Hyperemesis Gravidarum

Author: Matthew Streitz, MD (EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

A 28 y/o F who is a G3P2 with no significant past medical history presents with persistent nausea and vomiting 7 weeks after her last known menstrual period.  Her primary doctor sent her to the ED for treatment and further evaluation.  She has lost 6 lb (2.6 kg) over that time frame.  What are your next steps?  How should her nausea and vomiting be managed in the ED?  What about at home?

Background

Nausea with or without vomiting is very common in early pregnancy, affecting nearly 75% of pregnancies 1,2,3.  Approximately 25% of women will have nausea without vomiting, and the remaining 50% will have nausea and vomiting, which is often present throughout the majority of the day 1,2,9,10,23,54,55.  Of the women who have nausea and vomiting, roughly 35% of those women will have clinically significant disease resulting in lost work, hospitalization, and family relationships which are negatively affected.  The small minority of women who go on to develop hyperemesis gravidarum is roughly 0.3 to 2% of pregnancies affected by nausea and vomiting 1-12.

The etiology behind nausea and vomiting in pregnancy is not completely clear and likely multifactorial, and the clinical course of the disease closely follows that of human chorionic gonadotropin (hCG) levels 1,2,4,5,9-11,23-25.  Onset is typically around 4 weeks gestation, peaking at the 9th to 12th weeks, and the symptoms typically resolve (91% of women) by midpregnancy (20 weeks) regardless of severity and therapy.  Women who are younger and those with a history of motion sickness, migraines, and oral contraception associated nausea and vomiting are more likely to develop pregnancy-related nausea and vomiting 1,3,9-11,19,45,46.

Hyperemesis gravidarum is the spectrum of severe vomiting that results in weight loss (>5%), ketonuria, electrolyte abnormalities (hypokalemia, alkalosis from loss of hydrochloric acid), and dehydration (high urine specific gravity) that are unresponsive to dietary modifications and medications.  It is more common in pregnancies with twins or hydatidiform moles (those with rapidly increasing serum levels of pregnancy-related hormones) as well as in pregnancies complicated by triploidy, trisomy 21, and hydrops fetalis 1,2,9-11,19.  In addition, there is an association with preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy (AFLP).  In hyperemesis gravidarum up to 20% of those hospitalized in a prior pregnancy will require hospitalization in subsequent pregnancies.  Other risk factors for admission are hyperthyroidism, previous molar pregnancies, diabetes, gastrointestinal illnesses, asthma, and allergic disorders.  It is considered by many to be a diagnosis of exclusion, particularly in the emergency department 9,10.

Presentation

Patients will often present to the ED from their primary doctor or of their own accord when they just cannot take the nausea and vomiting anymore.

Let’s go back to our case:  We have a 28 y/o F with her third pregnancy.  She tells you that this happens each time and that with her last pregnancy, which was about 3 years ago, the nausea and vomiting got so bad she was admitted to the hospital for a night.   She appears well though dehydrated.  Her heart rate is 115, normotensive, and is actively vomiting as you enter the room.  What do you do?

Hyperemesis gravidarum presents with known pregnant patients with persistent vomiting and dehydration, elevated urine specific gravity with ketonuria, and hemoconcentration.  Those patients may require hospitalization for parenteral hydration and nutrition if signs and symptoms cannot be controlled in the ED or at home once discharged.  Patients with hyperemesis frequently will present with postural dizziness, presyncope, weight loss, hyperolfaction, dysgeusia (altered or metallic taste), decreased taste sensation, or other signs of dehydration (tachycardia, dry mucous membranes, collapsed neck veins, and poor skin turgor) 1,4,9.

As discussed earlier hyperemesis gravidarum should be a diagnosis of exclusion.  Other causes of vomiting should be sought after including; infection, diabetes mellitus, gastroenteritis, gastroparesis, biliary colic or biliary tract disease, hepatitis, peptic ulcer disease, pancreatitis, appendicitis, pyelonephritis, ovarian torsion, diabetic ketoacidosis, migraines, toxic ingestion, psychologic conditions, HELLP, and AFLP, as well as preeclampsia and eclampsia.  Onset of nausea and vomiting over 8 weeks after the LMP should be a red flag, as this is rare.   Fever, abdominal pain, and headache are also atypical of women with hyperemesis gravidarum or even nausea and vomiting of pregnancy and should be another red flag.  Of note, patients with hyperemesis gravidarum are rarely in severe shock. 1,2,4,7,9,10,59.

Case:  Our patient is found to have large ketones in her urine, urine specific gravity of >1.030, and a Chloride of 98.  What are the next steps in treatment?

Evaluation

The emergency department evaluation consists of primarily ruling out life threats and other more concerning causes of nausea and vomiting.  Frequently labs that are used in the evaluation are urinalysis and urinary ketones, a basic metabolic panel with blood urea nitrogen, creatinine, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), electrolytes, serum quantitative HCG, and thyrotropin (as well as free thyroxine – T4 – if the thyrotropin is suppressed) 1,9,10,11.

Laboratory tests can show ketones in the urine, a hypochloremic alkalosis, and slightly elevated liver enzymes on initial evaluation.  Ketonuria is an important finding due to the early onset of ketones in the urine.  Aminotransferase elevations are typically 2 to 3 times the upper limit of normal but can be elevated up to 15 to 20 times the normal.  Liver enzyme elevation should resolve as the hyperemesis resolves.  Hypokalemia as well as hemoconcentration can also be seen.  Jaundice is very rare and likely is due to other etiologies.  Transient hyperthyroidism is also seen in women with hyperemesis. Patients typically will not have a prior history of hyperthyroidism and on physical exam will not have a goiter.  Tests for thyroid antibodies will be negative, and T3 will be lower than values seen in true hyperthyroidism (typically high T4 and T3 with true hyperthyroidism). Serum HCG levels greater than 100,000 mIU/mL warrant consideration for hydatidiform mole with ultrasound.

Imaging is not often needed for nausea and vomiting of pregnancy or with hyperemesis gravidarum but should be used to rule-out or aid in the diagnosis of the other possible etiologies of nausea and vomiting in pregnancy.  An example includes a right upper quadrant abdominal ultrasound in a patient with right upper quadrant pain1,4,9.

Complications

Maternal complications related to hyperemesis gravidarum include Wernicke’s encephalopathy (Thiamine deficiency), acute tubular necrosis, central pontine myelinolysis, Mallory-Weiss tear, pneumomediastinum, and splenic avulsion 1,2,4,9,10, 38,39,49-52.  Other not easily stratified complications include the social isolation and psychological burden that can be seen with the disease, which include anxiety, depression, and lost work time.  Rarely peripheral neuropathies can develop with vitamin B6 and vitamin B12 deficiencies.  There are no clear fetal complications (fetal anomalies, miscarriage, or stillbirth) but there may be some association with low birth weight.

Case:  Our patient is weighed in the ED.  She is down from her prior weight with a weight loss of about 6% based on EMR evaluation. She is given Zofran, 8mg IV, and a 2L bolus of IV fluids.  Two hours later, her urine shows no change in her ketonuria.  A 12.5 mg dose of Phenergan is then given due to persistent vomiting.  She is also started on D5% with 1/2NS, and a call to Obstetrics is placed for consideration for admission.

Management

Management of women affected with nausea and vomiting of pregnancy depends upon the severity of symptoms, the psychosocial aspects of her symptoms, and the safety of treatment for both her and the baby.  Treatment approaches depend on the severity, gestational age, patient desires, and are guided by symptomatic relief.  Roughly 10% of women affected by nausea and vomiting of pregnancy will go on to require medication for symptom relief 1,3,4,9,10.

Mild Nausea and Vomiting — This can often be managed and treated with dietary or lifestyle modifications.  Evidence has shown that early intervention of symptoms with these changes is more efficacious if stated early.  Once nausea and vomiting are significant they are more difficult to control.  Some of the easiest of these can be avoidance of triggers such as odors, foods, or supplements that increase or exacerbate nausea.  Dietary modifications include avoiding spicy or fatty foods as well as iron tablets 13.  It is advised that when women feel hungry, they should eat as soon as or before they feel sick.  Patients should also eat small meals about 6 times per day and should drink fluids in-between meals 9,10.   Fluids that are recommended are cold, clear, and carbonated like ginger ales and lemonades as well as smoothies or slushies.  There are no good randomized trails looking at the efficacy of different diets, but in a very small trial, diets higher in protein tended to have greater relief from nausea than those diets with higher carbohydrate content.  Other therapies that are mentioned and utilized are ginger, herbal teas, acupuncture, and hypnotherapy 14.  Ginger is typically dosed 1 to 5 grams/day divided over 24 hours (every 6 hours).  Over-the-counter preparations for ginger are 250 mg capsules.  All of them, again like the dietary recommendations, lack solid evidentiary support.  Pharmacologic options for mild nausea and vomiting include pyridoxine or doxylamine added along with pyridoxine if symptoms do not improve. Pyridoxine dosing is from 10 to 25 mg orally very 6 to 8 hours with a maximum daily dose of 200 mg, although most recommendations are for 100mg/day or less. Both are considered first-line agents 1,3,9,10,15,16,17,19.  There is a combination of doxylamine-pyridoxine available when pyridoxine as a single agent for the treatment of mild nausea and vomiting of pregnancy fails to improve symptoms.   In one study the decrease of symptoms neared 70%3.  It is important to remember that combination tablets may be costly and that both drugs can be purchased over-the-counter.  Unisom is the common over-the-counter formulation of doxylamine.  The drugs in combination appear to be more effective than either drug alone 1,3,4,7,9,10.

Nausea with Frequent Vomiting— When women present with more than just occasional vomiting but are still able to maintain hydration, providers should still have patients attempt dietary changes and trigger avoidance as well as the initial interventions for mild nausea and vomiting 1,3,9,10,18,19.  Additional medications that can be effective are then added one at a time to find maximal benefit while maintaining the lowest risk possible (there have been very few studies with pregnant women evaluating medications).  Typically a drug is continued for a couple days to see if there are any signs of improvement.  If there are no signs if decreasing nausea and vomiting, another drug can be added.

Typical second-line agents (for those failing doxylamine and pyridoxine) once the mild nausea and vomiting have moved to persistent include antihistamines (H1 antagonists) like meclizine, diphenhydramine, dimenhydrinate, hydroxyzine, and one which should have already been tried – doxylamine-pyridoxine 1-12,15-22.  These medications have few maternal side effects and have a relatively more established fetal safety profile than others.  A meta-analysis of 24 controlled studies, including over 200,000 exposures during the first trimester, found a relative protective effect on malformation risk (odds ratio [OR] 0.76, 95% CI 0.60-0.94). Subsequent reviews have confirmed these findings.  Patients should be made aware of the common side effects of this medication class.  They include constipation (already an issue for pregnancy), sedation, dry mouth, and lightheadedness 9,10,20-22.

Recommendations for dosing of antihistamines include diphenhydramine 25 to 50 mg orally every four to six hours, as needed 1,3,26,27,28. In the ED it can also be given intravenously 10 to 50 mg every four to six hours, as needed.  Other common uses in pregnancy include insomnia as well as pruritus.  Meclizine is another option.  Typical dosing is 25 mg orally every four to six hours, as needed.  Another medication available is dimenhydrinate 25 to 50 mg orally every four to six hours, as needed.  The medication can be given IV and rectally as an inpatient or in the ED.  Maximum dose/day is 400 mg.

Third-line agents include dopamine antagonists such as metoclopramide, a benzamide, and promethazine and prochlorperazine, which are both phenothiazines.  Reglan (metoclopramide) is typically dosed 10 mg orally, intravenously, or intramuscularly every six to eight hours 1,3,5,9-11,19,25,28,29.  It is recommended to administer these doses approximately 30 minutes prior to a meal or bedtime for maximum effect/relief of symptoms.  Long-term use is of concern when discussing maternal side effects.  Tardive dyskinesia is the main side effect of this medication, and early discontinuation of the medication as well as maternal education of the side effects are of the utmost importance.  Promethazine, a weak dopamine antagonist, is also an H1 receptor blocker1,3,5,9-11,19,25,28,29.  The typical dosing is 12.5 to 25 mg orally or rectally every 4 hours as needed.  Rectal administration is preferred if oral tolerance is decreased in an effort to obtain PO tolerance and avoidance of an emergency department visit.  Sedation is the largest drawback to promethazine use, particularly in women who work or have small children at home.  Dystonic reactions are also a concern and are seen typically with higher dosing and with prolonged exposure1,3,5,9-11,19,25,28,29.

Fourth-line agents are serotonin antagonists such as ondansetron.  Recommended dosing is 4 to 8 mg as an oral tablet or an oral dissolving tablet (ODT) every 8 hours.  It can also be given intravenously in the ED or as an inpatient 1-12, 28-33,37.  Benefits of this medication are availability of a dissolvable tablet and less sedation than both promethazine and diphenhydramine without loss of efficacy.  Headache, drowsiness, constipation as well as fatigue are common side effects.  In patients with a history of cardiac or arrhythmia risk factors such as a family or personal history of long QT syndrome, caution should be used.  Avoidance of other medications that could prolong QT intervals is advised.  Electrocardiograms and electrolyte monitoring are also recommended.  The controversies over ondansetron in pregnancy lately regarding septal defects have not been consistently proven 33-36.

SEVERE VOMITING (ELECTROLYTE ABNORMALITIES, DEHYDRATION, WEIGHT LOSS AND ACID-BASE ABNORMALITIES) – HYPEREMESIS GRAVIDARUM — Once nausea and vomiting become persistent, severe, or unresponsive to the above mentioned therapies, patients should be evaluated by their Obstetrician, Family Medicine provider, or in the emergency department.

EVALUATION — As discussed, life threats and other causes of nausea and vomiting in pregnancy should be worked up with pertinent labs and radiographic studies as warranted.  Treatment should be provided while evaluation is underway.

TREATMENT — Treatment consists of making the patient NPO or nothing by mouth, and large bore (18 ga) intravenous access with fluid boluses (2 liters of Ringer’s lactate) should be achieved.  Once this has been achieved, Thiamine 100 mg should be given intravenously to avoid Wernicke’s encephalopathy, and the patient should be transitioned to fluids containing 5% Dextrose 1,9,10,38,39.  Although no major differences in short-term or long-term outcomes was seen in trials seeking optimal fluid replacement strategies, nausea was noted to resolve faster with fluids containing dextrose.  Other electrolytes such as magnesium, potassium, and calcium should be repleted as needed.  Banana bags containing folic acid1 mg, magnesium 3 grams, thiamine 100 mg, and a Multivitamin for infusion (1 ampule) are often given by providers in the ED and as an inpatient.

Medication treatment in the ED should consist of intravenous administration of ondansetron 4 to 8 mg and/or promethazine 12.5 to 25 mg along with the fluid replacement.

Glucocorticoids such as methylprednisolone are used for severe and refractory hyperemesis gravidarum and only after the 10th gestational week due to a 3 to 4 fold risk of cleft lip with or without cleft palate 1,3,9,10,11,40-42.  Dosing is 16 mg intravenously every eight hours for 48 to 72 hours.  Following an intravenous course of steroids, it is recommended to follow-up with a 40 mg oral dose for a single day followed by 20 mg/day for three days, then 10 mg for three days followed by 5 mg per day for 7 days.

Case:  Obstetrics evaluates the patient.  Despite the fluids and IV medications to decrease nausea and vomiting, the patient’s weight loss and prior admission history for the same in her previous pregnancy leads to an admission.

Disposition

The process of nausea and vomiting of pregnancy can for many moms be a long and tedious course.   Thankfully, nausea and vomiting of pregnancy is typically not associated with adverse pregnancy outcomes other than severe malnutrition requiring hospitalization.  Hyperemesis gravidarum, despite having a significant morbidity for some women has a small, if any differences in birth weight 1,9-12,44-48.  Early and frequent assessment and reassessment of weight and nutritional status of patients has led to an even smaller footprint of adverse outcomes.  Parenteral nutrition, outside the scope of this topic, has virtually erased maternal morbidity and mortality of those women who are treated 3,9,10,43,44,45,46.  It is important to know that if presented with a patient receiving parenteral nutrition, line sepsis is not an infrequent complication, affecting up to 35% of patients 43-46.

It would be a disservice to our patients to let the psychosocial morbidity associated with nausea and vomiting of pregnancy, as well as hyperemesis, go unmentioned as this can lead to a significant strain on the home and work for patients and families.  One study reported a 15% termination rate due to the stressors and morbidity associated with hyperemesis 56.  This was in a survey of over 800 women with the diagnosis of hyperemesis gravidarum.

Patients who are see in the ED and have persistent vomiting and ketonuria require hospitalization.  If their ketonuria is resolving and they are PO tolerant, they can be discharged with a 1-2 day follow-up with their primary obstetric provider as long as no electrolyte abnormalities are present.  Patients with weight loss should be admitted for close monitoring of weight.  Patients should be discharged home with both PO and PR medications as well as ODT if ondansetron is a medication that works well for them.  Strict return precautions and adverse side effects of medications should be discussed prior to departing the emergency department.  The presence of a hydatidiform mole always requires admission 1,8-12,44-48. 

Key points

  1. Nausea and vomiting of pregnancy is very prevalent and will be seen in your emergency medicine practice. Become comfortable with its management.
  1. Hyperemesis Gravidarum should be a diagnosis of exclusion.
  1. Your short list of go-to pharmacologic treatment includes: Benadryl 25 to 50 mg Q8 hours; Meclizine 25 mg PO every 6 hours; Phenergan 12.5 to 25 mg PO, IV, PR Q4 to 6 hours; Reglan 10 mg Q6 hours; Zofran 4 to 8 mg PO, ODT, or IV Q6 hours.
  1. After adequate hydration and before dextrose administration patients should receive Thiamine 100 mg IV to avoid Wernicke’s.
  1. Admission criteria include: Weight loss >10%, Intractable vomiting, Persistent ketone or electrolyte abnormalities despite rehydration, or Uncertainty of diagnosis.

 

References/Further Reading

  1. Current Diagnosis and Treatment Emergency Medicine 7e, Chapter 38. Obstetric and Gynecological Emergencies and Rape. Ryan Tucker, MD; Melissa Platt, MD
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  4. Current Diagnosis and Treatment Gastroenterology, Hepatology and Endoscopy 3e, Chapter 7: Gastrointestinal & Biliary Complications of Pregnancy, Sonia Friedman; Jaya R. Agrawal
  5. Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol. 2014;123:1272–1279.
  6. Irving PM, Howell RJS, Shidrawi RG. Percutaneous endoscopic gastrostomy with a jejunal port for severe hyperemesis gravidarum. Eur J Gastroenterol Hepatol. 2004;16:937–939.
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  9. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide 8e.  Chapter 99: Comorbid Disorders in Pregnancy, Lori J. Whelan
  10. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide 8e. Chapter 98: Ectopic Pregnancy and Emergencies in the First 20 Weeks of Pregnancy, Heather A. Heaton
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