin appear to elevate thyroxine levels and 60%of women with hyperemesis have biochemical or clinical hyperthyroidism.

TREATMENT OF HYPEREMESIS1. Admit to hospital.2. Exclude other causes of vomiting such as urinary tract infection and surgical causes such

as appendicitis and bowel obstruction.3. Blood taken for haemoglobin, urea & electrolytes, glucose, liver function tests, thyroxine

and TSH levels.4. Restrict oral intake initially.5. Intravenous fluids should be given to treat any dehydration.6. Prepared feeds via a fine naso-gastric tube are usually effective, the volume being given

ideally through a pump system delivering small volumes over time. The volume givencan progressively be increased.

7. Gradual reintroduction of oral foods.8. Pyridoxine, 25 mg three times daily by mouth may be effective in severe nausea.9. Low dose intravenous infusions of Promethazine have been found useful in some

centres.10. Rarely, total parenteral nutrition or even termination of pregnancy may be indicated. 103

21

2. Hiperemesis Dalam Kehamilan

Definisi

Muntah yang berlebihan dalam kehamilan yang menyebabkan terjadinya: Ketonuria Penurunan Berat Badan > 5%

Prinsip Dasar

Muntah dan enek adalah bagian dari adaptasi/reaksi fisiologi kehamilan

akibat adanya pengaruh hormon kehamilan seperti: Progesteron, hCG dll. Hiperemesis dapat merupakan gejala penyakit-penyakit:

Mola hidatidosa Hipertiroid Defisiensi vitamin B kompleks Stress berat

Setiap liter cairan lambung yang dimuntahkan mengandung 40 meq Kalium.

Diagnosis

Anamnesis Pemeriksaan Fisik Laboratorium:

Urinalisa lengkap Gula darah Elektrolit Fungsi hati Fungsi ginjal

USG: menilai dan memastikan kehamilan.

22

Manajemen

Atasi dehidrasi dan ketosis Berikan Infus Dx 10% + B kompleks IV Lanjutkan dengan infus yang mempunyai komposisi kalori dan

elektrolit yang memadai seperti: KaEN Mg 3, Trifuchsin dll. Atasi defisit asam amino Atasi defisit elektrolit Balans cairan ketat hingga tidak dijumpai lagi ketosis dan defisit elektrolit Berikan obat anti muntah: metchlorpropamid, largactil anti HT3 Berikan suport psikologis Jika dijumpai keadaan patologis: atasi Jika kehamilannya patologis (misal: Mola Hidatidosa) lakukan evakuasi Nutrisi per oral diberikan bertahap dan jenis yang diberikan sesuai apa

yang dikehendaki pasien (prinsip utama adalah pasien masih dapat makan) dengan porsi seringan mungkin dan baru ditingkatkan bila pasien lebih segar/enak.

Perhatikan pemasangan kateter infus untuk sering diberikan salep heparin karena cairan infus yang diberikan relatif pekat.

Infus dilepas bila kondisi pasien benar-benar telah segar dan dapat makan dengan porsi wajar (lebih baik lagi bila telah dibuktikan hasil laboratorium telah normal) dan obat peroral telah diberikan beberapa saat sebelum infus dilepas.

Prognosis

Umumnya baik, namun dapat menjadi fatal bila terjadi deplesi elektrolit

dan ketoasidosis yang tidak dikoreksi dengan tepat dan cepat.

123

Early pregnancy

CASE 50: VOMITING IN PREGNANCY

HistoryA 28-year-old Asian woman is referred by her general practitioner (GP) with persistentvomiting at 7 weeks’ gestation. She is in her second pregnancy having had a normal vagi-nal delivery 3 years ago. She is now vomiting up to 10 times in 24 h, and has not man-aged to tolerate any food for 3 days. She can only drink small amounts of water.

She saw her GP a week ago who prescribed prochlorperazine suppositories but these onlyhelped for a few days. She feels very weak in herself and is unable to care for her son now.

On direct questioning she has upper abdominal pain that is constant, sharp and burning.She has not opened her bowels for 5 days. She is passing small amounts of dark urineinfrequently but there is no dysuria or haematuria. There has been no vaginal bleeding.

There is no other medical or gynaecological history of note except that she suffered per-sistent vomiting in her first pregnancy requiring two overnight admissions.

ExaminationShe is apyrexial. Lying blood pressure is 115/68 mmHg and standing blood pressure98/55 mmHg. Heart rate is 96/min. The mucus membranes appear dry. Abdominal exam-ination reveals tenderness in the epigastrium but no lower abdominal tenderness. Theuterus is not palpable abdominally.

Normal range for pregnancyHaemoglobin 11.1 g/dL 11–14 g/dLMean cell volume 90 fL 74.4–95 fLWhite cell count 8.9 � 109/L 6–16 � 109/LPlatelets 298 � 109/L 150–400 � 109/LSodium 131 mmol/L 130–140 mmol/LPotassium 3.0 mmol/L 3.3–4.1 mmol/LUrea 8.2 mmol/L 2.4–4.3 mmol/LCreatinine 65 μmol/L 34–82 μmol/LAlanine transaminase 30 IU/L 6–32 IU/LAlkaline phosphatase 276 IU/L 30–300 IU/LGamma glutamyl transaminase 17 IU/L 5–43 IU/LBilirubin 12 μ/L 3–14 μmol/LAlbumin 34 g/L 28–37 g/L

Pregnancy test: positive

Urinalysis: protein negative; blood negative; nitrites negative; leucocytes negative; �� ketones; glucose negative

INVESTIGATIONS

Questions• What is the diagnosis?• What are the potential complications of this disorder?• How would you further investigate and manage this patient?

124

100 Cases in Obstetrics and Gynaecology

ANSWER 50

The woman is suffering from hyperemesis gravidarum. This affects only less than 2 per centof pregnancies, although more than 50 per cent of women report some nausea or vomit-ing when pregnant.

• Urinary tract infection• Gastroenteritis• Thyrotoxicosis• Hepatitis

Differential diagnosis of vomiting in early pregnancy!

• Wernicke’s encephalopathy (from vitamin B deficiency)• Korsakoff’s syndrome (from vitamin B, deficiency)• Haematemesis (from Mallory–Weiss tear)• Psychological – resentment towards the pregnancy and expression of desire to

terminate the pregnancy

Complications of hyperemesis gravidarum!

Severe or protracted vomiting appearing for the first time before the 20th week ofpregnancy that is not associated with other coincidental conditions and is of suchseverity as to require the patient’s admission to hospital.

Definition of hyperemesis gravidarum!

The diagnosis in this case can be made because the urinalysis is negative apart from theketones, so urinary tract infection is very unlikely. She has not opened her bowels but thisis likely to be secondary to poor dietary intake and dehydration. Liver function is normal,so liver disease causing vomiting is unlikely (though abnormal liver function may occuras a result of hyperemesis itself). Thyroid function is normal, so an alternative diagnosisof hyperthyroidism causing the vomiting is unlikely.

The fetus is not at risk from hyperemesis and the nutritional deficiency in the mother doesnot seem to affect development. The risk of miscarriage is lower in women with hyper-emesis. The risk of twins and molar pregnancy has traditionally been thought to be greaterin women with hyperemesis, but this is refuted in more recent research.

Further investigation and managementHyperemesis is a self-limiting disease and the aim of treatments is supportive, with discharge of the woman once she is tolerating food and drink and is no longer ketotic onurinalysis.

• Fluids: 3–4L of normal saline should be infused per day. Dextrose solutions arecontraindicated as they may precipitate Wernicke’s encephaolopathy and also becausethe woman is hyponatraemic and needs normal saline.

125

Early pregnancy

• Potassium: excessive vomiting generally leads to hypokalaemia, and potassiumchloride should be administered with the normal saline according to the serumelectrolyte results.

• Anti-emetics: first-line antiemetics include cyclizine (antihistamine), metoclopramide(dopamine anatagonist) or prochlorperazine (phenothiazine). In severe cases,ondansetron or domperidone may be effective. There is no evidence of teratogenicityin humans from any of these regimes.

• Thiamine and folic acid: vitamin B1 (thiamine) can prevent Wernicke’s encephalopathyor the irreversible Korsakoff’s syndrome (amnesia, confabulation, impaired learningability).

• Antacids: for epigastric pain• Total parenteral nutrition (TPN): TPN is rarely indicated but may be life saving where

all other management strategies have failed.• Thromboembolic stockings (TEDS) and heparin: women with hyperemesis are at risk of

thrombosis from pregnancy, immobility and dehydration, and should be considered forlow-molecular-weight heparin regime as well as TEDS.

MonitoringDaily monitoring should be carried out, with weight measurement and urinalysis forketones and renal and liver function.

• Hyperemesis gravidarum is a diagnosis of exclusion.• There is no adverse effect on the fetus.• Treatment is supportive.• Thiamine replacement prevents Wernicke’s encephalopathy and Korsakoff’s syndrome.

KEY POINTS

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153

Case 24 A 29 - year - old woman with vomiting in early pregnancy

Mrs Begum, a 29 - year - old para 1, is referred to the

assessment unit at the maternity hospital by her GP on

account of persistent vomiting. She is approximately 7

weeks pregnant by dates, has been unable to keep anything

down because of ongoing vomiting. She feels exhausted

and unable to cope.

What d ifferential d iagnosis c omes to y our m ind? • Hyperemesis gravidarum

• Gastritis/gastroenteritis

• Urinary tract infection

• Other rare causes of vomiting, e.g. thyrotoxicosis, pan-

creatitis, Addison ’ s disease, cholecystitis, hepatitis

Obstetric h istory Details of previous pregnancy including a history of

hyperemesis.

Past m edical h istory i ncluding a llergies Any medical problems, e.g. pancreatitis, Addison ’ s

disease, hyperthyroidism

Family h istory • Anybody else in the family with similar symptoms

• Is there a history of twins in the family?

Mrs Begum states that her nausea and vomiting started a

week ago and has been getting progressively worse .She

now feels sick all the time, is unable to keep any food

down. She vomits small amounts approximately 10 – 12 times

a day. She also admits to having some heartburn but denies

any abdominal pain, diarrhoea or urinary symptoms. She has

been feeling low and is unable to cope any more.

She has had one pregnancy in the past and her daughter,

Ayesha, is now 2 years old. She has a history of two

admissions early in her fi rst pregnancy with intractable

vomiting requiring intravenous fl uids and antiemetics.

She gives no history of medical problems or allergies. She

has non - identical twin brothers and reports that no one else

in the family has experienced similar symptoms

Obstetrics and Gynaecology: Clinical Cases Uncovered.

By M. Cruickshank and A. Shetty. Published 2009 by Blackwell

Publishing. ISBN 978-1-4051-8671-1.

KEY POINT

Hyperemesis gravidarum (HG) is defi ned as persistent

vomiting in pregnancy, which leads to weight loss ( > 5%

body mass) and ketosis. Although over 50% of pregnant

women experience nausea and vomiting, HG affects 1%

of pregnancies.

What would y ou l ike to e licit from the h istory? Presenting c omplaints • Duration, frequency and amount of vomiting

• Any heartburn, abdominal pain or diarrhoea

• Any urinary symptoms

• Mood changes

KEY POINT

Hyperemesis gravidarum: onset is always in fi rst trimester,

commonly around 6 – 8 weeks.

What k ey f eatures would y ou l ook for d uring p hysical e xamination? General e xamination • Signs of dehydration, e.g. dry skin and mouth,

decreased skin turgor

154 Part 2: Cases

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• Pulse, blood pressure and temperature recording:

tachycardia and postural hypotension suggest

dehydration

• Assess mood – e.g. unkempt appearance, tearfulness

Routine s ystemic e xamination To assess general health and exclude medical problems.

Mrs Begum is very tearful during the consultation. She

appears tired and run down but not in any pain. Her skin

and lips appear dry and there is tenting of her skin. Her

pulse is 98 beats/minute, of low volume and she appears to

have postural hypotension as indicated by lying and standing

blood pressures. These vital parameters indicate that she is

moderately dehydrated ( Table 24.1 ). Systemic examination is

unremarkable.

What would be the n ext s tep? Obtain a sample of urine for dipstick analysis and urine

pregnancy test

• Confi rm pregnancy

• Increased specifi c gravity (dehydration)

• Presence of ketones (dehydration)

• Presence of nitrites/leucocytes/blood (may suggest

urinary infection)

What i nvestigations would y ou l ike to c arry o ut? Blood t ests • Full blood count (FBC): an increased haematocrit sug-

gests haemoconcentration

• Urea and electrolytes (U & E): to look for hyponatrae-

mia, hypokalaemia, low serum urea, hypochloraemic

alkalosis

• Liver function test (LFT): LFTs are abnormal in up to

50% of women with HG

• Thyroid function test (TFT): there may be transient

biochemical hyperthyroidism (Box 24.1 ). Resolves

without treatment by 18 weeks

Mid - s tream s ample of u rine ( MSSU ) To exclude urinary tract infection.

Pelvic u ltrasound • Confi rms viability of the pregnancy

• Diagnoses twin gestation

• Excludes molar pregnancy

Mrs Begum is not anaemic but has a raised haematocrit

along with hyponatraemia and hypokalaemia. Her LFTs and

TFTs are within the normal range. A urine dipstick shows the

presence of +++ ketones but is negative for nitrites,

leucocytes and blood. The clinical features along with

ketonuria and high urine specifi c gravity confi rm

dehydration. A pelvic ultrasound scan shows a dichorionic

twin pregnancy of 7 weeks ’ gestation.

Table 24.1 Clinical signs of dehydration.

Dehydration Mild Moderate Severe

Skin turgor Normal Dry Clammy

Buccal

mucosa/lips

Moist Dry Parched/

cracked

Pulse Regular Slightly increased Increased, low

volume

Urine output Normal Decreased Anuric

Box 24.1 Gestational hyperthyroidism

• Biochemical hyperthyroidism found in approximately

60% women with HG

• Self - limiting

• Patient clinically euthyroid

• Findings: ↑ free thyroxine (T4), ↓ thyroid stimulating

hormone (TSH), negative thyroid antibodies

• Mechanism:

• human chorionic gonadotrophin (HCG) shares α subunit

with TSH

• increased secretion of HCG/HCG oversensitive

thyrotrophin receptors/secretion of variant of HCG

• Thyroid function tests provide an index of severity of HG

• More common in Asian women

• Rarely, Graves disease may present in pregnancy. The

absence of TSH receptor, antiperoxidase, and

antithyroglobulin autoantibodies supports the diagnosis

of HG

KEY POINT

Hyperemesis gravidarum is a diagnosis of exclusion. There

is no single confi rmatory test.

Thus, by a focused history, thorough clinical examination

and relevant investigations other causes of vomiting are

excluded. We can conclude that the likely diagnosis in Mrs

Begum ’ s case is that of hyperemesis gravidarum (Box 24.2 ).

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The diagnosis is explained to Mrs Begum, who is very

anxious, as her symptoms are much worse in her present

pregnancy. She wonders if it could lead to any harm to

herself or to her babies.

What are the c omplications a ssociated with h yperemesis g ravidarum? Maternal c omplications of h yperemesis g ravidarum • Can lead to serious morbidity

• Mallory – Weiss tears of oesophagus and haematemesis

because of persistent vomiting and retching

• Malnutrition

• Weight loss (up to10 – 20% of body mass), muscle

wasting, weakness

• Hyponatraemia (plasma sodium < 120 mmol/L):

� can cause lethargy, seizures and respiratory arrest

� severe hyponatraemia and its rapid correction can

precipitate central pontine myelinolysis

• Vitamin defi ciency:

� thiamine (B 1 ) – acute defi ciency causes Wernicke ’ s

encephalopathy (Box 24.3 ) Residual impairment leads

to Koraskoff ’ s psychosis

� vitamin B 12 and pyridoxine (B 6 ) – anaemia and

neuropathy

• Thrombosis: the combination of dehydration and bed

rest increase the risk of thrombosis

• Psychological problems: these are often

underestimated

Fetal c omplications of h yperemesis g ravidarum • Severe HG is associated with low birth weight babies

• HG leading to Wernicke ’ s encephalopathy is associ-

ated with fetal death in 40% of cases

How will y ou m anage this w oman, w ho h as been d iagnosed with h yperemesis at 7 w eeks ’ g estation?

Box 24.2 Pathophysiology of hyperemesis gravidarum

• Poorly understood, multifactorial

• Temporal relationship exists between level of human

chorionic gonadotrophin (HCG) and severity of

symptoms

• HCG peaks between 6 and 12 weeks coinciding with

peak symptomatology

• Correlation with high HCG levels explains the increased

incidence of HG in women with multiple pregnancy and

hydatiform mole, both conditions associated with very

high HCG levels

• Mechanical factors, e.g. decreased peristalsis and

delayed gastric emptying, exacerbate the symptoms, but

are not thought to be causative

• Psychological and behavioural theories exist but are not

proven

• Risk factors: multiparity, past history of HG and eating

disorder, multiple gestation, hydatiform mole

• Cigarette smoking and maternal age > 30 years appear

to be protective

• Evidence suggests infection with Helicobacter pylori may

have a role

Box 24.3 Wernicke ’ s encephalopathy

• Syndrome characterized by diplopic abnormal ocular

movements, ataxia and confusion

• Precipitated by administration of IV dextrose/glucose in

thiamine defi ciency

• Residual impairment is common despite replacement

• Koraskoff ’ s psychosis is characterized by amnesia,

impaired ability to learn and confabulation (invented

memories which are then taken as true because of gaps

in the memory)

KEY POINT

Hyperemesis is a leading cause of hospitalization in early

pregnancy.

Rehydration Appropriate and adequate parentral fl uid along with

electrolyte replacement forms the mainstay of treatment.

Rehydration with normal saline (0.9% saline, 150 mmol/L

sodium) or Hartman ’ s solution (0.6% saline, 132 mmol/L

!RED FLAG

Management should be early and aggressive in view of

increased risk of complications for mother and her fetus in

the absence of treatment.

If tolerating orally the management includes rest, small

but frequent carbohydrate meals along with adequate

fl uids orally. However, if she is unable to maintain hydra-

tion she should be admitted to hospital.

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sodium) is recommended. Add potassium chloride to

fl uid bags as directed by electrolyte levels. Check U & E

daily while on intravenous fl uids.

The patient should be weighed twice weekly for objec-

tive assessment of dehydration. Continue treatment until

the patient can tolerate oral fl uids and until test results

show little or no ketones in the urine.

Thiamine ( v itamin B 1 ) s upplementation Thiamine defi ciency leads to Wernicke ’ s encephalopathy.

Thiamine supplementation is recommended in HG. If

the patient is unable to tolerate this orally thiamine is

administered as an infusion once a week.

Thromboprophylaxis

Table 24.2 Antiemetic agents.

Antihistamines Cyclizine H1 receptor antagonist

Promethazine Commonly used

Good safety profi le

Phenothiazines Cholpromazine Side - effects: drowsiness,

extrapyramidal effects,

oculogyric crisis Prochlorperazine

Dopamine

antagonist

Metclopramide Promotility agents

Domperidone Oculogyric crisis and

extrapyramidal effects

Selective

serotonin

(5 - HT3)

antagonist

Ondansetron Used for refractory HG

Limited safety data

Routine use not

recommended

!RED FLAG

An infusion of dextrose - containing fl uid can precipitate

Wernicke ’ s encephalopathy and is not recommended.

Double strength saline should be avoided as rapid

correction of hyponatraemia can cause central pontine

myelinolysis.

Antiemetics Antiemetics are recommended if rehydration and electro-

lyte replacement fail to improve the symptoms. Antiemet-

ics should be prescribed on regular basis rather than as

required. The intravenous or rectal route can be used

initially and changed to oral route when tolerating orally

(Table 24.2 ).

KEY POINT

The commonly used antiemetics, e.g. antihistamines,

phenothiazines and dopamine antagonists, are not known

to be associated with teratogenesis.

!RED FLAG

Dehydration, bed rest and reduced mobility and pregnancy

are risk factors for thrombosis.

Women requiring hospitalization with HG should receive

thromboprophylaxis. Prophylactic doses of low molecu-

lar weight heparin along with thromboembolic deterrent

stockings (TEDS) should be used.

Psychological s upport Emotional support from the medical team and the family

aid the medical treatment. Psychotherapy, hypnotherapy

and behavioural therapy have been reported to be of

benefi t.

Alternative t herapies Pyridoxine (vitamin B 6 ) has been reported to reduce the

severity of nausea. Ginger, available as capsules, is helpful

with nausea and vomiting with no apparent side - effects.

Acupuncture is thought to reduce the symptoms and

encourages weight gain.

Mrs Begum is commenced on 0.9% saline IV along with

prochlorperazine (Stemetil) IM on a regular basis. She is

given thromboprophylaxis in the form of low molecular

weight heparin and TEDS. Her fl uid therapy is monitored

with daily U & E and urinary ketones. Thiamine is prescribed

as a weekly infusion.

After 72 hours of aggressive fl uid and regular antiemetic

therapy Mrs Begum ’ s condition shows marked improvement.

Her symptoms settle and her urine is negative for ketones.

She is commenced on oral antiemetics along with small

frequent meals, which she tolerates well. She is keen to go

home, as she feels much better. She is therefore discharged

home with dietary advice on antiemetic therapy.

However, over the course of next few weeks she has

several admissions with similar symptoms, which appear not

to respond to conventional therapy. The doctor tells her she

has ‘ refractory hyperemesis ’ .

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What would be the n ext s tep? Ondensetron This strong antiemetic is mostly used to treat nausea and

vomiting postoperatively and following chemotherapy. It

is an option for managing refractory HG. There are

limited data on its safety in pregnancy.

Corticosteroids Steroid therapy reported to be of benefi t with dramatic

improvement of symptoms with a signifi cant reduction

in readmission rates. Hydrocortisone IV followed by oral

prednisolone are the preferred preparations. Dosage is

gradually reduced to a maintenance dose of 5 – 10 mg/day

by 20 weeks. No adverse fetal effects have been reported.

Total p arentral n utrition and e nteral f eeding This is expensive but can be life - saving in severe cases.

Total parenteral nutrition (TPN) requires monitoring

and protocol as can lead to infectious and metabolic

complications.

Mrs Begum ’ s consultant suggests a trial of ondensetron and

steroids, to which she responds dramatically. She is

eventually discharged home a week later on oral steroids

with a follow - up plan. Her steroid dose is gradually reduced

to a maintenance dose by 16 weeks ’ gestation and

eventually stopped at 23 weeks.

The rest of her pregnancy was uneventful and she

delivered the twins spontaneously at 37 weeks. The babies

had normal Apgar scores and birth weights. She was

advised that her symptoms could recur in subsequent

pregnancies.

KEY POINT

• HG refractory to conventional therapy is a diffi cult

condition to treat

• Refractory HG is associated with multiple hospital

admissions and psychological morbidity

• Women may request termination of pregnancy in

extreme cases

CASE REVIEW

This 29 - year - old para 1 presented with vomiting and dehy-

dration in early pregnancy. After excluding the other causes

of vomiting the diagnosis was that of HG. The mainstay of

management of this condition is rehydration by means of

intravenous fl uids containing adequate sodium and potas-

sium along with regular antiemetics. HG is associated with

increased risk of venous thrombosis, therefore thrombo-

prophylaxis is recommended. Thiamine is prescribed to

prevent Wernicke ’ s encephalopathy.

Mrs Begum responded well to conventional treatment;

however, she experienced recurrence of her symptoms,

which were refractory to hydration and antiemetics. She

responded well to ondensetron and corticosteroids, drugs

reserved for refractory HG. Corticosteroids were stopped

at 23 weeks after a gradual dosage reduction.

The twins born at 37 weeks gestation, were of normal

weight and did not require admission to neonatal unit.

Thus, with appropriate management there was no evidence

of long - term effects of hyperemesis or its treatment for the

mother and her babies. In view of her history, Mrs Begum

was counselled about the risk of recurrence of symptoms

in subsequent pregnancies.

KEY POINTS

• HG is a diagnosis of exclusion

• Onset is usually around 6 – 8 weeks ’ gestation

• Transient but self - limiting hyperthyroidism may occur in up

to 60% of cases

• Early, aggressive and appropriate fl uid and electrolyte

replacement is the mainstay of management

• Antiemetics should be prescribed on a regular basis

• Common antiemetics are not teratogenic

• Thromboprophylaxis and thiamine replacement are

important components of management

• Serious complications are rare

• Ondensetron and short - term corticosteroids have a role

in managing refractory HG

Hyperemesis Gravidarum Compilation from many E-books

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