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Clinical Policy Title: Treatments of Hyperemesis Gravidarum

Clinical Policy Number: 12.02.02


Effective Date:
Initial Review Date:
Most Recent Review Date:
Next Review Date:

June 1, 2014
February 19, 2014
September 19, 2014
September 2015

Policy contains:
Ondansetron (Zofran) subcutaneous
pump.
Intravenous hydration.
Hyperemesis gravidarum treatment.

ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health
of South Carolina clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services
(CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer -reviewed professional
literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including
any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of
South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal
laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of
South Carolina clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians a nd other
health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina clinical policies are
reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies
as necessary. Select Health of South Carolina clinical policies are not guarantees of payment.

Coverage Policy
1.) Select Health of South Carolina considers the use of Zofran via subcutaneous microinfusion pump to be
clinically proven for the treatment of hyperemesis gravidarum during pregnancy and, therefore, medically
necessary when ALL of the following criteria are met:

Clinical criteria
(ALL criteria must be met)
Hyperemesis gravidarum is diagnosed after nine weeks of gestation.
All other causes of nausea and vomiting have been ruled out.
Evidence of persistent vomiting, weight loss of more than 5 percent.
Documentation of one of the following: ketouria, hypokalemia or high urine
specific gravity (dehydration).
A step trial in the following order unless contraindicated:
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

1.) A trial of at least one of the following five drugs has been
attempted and failed:
1. Prochlorperazine (Compazine IM/PO).
2. Trimethobenzamide
(Tigan PR).
3. Promethazine (Phenergan IM/PO/PR).
4. Metoclopramide (Reglan PO).
5. Ondansetron (Zofran PO).
2.) If control not achieved with drugs in step #1, then a trial of doxylamine and
pyridoxine (Diclegis PO) has been attempted.
3.) If drugs in steps #1 and #2 have been tried without success, then either
intravenous metoclopramide (Reglan) or intravenous ondansetron (Zofran) has
been attempted and failed.
4.) Upon failure of drugs in steps #1, #2 and #3, the continuous infusion of
ondansetron (Zofran).

2.) Select Health of South Carolina considers the use of intravenous (IV) hydration (CPT codes 96360,
96361) for hyperemesis gravidarum to be clinically proven and, therefore, medically necessary when
EITHER of the following criteria is met:
Clinical criteria
(Either criterion must be met)
Presence of clinical signs of dehydration (e.g., high urine specific gravity,
ketonuria or hypokalemia).
Inability to tolerate oral liquids without vomiting for more than three
weeks.

IV hydration should be continued until ketosis and vitamin deficiency have been corrected
and until the patient can tolerate oral fluids.

At any step consider parenteral nutrition if dehydration persists or persistent weight loss is noted.

Alternative therapies may be added any time depending on patient acceptance and clinician
familiarity.

Thiamine, 100 mg daily, IV for 2 3 days (followed by IV multivitamins) is recommended for every
woman who requires IV hydration and has vomiting for more than three weeks.
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

Limitations:
All other uses of Zofran subcutaneous microinfusion pumps are not medically necessary. All other uses of IV
hydration for hyperemesis during pregnancy (e.g., prevention of dehydration) are not medically necessary.

In general, an imbalance of less than 500 ml of volume is not likely to require IV rehydration.
Therefore, rehydration with the administration of an amount of fluid equal to or less than 500 ml is
not medically necessary.

NOTE: The following codes are not reimbursed under Medicaid in South Carolina:
E0779 - Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater.
E0780 - Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater.
Alternative Covered Services:
Nutritional counseling, physician office visits.

Background
Nausea and vomiting of pregnancy affects approximately 80 percent of pregnant women (Einarson 2013).
Uncomplicated nausea and vomiting of pregnancy, commonly known as morning sickness, is generally a
mild, self-limited condition that may be controlled with conservative measures. A small percentage of
pregnant women have a more profound course, with the most severe form being hyperemesis gravidarum
(HG). Severe hyperemesis requiring hospital admission occurs in 0.3 percent 2 percent of pregnancies
(Einarson 2013, Piwko 2013).
There is no one accepted definition of HG. According to the American College of Obstetricians and
Gynecologists (ACOG), the most commonly cited criteria for HG include persistent vomiting not related to
other causes, a measure of acute starvation (usually large ketonuria), and some discrete measure of weight
loss, most often at least 5 percent of pre-pregnancy weight. Electrolyte, thyroid, and liver abnormalities
may be present (ACOG 2014). The International Statistical Classification of Disease and Related Health
Problems, Ninth Revision (ICD-9-CM) defines HG as persistent and excessive vomiting starting before the
end of the 22nd week of gestation; HG is further subdivided into mild and severe, with severe being
associated with metabolic disturbances, such as carbohydrate depletion, dehydration, or electrolyte
imbalance (AMA 2014).
While the etiology of HG unknown, it is most likely a multifactorial condition and has been associated with
largely non-modifiable risk factors. HG is associated with family history (genetics) or a history of HG in a
previous pregnancy (ACOG 2004). Hyperemesis is also associated with female gestation, multiple gestation,
triploidy, trisomy 21, current or prior molar pregnancy, and hydrops fetalis. Additionally, women with a
history of motion sickness, migraine headaches, psychiatric illness, pregestational diabetes, being
underweight pregestation, hyperthyroidism, pyridoxine deficiency, and gastrointestinal disorders are at an
increased risk. Women with HG are more likely to be younger, pregnant for the first time, persons of color,
and less likely to drink alcohol. Limited evidence suggests infection with Helicobacter pylori may play a role
in the development of HG in some women (ACOG 2004, McCarthy 2014).
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

Other factors have been implicated in the etiology of HG, but their association with HG has not been
established. These include body mass index, smoking, socioeconomic status, estrogen, stress, depression,
and free human chorionic gonadotropin (hCG) (McCarthy 2014).
Unlike morning sickness, HG may have negative implications for maternal and fetal health. Women with
uncomplicated nausea and vomiting of pregnancy have been noted to have improved pregnancy outcomes,
including fewer miscarriages, preterm deliveries and stillbirths, as well as fewer instances of fetal low birth
weight, growth retardation and mortality (Vandraas 2013, Veenendaal 2011). In contrast, HG has been
associated with increases in maternal adverse effects, including splenic avulsion, esophageal rupture,
Mallory-Weiss tears, pneumothorax, peripheral neuropathy, and preeclampsia, as well as increases in fetal
growth restriction and mortality.
Early evaluation of nausea and vomiting during pregnancy is essential for preventing delay in diagnosis, as it
may prevent progression to HG. Diagnosing HG is determined primarily by ruling out other underlying
complications associated with persistent vomiting, such as gastrointestinal conditions (e.g., hepatitis,
pancreatitis or biliary tract disease), pyelonephritis, and metabolic disorders (e.g., diabetic ketoacidosis,
porphyria, or Addisons disease) (Niebyl 2010). Laboratory assessment may help in the differential diagnosis
of HG and assessment of its severity, but studies of diagnostic biomarkers for HG have produced
inconsistent results (Niemeijer 2014).

Treatment of hyperemesis gravidarum


Once other causes of nausea and vomiting in pregnancy have been ruled out, the management of HG is
based on correcting electrolyte imbalance and dehydration, prophylaxis against recognized complications,
and providing symptomatic relief (McCarthy 2014). Treatment may be administered singularly or in
combination in inpatient and outpatient settings.
Pharmacologic approaches for the treatment of nausea and vomiting in pregnancy have been based on the
pathophysiology of nausea and vomiting, and on treatments found to be safe and effective for nonpregnant subjects. Guidelines encourage early, safe and effective treatment with vitamins and nonpharmacologic alternatives that may prevent complications or reduce the need for pharmacologics or IV
hydration and hospitalization associated with HG (ACOG 2004, Arsenault 2002). Non-pharmacologic options
such as ginger, acupressure, acupuncture and chiropractic may be offered for symptom relief.
Pharmacological treatments include antihistamines, anticholinergics, dopamine antagonists, 5-HT3
antagonists, corticosteroids, cisapride, and cannabinoids (Niebyl 2010). If oral and intravenous (IV)
administrations prove inadequate, subcutaneous drug microinfusion may be necessary.
Infusion pumps are used for many clinical applications, including IV, epidural, and subcutaneous delivery of
analgesic and anesthetic, antibiotics, cardiovascular drugs, antiemetic and insulin. Drug delivery via infusion
reduces the plasma drug concentration fluctuation associated with oral delivery and the slow onset and
long depot effect associated with transdermal patch delivery. Infusion pumps are commonly used with
continuous, intermittent or pulsatile delivery of drug is needed. They also provide an alternative for
patients intolerant to oral administration and can be programmed to achieve special delivery profiles.
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

Notes on treatment of hyperemesis

IV hydration should be continued until ketosis and vitamin deficiency have been corrected and until
the patient can tolerate oral fluids.

At any step consider parenteral nutrition if dehydration persists or persistent weight loss is noted.

Alternative therapies may be added any time depending on patient acceptance and clinician
familiarity.

Thiamine, 100 mg daily, IV for two three days (followed by IV multivitamins) is recommended for
every woman who requires IV hydration and has vomiting for more than three weeks.

Continuous subcutaneous antiemetic therapy


Recently, a compact, disposable drug delivery device that incorporates a relatively short, 5-mm-long
hypodermic needle has been shown to continuously and subcutaneously infuse drug solutions. This type of
device can be worn on the skin in a discrete and convenient manner and deliver drug from a pressuredriven reservoir through the needle into the skin. Micro needles can be coupled with a micropump to make
a wearable infusion device that is highly patient friendly and can serve as a potential replacement for
conventional hypodermic needles and infusion sets. Microneedles are expected to be safe because they
are minimally invasive devices that are inserted only into skins superficial layers and are typically bloodless
and painless.
In the mid-80s, continuous subcutaneous antiemetic therapy was widely employed in clinical practice for
treating nausea and vomiting in pregnancy, despite the dearth of published clinical evidence to support the
intervention. At that time, physicians began prescribing continuous subcutaneous metoclopramide (Reglan)
via a portable, programmable Micro-infusion pump (MiniMed 404SP-MiniMed Technologies, Sylmar, Ca.)
called the Reglan pump. In the late 90s, after ondansetron (marketed in the U.S. as Zofran) was widely
promoted as an anti-emetic for patients with chemotherapy-induced nausea and vomiting, obstetricians
began prescribing it in much the same way as had been done a decade earlier with metoclopramide. This
became commonly referred to as a Zofran pump.
IV hydration
Correction of dehydration with IV fluid is one of the key aims of management (Bottomley 2009). The
volume of fluid should be adequate to replenish the deficit and continuing loss through vomiting, as well as
to meet normal fluid and electrolyte requirements. Sodium chloride IV infusion 0.9% ( normal or
physiological saline) is generally preferable, and compound sodium lactate IV solution containing other
electrolytes (chloride, lactate, potassium and calcium), as well as sodium chloride may be used. Fluid
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

replacement can be tailored to ketonuria or electrolytes and stopped once these have normalized and a
normal diet has resumed (Bottomley 2009).
An online survey of women with a history of HG found that over the last two decades, use of IV hydration
has nearly doubled, along with use of antihistamines, bed rest and vitamins (Goodwin 2008). Yet, this same
survey found significant continued under-prescribing of vitamins, such as pyridoxine and thiamine during
pregnancy when HG commonly presents. Respondents living in the U.S. appear to have been treated
primarily with ondansetron, which is more expensive than conventional antiemetics (Goodwin 2008).
A survey of ACOG fellows who constitute the Collaborative Ambulatory Research Network (CARN) reported
that those who were familiar with the ACOG (2004) guidelines were more aware of the need for early,
aggressive treatment to prevent progression to HG and were more likely to recommend ginger (59.7
percent vs. 47.9 percent, p = 0.014) and prescribe vitamin B6 (84.1 percent vs. 73.8 percent, p = 0.005) and
vitamin B6 plus doxylamine (70.9 percent vs. 59.3 percent, p = 0.009) (Power 2007). Both surveys suggest
continued underuse of early safe and effective treatment with vitamins and non-pharmacologic alternatives
that may prevent complications or reduce the need for IV hydration and hospitalization associated with HG.
Methods
Searches:
Select Health of South Carolina searched PubMed and the databases of:
UK National Health Services Centre for Reviews and Dissemination.
Agency for Healthcare Research and Qualitys National Guideline Clearinghouse and other evidence-based
practice centers.
The Centers for Medicare & Medicaid Services.
Searches were conducted January 2014 using the terms Zofran, infusion pump and nausea and vomiting and on
August 18 19, 2014, using the terms "hyperemesis gravidarum" [MeSH] and free text terms nausea and vomiting of
pregnancy and hydration. We included:
Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision
of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods
to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidencegrading hierarchies.
Guidelines based on systematic reviews.
Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies),
reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top
of evidence hierarchies.

Findings
Limited high-quality research is available to inform clinical practice on advanced treatment of HG. The
ACOG summarized the evidence for guidance on treatment of nausea and vomiting during pregnancy and
serves as the basis of this policy (ACOG 2004).
The ACOG guidance focuses on treatment for all stages of nausea and vomiting of pregnancy, as failure to
treat early manifestations of nausea and vomiting of pregnancy increases the likelihood of hospital
admission for HG. ACOG presents an algorithm of treatment options according to the strength of evidence
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

for fetal safety and efficacy of treatments available in the U.S. A Cochrane review determined there was
insufficient strong evidence of safety and effectiveness to support any one intervention over another
(Matthews 2014). In the absence of one pharmacologic regimen clearly demonstrating benefit over any
other, a decision algorithm that begins with the most cost-effective and readily accessible treatment
options as depicted in the ACOG treatment hierarchy is a reasonable approach to managing HG, although
evidence suggests that greater adherence to these guidelines may be needed (Power 2007, Goodwin 2008).

ACOG recommends treatments with the strongest safety-efficacy profile as first-line treatments.
These include dietary changes, emotional support, vitamin B6 and doxylamine (ACOG 2004).
Pharmacologic management is indicated for relatively mild cases and progressing to patients who
cannot tolerate oral treatment or are dehydrated, or both. Sufficient data on the safety of
antihistamines, phenothiazines and metoclopromide in early pregnancy show no teratogenicity
with any of these agents. Therefore, antiemetic treatment should not be withheld on the basis of
teratogenicity concerns.
For use of continuous subcutaneous anti-emetic therapy for treatment of nausea and vomiting
during pregnancy, the entire body of evidence consists of five industry-sponsored and authored
nonrandomized reports. These therapies do not appear, based on published payment levels, to be
cost-effective when compared to conventional treatment alternatives, including episodic
hospitalization (Reichmann, 2012). Managed care organizations that design evidence-based clinical
coverage guidelines may want to limit their use to extremely recalcitrant cases of HG until
sufficiently powered, independent, randomized, controlled trials demonstrate clinical efficacy and
cost-effectiveness.
IV hydration should be used for the patient who cannot tolerate oral liquids for a prolonged period
or if clinical signs of dehydration are present.
o

Signs of dehydration may include:

Decreased skin turgor.

Postural changes in blood pressure and pulse.

Abnormal electrolyte, BUN, creatinine, and serum ketone levels.

Abnormal urine specific gravity and ketone levels.

IV hydration should be continued until ketosis and vitamin deficiency have been corrected
and until the patient can tolerate oral fluids. IV thiamine 100 mg daily for two to three days
(followed by IV multivitamins) is recommended for every woman who requires IV hydration
and has vomited for more than three weeks.

The evidence is inconclusive for determining if there is any clinical benefit of using a
compound solution over normal saline 0.9%. One study randomized women with HG to
either treatment with IV 5% dextrose and saline vs. normal saline for rehydration (Tan
2014). All participants received IV thiamine and an antiemetic. Women treated with 5%
dextrose experienced short-term (< 24 hours) improvement in vomiting, but the effects had
dissipated by 24 hours. Other outcomes were similar between groups. These results
suggest no clear advantage of a compound solution over normal saline for rehydration.
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Administering dextrose may stop the breakdown of fat, but it may also precipitate
Wernicke encephalopathy in the presence of a thiamine deficiency. For any patient in
whom vitamin deficiency is a concern, thiamine 100 mg should be given before initiating
dextrose-containing fluids.

Other interventions such as enteral tube feeding may be needed to serve as either as a
supplemental or primary source of nutrition.

Hospitalization is recommended when a woman cannot tolerate liquids without vomiting and has
not responded to outpatient management. No controlled trials have compared hospitalization with
outpatient management of HG. The option of hospitalization for observation and further
assessment should be preserved for patients who experience a change in vital signs or a change in
affect or who continue to lose weight. After the patient has been hospitalized on one occasion and
a workup for other causes of severe vomiting has been undertaken, IV hydration, nutritional
support, and modification of antiemetic therapy often can be accomplished at home.

Future research
Greater awareness of evidence-based guidance, particularly for safe and effective early prevention
strategies using vitamins/B6 therapy, is needed as are high-quality studies that focus on safe nonpharmacologic treatments, preventive measures in high-risk women, new biomarkers underlying
the etiology of HG, and interventions that may reduce adverse pregnancy outcomes (McCarthy
2014).

A recently completed randomized controlled trial comparing the effect of day care services versus
standard inpatient management on duration of hospitalization and patient satisfaction for the
initial treatment of nausea and vomiting of pregnancy, including HG, will soon publish its findings
(Clinicaltrials.gov NLM identifier: NCT00795561).

A systematic review and economic evaluation is underway in the United Kingdom to assess the
relative clinical- and cost-effectiveness of interventions for HG. The estimated completion of this
report is June 2015 (Vale 2013).

Summary of Clinical Evidence


Citation

Content, Methods, Recommendations

Reichmann
2012

OBJECTIVE: To examine the medical evidence regarding the clinical efficacy and cost-effectiveness of
the application of continuous subcutaneous metoclopramide and ondansetron to treat nausea and
vomiting during pregnancy. STUDY DESIGN: All of the published peer-reviewed articles on the subject
were assembled and assigned a level of evidence based on research design. The search uncovered one
level II matched, controlled trial and three level III uncontrolled, retrospective case series published in
peer review journals, as well as a book chapter. The book chapter, although not subjected to the peerreview process, is included in this review due to the paucity of other evidence. RESULTS: The matched
cohort trial showed that continuous subcutaneous metoclopramide is significantly less-tolerated than
continuous subcutaneous ondansetron (31.8% vs. 4.4%; P < 0.001). The four case series reported
complete symptom resolution for 63.9% to 75% of the patients. Complications arose in 24.9% to 30.5% of

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Content, Methods, Recommendations


the selected cases that were severe enough to require discontinuation of therapy. Complications included
side effects of a worsening of symptoms. All of the trials are retrospective and observational in nature
and, therefore, subject to the limitations inherent in the research design. Absent the benefit of meaningful
cohort controls, comparative statements effectiveness cannot be substantiated with the available data.
CONCLUSION: Randomized, controlled trials of sufficient power are necessary before long-term
continuous subcutaneous metoclopramide or ondansetron can be used on a widespread basis to treat
nausea and vomiting during pregnancy. Cost approximations in the case series are reported and, when
compared to the cost of other methods of treatment previously published in the medical literature, the
therapy appears to be cost-prohibitive. However, definitive statements cannot be made regarding costeffectiveness until clinical efficacy is demonstrated through a sufficiently powered, well-designed,
randomized control trial (RCT). Until such time, the therapy should remain experimental and coverage is
restricted to intractable Hyperemesis gravidarum (HG) that is unresponsive to more-conventional
treatment options.
Study

Research
design

Level of
evidence

Symptom
resolution

Symptom
improvement

Failed
therapy

Side effect
rate

Buttino
1998

301

Case
series

III

195
(64.8%)

91
(30.1%)

164
(54.5%)

Buttino
2000a

646

Cases
series

III

413
(63.9%)

NR

192

Buttino
2000b

11541

Cases
series

III

N/A

N/A

N/A

N/A

Lombardi
20042

428

Cases
series

III

382 (89.3%)

NR

167 (39%)

Klauser
2011

355
CSMT3
521CSOT3

Matched
cohort

II

NR
NR

31.8%
4.4%

NR
NR

68.2%
95.8%

N/A, not applicable; NR, not reported.


1947 (82.1%) of the patients were previously reported in the first two trials.
Two included patients receiving subcutaneous metoclopramide as well as patients moved to
continuous subcutaneous ondansetron. Reported results rendered continuous subcutaneous
ondansetron outcomes indiscernible.
Three CSMT = Continuous subcutaneous metoclopramide and CSOT = Continuous subcutaneous
ondansetron.
Naef RW,
III., et al.
(1995)

Our objective was to determine whether medical therapy in the home for patients with Hyperemesis
Gravidarum is safe, efficacious, and cost effective compared with hospitalization. In this retrospective,
matched control study 50 women with Hyperemesis were treated in the home and were matched for
gravidity, gestational age, and weight loss from prepregnancy weight with 47 patients who were
hospitalized for traditional treatment. Both groups had similar intravenous fluid and medical support until
they could tolerate adequate oral intake. Women in the home had 9.7 +/- 8.0 days of intravenous therapy
compared with 9.5 +/- 6.2 days in hospitalized patients (not significant). The mean percent of weight loss
at initiation of therapy was similar in both groups (4.6% +/- 5.7% vs 4.5% +/- 6.1%, not significant). The
mean weight change during therapy in the home group was + 1.0 +/- 4.3 pounds compared with +1.2 +/8.6 pounds in the hospitalized group (not significant). The only complication was infiltration of the

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Content, Methods, Recommendations


intravenous site, the occurrence of which was similar in the two groups (40% vs. 57%, not significant). At
discontinuation of therapy 90% of the home patients no longer required any supportive therapy; 10% (n =
5) required hospitalization because of relapse. The cost of therapy was significantly lower for patients in
the home group ($708 +/- $533 vs $2701 +/- $1717, p < 0.001). These data show that management of
Hyperemesis in the home is safe. Furthermore, successful therapy can be achieved in the home at a
significantly reduced cost.

Buttino, L.
et al.
(2000)

OBJECTIVE: To describe the use of subcutaneous (s.c.) metoclopramide in the outpatient treatment of
Hyperemesis Gravidarum. STUDY DESIGN: In a retrospective design, women who received continuous
s.c. metoclopramide for treatment of Hyperemesis Gravidarum were identified from a national database.
Data analysis included weight at start and stop of treatment, frequency of resolution of symptoms, and
side effects of medication. In addition, data were collected on adjuvant therapies. RESULTS: Between
January and December of 1997, there were 646 women with Hyperemesis Gravidarum who received
continuous s.c. metoclopramide on an outpatient basis. A total of 413 patients (63.9%) had complete
resolution of symptoms. Seventy-five percent of patients had received one or more antiemetic medications
before initiation of s.c. metoclopramide. A total of 192 patients (30.5%) reported at least one side effect
related to treatment. The majority of reported side effects was considered mild and did not require
discontinuation of s.c. metoclopramide. CONCLUSION: S.c. metoclopramide appears to be a safe,
effective treatment for Hyperemesis Gravidarum. Outpatient treatment may result in decreased costs
compared with inpatient hospitalization.

Matthews
2014

OBJECTIVES: To assess the effectiveness and safety of all interventions for nausea, vomiting and
retching in early pregnancy, up to 20 weeks' gestation and update a 2010 review. 37 trials involving 5049
women, met the inclusion criteria. These trials covered many interventions, including acupressure,
acustimulation, acupuncture, ginger, chamomile, lemon oil, mint oil, vitamin B6 and several antiemetic
drugs. We identified no studies of dietary or other lifestyle interventions. Evidence regarding the
effectiveness of P6 acupressure, auricular (ear) acupressure and acustimulation of the P6 point was
limited. Acupuncture (P6 or traditional) showed no significant benefit to women in pregnancy. The use of
ginger products may be helpful to women, but the evidence of effectiveness was limited and not
consistent, though two recent studies support ginger over placebo. There was only limited evidence from
trials to support the use of pharmacological agents including vitamin B6, and anti-emetic drugs to relieve
mild or moderate nausea and vomiting. There was little information on maternal and fetal adverse
outcomes and on psychological, social or economic outcomes. We were unable to pool findings from
studies for most outcomes due to heterogeneity in study participants, interventions, comparison groups,
and outcomes measured or reported. The methodological quality of the included studies was mixed.
AUTHORS' CONCLUSIONS: Given the high prevalence of nausea and vomiting in early pregnancy,
women and health professionals need clear guidance about effective and safe interventions, based on
systematically reviewed evidence. There is a lack of high-quality evidence to support any particular
intervention. This is not the same as saying that the interventions studied are ineffective, but that there is
insufficient strong evidence for any one intervention. The difficulties in interpreting and pooling the results
of the studies included in this review highlight the need for specific, consistent and clearly justified
outcomes and approaches to measurement in research studies.

Cochrane
review

Organization

Policy

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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

CMS
L32738 Hydration
Therapy Louisiana
(07202)
http://www.cms.gov
/medicare-coveragedatabase/details/lcd
details.aspx?LCDId=
32738&ver=21&Con
trId=250&ContrVer=
1

Indications:
The clinical manifestations of dehydration or volume depletion are related to the
volume and rate of fluid loss, the nature of the fluid that is lost, and the
responsiveness of the vasculature to volume reduction. Rehydration with fluids
containing sodium as the principal solute, preferentially expand the extracellular
fluid volume; a 1-liter infusion of normal saline may expand blood volume by
about 300 ml. In general, an imbalance of less than 500 ml of volume is not likely
to require intravenous rehydration.

These CPT codes require the direct supervision of the physician. Under
levels of supervision (see 42 CFR 410.32 (b)(3)(ii)), direct supervision in
the office setting means the physician must be present in the office suite
and immediately available to furnish assistance and direction throughout
the performance of the procedure. It does not mean that the physician
must be present in the room during the entire time the procedure is
performed.
When performed in conjunction with chemotherapy, these CPT codes are
covered only when infusion is prolonged and done sequentially (done
hour(s) before and/or after administration of chemotherapy), and when
the volume status of a beneficiary is compromised or will be
compromised by side effects of chemotherapy or an illness.

Limitations:

Rehydration with the administration of an amount of fluid equal to or less


than 500 ml is not reasonable and necessary.
These CPT codes are not to be used for intradermal, subcutaneous or
intramuscular or routine IV drug injections.
Hanging of D5W or other fluid just prior to administration of
chemotherapy (minutes) is not hydration therapy and should not be
billed with these codes.
These services may not be used in addition to prolonged service codes.
When the sole purpose of fluid administration (e.g., saline, D5W) is to
maintain patency of the access device, the infusion is neither diagnostic
nor therapeutic; therefore, these infusion CPT codes should not be billed
as hydration therapy.
Administration of fluid in the course of transfusions to maintain line
patency or between units of blood product is, likewise, not to be
separately billed as hydration therapy.
Administration of fluid to maintain line patency or flush lines between
different agents given at the same chemotherapy session is not hydration
therapy.
Infusion of saline, an antiemetic, or any other non-chemotherapy when
these drugs are administered at the same time as chemotherapy (within
minutes) should not be billed as hydration therapy with these CPT codes.
Fluid used to administer drug(s) is incidental hydration and is not
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separately payable.
Notice: This LCD imposes diagnosis limitations that support diagnosis to
procedure code automated denials. However, services performed for any given
diagnosis must meet all of the indications and limitations stated in this policy, the
general requirements for medical necessity as stated in CMS payment policy
manuals, any and all existing CMS national coverage determinations, and all
Medicare payment rules.
As published in CMS IOM 100-08, Section 13.5.1, in order to be covered under
Medicare, a service shall be reasonable and necessary. When appropriate,
contractors shall describe the circumstances under which the proposed LCD for
the service is considered reasonable and necessary under Section 1862(a)(1)(A).
Contractors shall consider a service to be reasonable and necessary if the
contractor determines that the service is:

Safe and effective.


Not experimental or investigational (exception routine costs of
qualifying clinical trial services with dates of service on or after
September 19, 2000, that meet the requirements of the Clinical Trials
NCD are considered reasonable and necessary).
Appropriate, including the duration and frequency that is considered
appropriate for the service, in terms of whether it is:
o Furnished in accordance with accepted standards of medical
practice for the diagnosis or treatment of the patients condition
or to improve the function of a malformed body member.
o Furnished in a setting appropriate to the patients medical needs
and condition.
o Ordered and furnished by qualified personnel.
o One that meets, but does not exceed, the patients medical
needs.
o At least as beneficial as an existing and available medically
appropriate alternative.

Glossary
Antiemetic A drug that is effective against nausea and vomiting.
Dehydration A condition that occurs when the loss of body fluids, mostly water, exceeds the amount
taken in.
Emetogenic Having the capacity to induce emesis (vomiting), a common property of anticancer agents,
narcotics and morphine.
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

Hyperemesis gravidarum (HG) Severe nausea and vomiting during pregnancy that can lead to loss of
weight and body fluids.
Infusion pump A medical device that delivers fluids, such as nutrient, and medications, into a persons a
body in controlled amounts. Infusion pumps are in widespread use in clinical settings such as hospitals, and
in the home.
Ketonuria A condition in which abnormally high amounts of ketones and ketone bodies are present in
the urine.
Ketosis A metabolic state that produces ketones, which are byproducts of burning fat for fuel when the
diet does not provide sufficient carbohydrate to replenish glycogen stores. Excessive ketone levels can dull
the appetite and cause nausea. Ketones that are not used for fuel are excreted the kidneys and the urine.
Microinfusion pump Microinfusion pumps (MIPs) are used to administer medications at low infusion
rates and for chemotherapy and analgesia.
NVP Nausea and vomiting of pregnancy.
Ondansetron (Zofran) A selective 5-hydroxytryptamine (3) (5-HT (3)) receptor antagonist that has been
introduced to clinical practice as an antiemetic for cancer treatment-induced and anesthesia-related
nausea and vomiting. Its use under these circumstances is both prophylactic and therapeutic.
Parenteral nutrition - Intravenous feeding.
S.C. - Subcutaneous.
Wernicke encephalopathy - A serious neurologic disorder caused by Thiamine (vitamin B-1) deficiency.

Related policies: Select Health of South Carolina Utilization Management program description.

References
Professional society guidelines/others:
ACOG (American College of Obstetrics and Gynecology) Practice Bulletin. Nausea and vomiting of
pregnancy. Obstec Gynecol. 2004 Apr;103(4):803-14. (Reaffirmed 2013).
Arsenault MY, Lane CA, MacKinnon CJ, Barbells E, Cargill YM, Klein MC, et al. The management of nausea
and vomiting of pregnancy. J Oster Gynaecol Can. 2002 Oct;24(10):817-31; quiz 32-3.
Bailit JL. Hyperemesis gravidarium: Epidemiologic findings from a large cohort. American Journal of
Obstetrics and Gynecology 2005; 193(3 Pt 1):811-4.
Goodwin TM. Hyperemesis Gravidarum. Clinical Obstetrics and Gynecology 1998; 41(3):597-605.
Peer-reviewed references:

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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

American Medical Association (AMA). 2014 ICD-9-CM for Physicians, Volumes 1 & 2, Professional Edition
(Compact). Buck CJ, editor. St. Louis, MO: Saunders, an imprint of Elsevier Inc.; 2014.
Bottomley C, Bourne T. Management strategies for hyperemesis. Best Pract Res Clin Obstet Gynaecol. 2009
Aug;23(4):549-64.
Buttino L, et al. Home subcutaneous metoclopramide therapy for Hyperemesis Gravidarum. Journal of
Perinatology 2000; 20(6):359-62.
Dodds L, Fell DB, Joseph KS, Allen VM, Butler B. Outcomes of pregnancies complicated by hyperemesis
gravidarum. Obstet Gynecol. 2006 Feb;107(2 Pt 1):285-92.
Einarson TR, Piwko C, Koren G. Prevalence of nausea and vomiting of pregnancy in the USA: a meta analysis.
J Popul Ther Clin Pharmacol. 2013;20(2):e163-70.
Fejzo MS, Macgibbon KW, Romero R, Goodwin TM, Mullin PM. Recurrence risk of hyperemesis gravidarum.
J Midwifery Womens Health. 2011 Mar-Apr;56(2):132-6.
Goodwin TM, Poursharif B, Korst LM, MacGibbon KW, Romero R, Fejzo MS. Secular trends in the treatment
of hyperemesis gravidarum. Am J Perinatol. 2008 Mar;25(3):141-7.
Kuru O, Sen S, Akbayir O, Goksedef BP, Ozsurmeli M, Attar E, et al. Outcomes of pregnancies complicated
by hyperemesis gravidarum. Arch Gynecol Obstet. 2012 Jun;285(6):1517-21.
Magee LA. The Safety and Effectiveness of Antiemetic Therapy for NVP. Available at: http://www.nvpvolumes.org/p1_11.htm. Accessed October 6, 2014.
Matthews A, Haas DM, O'Mathuna DP, Dowswell T, Doyle M. Interventions for nausea and vomiting in early
pregnancy. Cochrane Database Syst Rev. 2014;3:CD007575.
McCarthy FP, Lutomski JE, Greene RA. Hyperemesis gravidarum: current perspectives. Int J Womens Health.
2014;6:719-25.
McCullough SG, Chronis Kuhn JP, Peskin E. One HMO's experience with the management of Hyperemesis
Gravidarum. HMO Practice 1996; 10(3):143-5.
Mullin PM, Ching C, Schoenberg F, MacGibbon K, Romero R, Goodwin TM, et al. Risk factors, treatments,
and outcomes associated with prolonged hyperemesis gravidarum. J Matern Fetal Neonatal Med. 2012
Jun;25(6):632-6.
Naef RW, III, et al. Treatment for Hyperemesis Gravidarum in the home: an alternative to hospitalization.
Journal of Perinatology 1995; 15(4):289-92.
Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med. 2010 Oct 14;363(16):1544-50.
Niemeijer MN, Grooten IJ, Vos N, Bais JM, van der Post JA, Mol BW, et al. Diagnostic markers for
hyperemesis gravidarum: a systematic review and metaanalysis. Am J Obstet Gynecol. 2014 Aug;211(2):150
e1- e15.
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FC-01262015-P-001 Clinical Guideline 12.02.02 Treatments of Hyperemesis Gravidarum

Piwko C, Koren G, Babashov V, Vicente C, Einarson TR. Economic burden of nausea and vomiting of
pregnancy in the USA. J Popul Ther Clin Pharmacol. 2013;20(2):e149-60.
Reichmann JP, Kirkbride MS. Reviewing the Evidence for Using Continuous Subcutaneous Metoclopramide
and Ondansetron to Treat Nausea & Vomiting During Pregnancy. Manag Care. 2012 May;21(5):44-7.
Spruill SC, Kuller JA. Hyperemesis Gravidarum complicated by Wernicke's encephalopathy. Obstet Gynecol.
2002; 99(5 Pt 2):875-7.
Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison J. A pilot study of intravenous
ondansetron for hyperemesis gravidarum. American journal of obstetrics and gynecology
1996;174(5):1565-8.
Tan PC, Norazilah MJ, Omar SZ. Dextrose saline compared with normal saline rehydration of hyperemesis
gravidarum: a randomized controlled trial. Obstet Gynecol. 2013 Feb;121(2 Pt 1):291-8.
Vale L. Protocol for a systematic review and economic modelling of the relative clinical- and costeffectiveness of interventions for hyperemesis gravidarum. Estimated completion: June 2015. UK. Available
at: http://www.nets.nihr.ac.uk/projects/hta/1215201. Accessed August 27, 2014.
Vandraas KF, Vikanes AV, Vangen S, Magnus P, Stoer NC, Grjibovski AM. Hyperemesis gravidarum and birth
outcomes-a population-based cohort study of 2.2 million births in the Norwegian Birth Registry. Bjog. 2013
Dec;120(13):1654-60.
Veenendaal MV, van Abeelen AF, Painter RC, van der Post JA, Roseboom TJ. Consequences of hyperemesis
gravidarum for offspring: a systematic review and meta-analysis. Bjog. 2011 Oct;118(11):1302-13.
Yost NP, et al. A randomized, placebo-controlled trial of corticosteroids for Hyperemesis due to pregnancy.
Obstetrics and Gynecology 2003; 102(6):1250-4.
Ziaei S, Hosseiney FS, Faghihzadeh S. The efficacy low dose of prednisolone in the treatment of
Hyperemesis Gravidarum. Acta Obstetricia et Gynecologica Scandinavica 2004; 83(3):272-5.

Clinical Trials:
No clinical trials found specific to microinfusion of Zofran for hyperemesis gravidarum as this writing in
ClinicalTrials.gov.
Searched August 28, 2014 using term hyperemesis gravidarum | Open Studies | Exclude Unknown. 2
relevant trials found:
Comparison of Gabapentin and Ondansetron for Treating Hyperemesis Gravidarum. Hyperemesis
Gravidarum. Available at: http://ClinicalTrials.gov/show/NCT02163434.
Hiperemezis [Hyperemesis] and Serotonin Elevated Serum Serotonin Levels in Hyperemesis.
Nausea|Vomiting|Markedly Reduced Food Intake|Severe Dehydration. Available at:
http://ClinicalTrials.gov/show/NCT01987869.
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One relevant completed study:


NCT00795561. Management of Nausea and Vomiting of Pregnancy (DIM). Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00795561?term=NCT00795561&rank=1. Accessed August 28,
2014.

Centers for Medicare & Medicaid Services (CMS) National Coverage Determination
Guidance, Pub. 100-03, Chapter 1, Part 4, Section 280.14. Effective Date: November 27, 2006.
Implementation Date: November 27, 2006.
The NCD for infusion pumps at section 280.14 sets forth specific coverage criteria under sections AD. Under section B.1.f other uses of external infusion pumps are covered if the contractors medical
staff verifies the appropriateness of the therapy and the prescribed pump for the individual
beneficiary.
Local Coverage Determinations
L32738 Hydration Therapy Louisiana (07202) http://www.cms.gov/medicare-coveragedatabase/details/lcd-details.aspx?LCDId=32738&ver=21&ContrId=250&ContrVer=1.

Commonly Submitted Codes


Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not
an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill
accordingly.
CPT Code

Description

99601

Home infusion/specialty drug administration, per visit ( up to 2 hours) each


additional hour.

99602

Each additional hour.

Comment

List separately in addition to


code for primary procedure

Intravenous infusion, hydration; initial, 31 minutes to 1 hour.


96360

(Do not report 96360 if performed as a concurrent infusion service.)


(Do not report intravenous infusion for hydration of 30 minutes or less.)
Each additional hour. (List separately in addition to code for primary
procedure.)
(Use 96361 in conjunction with 96360.)

96361

(Report 96361 for hydration infusion intervals of greater than 30 minutes


beyond 1 hour increments.)
(Report 96361 to identify hydration if provided as a secondary or subsequent
service after a different initial service [96360, 96365, 96374, 96409, 96413] is
administered through the same IV access.)

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ICD-9 Code
643.00
643.03

Description
Mild hyperemesis gravidarum; starting after nine (9) weeks of gestation.
Mild hyperemesis gravidarum, antepartum condition or complication.

643.10

Hyperemesis gravidarum with metabolic disturbance, unspecified as to


episode of care or not applicable.

643.13

Hyperemesis gravidarum with metabolic disturbance, antepartum condition or


complication.

ICD-10 Code
HCPCS
Level II
J2405
J2765

Comment

Description

Comment

Description

Comment

Injection, Injection,(Zofran) ondansetron hydrochloride, per 1 mg.


Injection, Reglan (metoclopramide HCl), up to 10 mg.

E0779

Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or


greater.

E0780

Ambulatory infusion pump, mechanical, reusable, for infusion less than 8


hours.

E0781

Ambulatory infusion pump, single or multiple channels, electric or battery


operated, with administrative equipment, worn by patient.

S9351

Home infusion therapy, continuous or intermittent antiemetic infusion therapy;


administrative services, professional pharmacy services, care coordination,
and all necessary supplies and equipment (drugs and nursing visits coded
separately), per diem.

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