Sarah Peterson
History of present illness
A 27-year-old gravida 3, para 1 woman with a dichorionic diamniotic twin gestation at 9 weeks’gestational age presented to the emergency department for 5 days of severe nausea and vomiting. The patient had been struggling with persistent nausea and vomiting for several weeks, and had been evaluated in another emergency department on two prior occasions for similar symptoms. Symptoms acutely worsened on the day prior to presentation, with an increased frequency of emesis and an inability to tolerate oral liquids or solids. The patient denied abdominal pain, fevers, chills, vaginal bleeding, or vaginal discharge. She complained of mild constipation and symptoms of acid reflux unrelieved by antacids. The patient reported that her symptoms were so distressing that she was considering termination of the pregnancy.
Review of systems was otherwise negative. The patient had no other medical problems and no prior surgeries. She was not on any medications other than prenatal vitamins, which she had been unable to take. Her prior pregnancy had mild nausea that resolved on its own without treatment, and was otherwise uncomplicated.
Physical examination
General appearance:Alert-and-oriented, thin woman in moderate distress with emesis but otherwise well appearing Vital signs:
Temperature: 36.8°C
Blood pressure: 106/70 mmHg Pulse: 116 beats/min
Respiratory rate: 22 breaths/min Oxygen saturation: 98% on room air HEENT:Dry mucus membranes
Neck:Supple, no lymphadenopathy, no thyromegaly Cardiovascular:Tachycardic, regular rhythm, normal S1/ S2, no murmurs, rubs, or gallops, no edema Lungs:Clear to auscultation bilaterally, nonlabored respirations, no wheezes or rales
Abdomen:Soft, mildly tender to palpation in epigastrium, nondistended, hypoactive bowel sounds, no rebound or guarding
Pelvic:
Speculum examination: No blood, discharge, or lesions Cervix examination: Normal appearing, no cervical motion or adnexal tenderness, cervix closed and long
Uterus: 9-weeks’size Laboratory studies:
Potassium: 2.9 mmol/L (normal 3.5–5.5 mmol/L) Leukocyte count: 16 400/àL (normal 3500–12 500/àL) with 77% neutrophils (normal 50–70%)
Urinalysis: 30 mg/dL protein, trace leukocytes, moderate ketones, and a specific gravity of 1.034
Serum lactate concentration: 0.7 mmol/L (normal 0.5–1.6 mmol/L)
Initial treatment in the emergency department consisted of intravenous hydration with two 1 L normal salinefluid boluses and intravenous promethazine. She continued to have emesis.
How would you manage this patient?
The patient has hyperemesis gravidarum. She was admitted for supportive care. Intravenous hydration was continued and her electrolytes were closely monitored. Her hypokalemia was corrected with intravenous potassium. Despite treatment with promethazine 12.5 mg IV every 4 hours and ondansetron 8 mg IV every 12 hours, the patient’s nausea and emesis persisted.
She continued to lose weight, which prompted initiation of enteral tube feedings. She was continued on a proton pump inhibitor for her gastroesophageal reflux symptoms. Tube feedings were eventually able to be discontinued and her diet was slowly advanced. She was discharged home on hospital day 12 with prescriptions for pyridoxine (vitamin B6), doxylamine, ondansetron, and promethazine. She was advised to eat small frequent meals and was scheduled to return to clinic in one week.
Hyperemesis gravidarum
Pregnancy is often complicated by nausea and vomiting, with up to 80% of women experiencing these symptoms at some point during their pregnancy [1]. While hyperemesis gravi- darum is imprecisely defined, it is generally felt to represent the more severe end of the pregnancy-associated nausea and vomiting continuum. Less severe symptoms are very common and are generally called nausea and vomiting of pregnancy.
Hyperemesis is second only to preterm labor as an indication for hospital admission during pregnancy, and affects approxi- mately 0.5–2.0% of pregnant women [2]. The symptoms can have significant physical and psychological impacts and can be so distressing that they may lead women to terminate their pregnancies [2].
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
While definitions for this condition vary, key components include intractable vomiting, weight loss of greater than 5% of prepregnancy weight, dehydration, ketosis, and electrolyte abnormalities [1]. Thyroid and liver abnormalities may also be present. Risk factors include increased placental mass (often due to multiple or molar gestations), female fetus, a personal or family history of hyperemesis, and a history of migraines or motion sickness [2]. Meta-analyses have demonstrated that infection with Helicobacter pylori is also associated with an increased risk of hyperemesis [3].
The exact mechanism of hyperemesis gravidarum is not well understood, but human chorionic gonadotropin (hCG) is thought to play a role because of the synchronous temporal relationship between peak hCG concentrations and symptoms of nausea and vomiting in the latefirst trimester [2]. Conditions causing higher levels of hCG such as multiple gestations and molar pregnancies have been associated with increased nausea and vomiting [1]. This patient’s twin pregnancy is a likely explanation for why she has hyperemesis in this pregnancy despite not having it in her prior pregnancy. Estrogen is also thought to contribute, as symptoms are more common with higher estradiol levels. Estrogen stimulates the production of nitric oxide, which relaxes smooth muscle, and it is postulated that this leads to nausea and vomiting by slowing gastrointest- inal motility [4]. Cigarette smokers are less likely to have hyper- emesis gravidarum, possibly because smoking decreases levels of both hCG and estradiol [2]. Progesterone has also been impli- cated, as it causes relaxation of the lower esophageal sphincter [4]. Theories of psychogenic causes have fallen out of favor.
Mothers are often concerned about the effects of protracted nausea and vomiting on their developing fetus, and they can generally be reassured that hyperemesis gravidarum is associ- ated with normal pregnancy outcomes. While hyperemesis has been associated with a slightly higher incidence of low-birth- weight infants, there has been no demonstrated increased risk of malformations [2]. Patients with hyperemesis gravidarum actually have a lower incidence of spontaneous abortion, which is hypothesized to result from the abundant synthesis of hCG [2]. Fetal death associated with hyperemesis is rare.
The psychosocial impact on the mother is significant, and may lead to depression, anxiety, somatization, or other psychiatric conditions [2]. While mortality rates are low, a number of severe complications can occur. There have been several reported cases of Wernicke’s encephalopathy from severe vitamin B1 deficiency caused by intractable vomiting.
Other rare but related complications include splenic avulsion, Mallory–Weiss tears, esophageal rupture, pneumothorax, and acute tubular necrosis [2].
Symptoms are typically worst in thefirst trimester, peaking around weeks 6–12. Nausea and vomiting can persist beyond 20 weeks’gestational age in up to 20% of women [1]. Timing is an important consideration, as hyperemesis gravidarum typic- ally manifests prior to nine weeks’gestational age. If symptoms begin after nine weeks or are associated with additional symp- toms such as abdominal pain, fever, or headaches, alternative
diagnoses should be considered [2]. Hyperemesis gravidarum is a diagnosis of exclusion. Other possible causes must be ruled out (Table 54.1[2]).
Evaluation should include ultrasonography to assess for pos- sible multiple gestation or molar pregnancy [2]. Laboratory testing is warranted when nausea and vomiting is severe and prolonged. Patients with hyperemesis will often have mild eleva- tions in their liver function tests (with AST [aspartate amino- transferase] and ALT [alanine transaminase] typically<300 U/L) [2]. Bilirubin and serum amylase or lipase may also be slightly elevated. A hypochloremic metabolic alkalosis can develop with intractable vomiting and urinalysis often shows increased specific gravity and ketonuria consistent with dehydration [2]. As many as two-thirds of patients with hyperemesis gravidarum will have abnormal thyroid function tests, likely due to cross-reactivity between hCG and thyroid-stimulating hormone (TSH) receptors [4]. Typicalfindings include increased free thyroxine and sup- pressed TSH. Patients are typically euthyroid, and the degree of thyroid dysfunction has not been correlated with the severity of symptoms [4]. Therefore, thyroid function studies should not be routinely obtained in patients without clinical features of thyroid dysfunction.
Table 54.1 Differential diagnosis of nausea and vomiting in pregnant women*
Gastrointestinal Peptic ulcers Cholecystitis Gastroenteritis Appendicitis Hepatitis Pancreatitis Achalasia Bowel obstruction Genitourinary Pyelonephritis
Nephrolithiasis Ovarian torsion Degeneratingfibroids Uremia
Metabolic Diabetic ketoacidosis Hyperthyroidism Addison disease Porphyria Neurologic Migraines
Pseudotumor cerebri Vestibular lesions
Central nervous system tumors Pregnancy-related Acute fatty liver of pregnancy
Preeclampsia
Mild nausea and vomiting of pregnancy Iatrogenic Medication intolerance
Other Drug or alcohol toxicity Psychological factors
* Modified from the American College of Obstetricians and Gynecologists [2].
Case 54: A 27-year-old woman with severe nausea and vomiting in pregnancy
Patients should be admitted to the hospital if they have failed outpatient management or cannot tolerate oral nutri- tional intake or oral anti-emetics. Subsequent management depends on the degree of the patient’s dehydration. If the patient is not significantly dehydrated, dopamine antagonists such as intramuscular or oral metoclopramide or rectal tri- methobenzamide should be initiated. Patients with intractable nausea and vomiting accompanied by significant dehydration should be intravenously hydrated with crystalloid solutions to correct dehydration, ketosis, electrolyte and acid-base abnor- malities. They should also be administered parenteral anti- emetics. Patients with preexisting psychiatric illnesses should have the management of these problems optimized with coun- seling, psychotherapy, and medications.
Many options exist for intravenous anti-emetics. Antihista- mines such as dimenhydrinate have been widely used and have not been shown to increase the risk of birth defects [5].
Large prospective studies have also demonstrated that metoclopramide and other dopamine antagonists are safe; how- ever, there are no trials demonstrating efficacy. Dopamine antagonists can be helpful in women suffering with reflux eso- phagitis and dyspepsia because they enhance motility [5]. Phe- nothiazines such as prochlorperazine, promethazine, and chlorpromazine are also commonly used, and do not appear to be associated with fetal malformations. Neonatal withdrawal and extra-pyramidal effects have been reported in neonates born to mothers using phenothiazines continuously in the third tri- mester [5]. Ondansetron, a serotonin receptor antagonist often used to control chemotherapy-induced nausea and vomiting, has also been used in patients with hyperemesis despite its cost.
One trial demonstrated equal effectiveness to promethazine [2,5]. Lastly, butyrophenones including droperidol have been used to treat hyperemesis gravidarum. A single study with limited power did not demonstrate a statistically significant increase in fetal malformations. Maternal QT interval prolonga- tion has been documented with this medication [2,5] It would be reasonable to commence therapy with either intravenous pro- methazine, metoclopramide, or dimenhydrinate, depending on provider preference and familiarity. Should these regimens fail, as in our patient, addition of ondansetron may prove helpful.
The use of corticosteroids is controversial. While some stud- ies have shown a decreased rate of hospital readmission with use of methylprednisolone, others have failed to confirm thesefind- ings. Methylprednisolone has been associated with a small risk of oral clefting, so corticosteroids should only be used when all alternative regimens have failed [2,5]. One suggested regimen is methylprednisolone 16 mg every 8 hours PO or IV for 3 days, and then tapered over 2 weeks to the lowest effective dose. Six weeks is the maximum recommended duration of use [2].
If patients experience persistent weight loss despite anti- emetics and hydration, enteral or parenteral nutrition options may be necessary. Dextrose and vitamins including intraven- ous thiamine are recommended when patients have been vomiting for longer than three weeks. Enteral tube feedings should usually be attempted prior to initiation of total
parenteral nutrition (TPN), as the latter is associated with potentially life-threatening complications such as infection, thrombosis, and hepatobiliary dysfunction [2,5]. TPN is appropriate for patients who require long-term nutritional support who cannot tolerate enteral feeds.
After initial stabilization, patients may be slowly transitioned to a general diet and oral or rectal anti-emetics. Rectal supposi- tories including promethazine or trimethobenzamide can be used in patients who are poorly tolerating oral medications.
Intravenousfluid resuscitation should be gradually tapered once patients are tolerating oralfluids. If nausea and vomiting persist, laboratory studies for electrolyte abnormalities and ketonemia should be repeated as necessary. Once electrolyte abnormalities have been corrected and patients are tolerating a general diet and oral medications, they may be discharged home with close outpatient follow-up. The Pregnancy-Unique Quantification of Emesis (PUQE) scoring system can be employed to help patients monitor the severity of their symptoms [4].
Patients will usually require continued anti-emetics at after discharge. Vitamin B6 (pyridoxine) and doxylamine (an H1-receptor blocker) in combination has been associated with decreased hospitalization [2]. Randomized, placebo-controlled trials have shown up to a 70% reduction in nausea and vomiting, and this combination has been demonstrated to be safe for the developing fetus [2,5]. Other agents that can be used orally or rectally to control nausea and vomiting in the outpatient setting include promethazine, prochlorperazine, or antihistamines such as dimenhydrate. This patient was sent home on pyridoxine, doxylamine, ondansetron, and prometh- azine because of the severity of her hyperemesis and the diffi- culty with which it was controlled. Even with optimal outpatient management, studies have shown a readmission rate of approximately 30% [6].
Key teaching points
Hyperemesis typically presents prior to nine weeks’
gestational age.
If hyperemesis starts after nine weeks’gestational age, other causes are likely.
Hyperemesis is a diagnosis of exclusion. Other possible causes of nausea and vomiting in pregnancy must be ruled out.
Management of patients with hyperemesis gravidarum includes aggressive intravenousfluid replacement,
correction of electrolyte abnormalities, thiamine repletion, and pharmacologic therapy with parenteral agents such as dimenhydrinate, metoclopramide, promethazine, and ondansetron.
Patients should be admitted to the hospital if they have failed outpatient management or cannot tolerate oral nutritional intake or oral anti-emetics.
Patients should be discharged on a regimen of promethazine and/or ondansetron, pyridoxine, and doxylamine.
References
1. Matthews A, Dowswell T, Haas DM, Doyle M, O’Mathuna DP. Interventions for nausea and vomiting in early pregnancy.Cochrane Database Syst Rev 2010, Issue 9. Art. No.: CD007575.
DOI: 10.1002/14651858.CD007575.
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2. American College of Obstetricians and Gynecologists. Nausea and vomiting of pregnancy. Practice Bulletin No. 52.
Obstet Gynecol2004;103:803–15.
3. Sandven I, Abdelnoor M, Nesheim Bl, et al.Helicobacter pyloriinfection and hyperemesis gravidarum: A systematic review and meta-analysis of case control studies.Acta Obstet Gynecol Scand2009;88:1190–200.
4. Lee NM, Saha S. Nausea and vomiting of pregnancy.Gastroenterol Clin North Am2011;40(2):309–34, vii. DOI 10.1016/j.gtc.2011.03.009.
5. Maltepe C, Koren G. The management of nausea and vomiting of pregnancy
and hyperemesis gravidarum–a 2013 update. Canadian Society of Pharmacology and Therapeutics.
J Popul Ther Clin Pharmacol2013;
20(2):e184–92.
6. Lacasse A, Laqoutte A, Ferreira E, Bérard A. Metoclopramide and diphenhydramine in the treatment of hyperemesis gravidarum: Effectiveness and predictors of rehospitalisation.Eur J Obstet Gynecol Reprod Biol2009;
143(1):43–9.
Case 54: A 27-year-old woman with severe nausea and vomiting in pregnancy