Hindawi Publishing Corporation
Obstetrics and Gynecology International
Volume 2012, Article ID 252676, 8 pages
Reviewof NVP andHG andEarly Pharmacotherapeutic
ShannonM. Clark,Maged M.Costantine,andGaryD.V.Hankins
Division of MFM, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Boulevard,
Galveston, TX 77555, USA
Correspondence should be addressed to Shannon M. Clark, firstname.lastname@example.org
Received 30 August 2011; Revised 15 October 2011; Accepted 15 October 2011
Academic Editor: Gideon Koren
Copyright © 2012 Shannon M. Clark et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
NVP occurs in 50–90% of pregnancies, making it a common medical condition in pregnancy. Women present differently with
any combination of signs and symptoms. It is appropriate to take the pregnancy-related versus nonpregnancy-related approach
when determining the cause of nausea and vomiting but other causes should be considered. The most common etiologies for
NVP include the hormonal changes associated with pregnancy, the physiologic changes in the gastrointestinal tract, and a genetic
predisposition. Up to 10% of women will require pharmacotherapy to treat the symptoms of NVP despite conservative measures.
ACOG currently recommends that a combination of oral pyridoxine hydrochloride and doxylamine succinate be used as first-
line treatment for NVP if pyridoxine monotherapy does not relieve symptoms. A review of NVP and early pharmacotherapeutic
management is presented due to the fact that NVP is largely undertreated, and investigations into the safe and effective
pharmacotherapies available to treat NVP are lacking.
Nausea and vomiting in pregnancy (NVP) is a very common
and oftentimes difficult medical condition to manage in
pregnancy. The spectrum of disease ranges from a limited,
mild to moderate course that resolves with conservative
treatment or with the addition of an antiemetic to a severe,
prolonged course requiring multiple triage visits and/or
hospital admissions and pharmacotherapy. Determining the
appropriate intervention while keeping fetal exposure in
mind can make management of the patient challenging. Fur-
thermore, while early recognition and treatment of symp-
toms is ideal, communication between the pregnant woman
and her heath care provider is often lacking, allowing for
progression of symptoms. A review of NVP and early phar-
macotherapeutic management is needed due to the fact that
NVP is largely undertreated, and there is a lack of investiga-
tion into the safe and effective pharmacotherapies available
to treat NVP. This allows pregnant women to be orphaned
from the benefits of existing knowledge. As a result, review
of NVP is presented here, along with recommendations for
early pharmacotherapeutic management.
NVP occurs in 50–90% of pregnancies, with nausea and
vomiting in approximately 50–55% and nausea alone in 25%
[1–7]. Although NVP has been commonly referred to as
“morning sickness,” nausea can occur at any time of the
day, last for varying periods of time, and occur with or
without episodes of vomiting. The usual onset for NVP is
between 4–9 weeks gestational age, with maximal symptoms
at 12–15 weeks, and resolution by 20 weeks gestational age
[1, 4, 8]. There are a small percentage of pregnant women
beyond 20 weeks gestational age and even throughout the
remainder of the pregnancy [8, 9]. Although this particular
group of women may indeed comprise a small percentage
with prolonged symptomatology, they present a clinical
dilemma with a great amount of time and effort utilized
to rule out other potential causes of their nausea and
2Obstetrics and Gynecology International
vomiting. Overall, NVP typically follows a usual course with
management consisting of conservative measures to hos-
pitalization for more acute management.
HG occurs in 0.3–3% of pregnancies and is typically
defined as severe and persistent nausea and vomiting with or
without retching, with a loss of 5% or more of prepregnancy
body weight, electrolyte abnormalities, ketonuria, dehydra-
tion, and potential vitamin or mineral deficiencies (i.e.,
thiamine) [1–7]. These patients often require multiple triage
visits for intravenous fluid hydration and antiemetics, with
inpatient admission in the more severe cases. A prolonged
hospital stay with a trial of multiple pharmacotherapies,
supplementation of intravenous fluids is typically required,
with the addition of thiamine to avoid the development
of Wernicke’s encephalopathy . The decision to admit
a patient for the treatment of NVP or HG is subjective.
However, any woman who is ketotic and dehydrated should
be hospitalized not only for treatment but to explore any
other potential causes for nausea and vomiting. HG can
precipitate from NVP that has been neglected or under-
treated. As a result, early recognition and inquiry regarding
symptoms by the health care provider is essential.
Although each woman with NVP can present differently, the
symptoms predominantly include any combination of the
following: nausea, gagging, retching, dry heaving, vomiting,
and odor and/or food aversion [11–13]. Each woman usually
has a certain precipitating factor that triggers the nausea
and vomiting, that is, movement-induced, heartburn, food
and/or odor triggers . During initial history taking,
questioning on the onset, timing, severity, and aggravating
and alleviating factors may point to another cause for the
nausea and vomiting. This information is also helpful when
formulating a treatment plan. One of the most important
aspects of the history is the duration of vomiting in order to
assess the potential risk for Wernicke’s encephalopathy due
to thiamine deficiency.
If the diagnosis of HG is made, the patient should be
evaluated for urinary ketones, BUN, creatinine, aspartate
aminotransferase (AST) and alanine aminotransferase
(ALT), amylase, and electrolytes . Thyroid stimulating
hormone (TSH) and free T4 (FT4) should also be checked
as human chorionic gonadotropin (hCG) cross-reacts with
thyrotropin and stimulates the thyroid gland . As a
result, thyrotropin is typically lower in these patients. In
fact, the values of TSH and FT4 in patients with HG may
be similar to that seen in Graves’ disease, but without the
clinical symptoms and findings of Graves’ disease or thyroid
antibodies . This form of hyperthyroidism usually re-
solves without treatment by 20 weeks gestational age, and
management of nausea and vomiting until then is as in-
The vomiting observed with NVP and HG can be
quantified with a scoring system, the Pregnancy-Unique
Quantification of Emesis scale (PUQE) . Similar to
the Rhodes Scale used for the assessment for nausea and
vomiting in patients receiving chemotherapy, the PUQE
of pregnancy [17, 18]. The 12 hour PUQE scoring system
assesses the severity of NVP by focusing on the number of
hours of nausea and the number of episodes of retching
and vomiting, as well as an overall well-being score in the
12 hours immediately before assessment . The 24 hour
PUQE scoring system, validated in 2009, was subsequently
ing the time spent sleeping and the severity of symptoms
throughout the first trimester [20, 21]. The PUQE scoring
system has a minimum score of 3 and maximum score of
15 with a score of <6 suggesting mild HG, 7–12 moderate,
and >13 severe NVP. This scoring system has been validated
hospitalization and women’s subjective feelings of well-being
. There is also a well-being score of 0 (the worst possible)
to 10 (the best possible), which is a general self-perception
score of physical and psychological health and a question on
the amount of sleep including naps in a 24 hour period of
qualify and quantify the nausea and vomiting, but to follow
the response to treatment and improvement over time.
Regardless of when the patient presents, it cannot be
assumed that nausea and vomiting is due to NVP. It is
more appropriate to take the pregnancy-related versus
nonpregnancy-related approach when determining the eti-
ology. More often than not, if the patient initially presents
and physical exam is still required to elicit any potential
contributing or confounding factors at any gestational age.
If the diagnosis of NVP or HG is made, but there is poor
response to initial interventions, an atypical presentation, or
initial presentation after 9–10 weeks, other causes must be
explored [3, 4, 6, 7]. Table 1 lists other potential causes of
nausea and vomiting in pregnancy. If there is fever, a source
of infection should be sought or if the history suggests a CNS
abnormality, check for signs of raised intracranial pressure
. Specific signs such as peritoneal signs, RUQ pain,
or jaundice should raise the suspicion for acute abdomen,
preeclampsia, and acute fatty liver of pregnancy, respectively
. In addition, headache with nausea and vomiting can
occur with dehydration, but preeclampsia should still be
ruled out, especially if there is elevated blood pressure.
Although epigastric pain and hematemesis is rare, if this is
observed, a Mallory Weiss tear from prolonged vomiting or
gastrointestinal ulcer may be the cause. Finally, heartburn
and gastric reflux occurs in a significant number of pregnant
women, and appropriate recognition and treatment of this
particular condition may improve symptoms quite rapidly.
Prolonged nausea and vomiting in the setting of NVP or
HG can lead to maternal vitamin deficiencies. As mentioned
above, Wernicke’s encephalopathy is a potential serious or
fatal maternal complication and is due to severe vitamin
B1 (thiamine) deficiency. Approximately 47% of patients
with this condition will present with a history of prolonged
nausea and vomiting along with the triad of abnormal ocular
Obstetrics and Gynecology International3
Table 1: Differential diagnosis of NVP.
H. pylori infection
Urinary tract infection
Acute fatty liver of pregnancy
Gastroesophageal reflux disease
movements, ataxia, and confusion; an additional percentage
will also have diplopia [22, 23]. Symptoms can also be
more variable and include memory loss, apathy, decreased
level of consciousness, or blurred vision . Although
this condition is reversible with prompt treatment, 60% of
loss rate . Because maternal serum thiamine levels are
not useful in making the diagnosis, any pregnant woman
who presents with prolonged nausea and vomiting and
neurologic abnormalities should be empirically treated with
intravenous thiamine. Deficiencies in vitamins B6 and B12
are rare and not as potentially serious, but can cause anemia
and peripheral neuropathy associated with hematemesis,
malnutrition, and psychological effects . Vitamin K de-
ficiency and coagulopathy can also occur, leading to an
abnormal coagulation profile and bleeding .
One consequence of NVP and HG that is commonly ne-
glected, especially when the focus is on treatment, is the
psychosocial impact of this disorder. NVP can adversely
affect family and social life, physical and mental health,
This can range from missing days of work to termination
of the pregnancy due to severe symptoms. Up to 25% of
pregnant women have to change their normal daily activities
due to symptoms . In addition, these women have
lower physical and social functioning and miss more days of
which can make management of the patient more com-
plicated. Koken et al. investigated the association between
depression and anxiety in early pregnancy, and nausea and
vomiting in a cross-sectional study of 230 women using
the Hospital Anxiety and Depression Scale as a measure of
anxiety and depression, and the Rhode’s System for nausea
score and both anxiety and depression scores was found.
Gestational age showed an inverse correlation with anxiety
scores. They also found an association between anxiety and
depression in early pregnancy and severity of NVP. They
concluded that recognizing depression in the early stages of
pregnancy might be a key step in assisting the mother. As a
and address the psychological situations of the patient .
Depression and anxiety can contribute to and confound the
symptoms of NVP and render treatment more challenging.
4.Etiology andRisk Factors
to the hormonal changes that occur during pregnancy
involving hCG, estrogen, progesterone, and thyroid hor-
mones. These hormone levels change throughout pregnancy
with the most marked changes occurring during the first
trimester [29, 30]. Because hCG and TSH have a similar
biomolecular structure, conditions that are associated with
an increase in hCG or hyperthyroidism may result in more
severe NVP or HG [29, 30]. Several studies have shown
a significantly higher level of serum hCG in HG patients
than in controls . This is further supported by the peak
incidence of HG occurring when the trophoblast is most
actively producing hCG. As a result, in pregnancies with
increased placental mass, that is, multiple gestations and
molar pregnancy, there is an increased incidence of HG [31–
thyroid function tests (TFTs) . Physiologic stimulation
of the thyroid gland is common in early pregnancy due
to the structural similarity between hCG and TSH, as
previously stated . In fact, it is recommended that
TFTs be obtained with the initial workup of nausea and
vomiting. Although, the TFTs may be abnormal, treatment
is not typically indicated as the TFTs will normalize as the
The physiologic changes in pregnancy notably involve
the gastrointestinal (GI) tract. Not only is the GI tract an-
atomically affected by the enlarging uterus, but it is also
affected by the hormonal influences during pregnancy.
Changes within the GI tract include gastric dysrhythmia
(tachygastria or bradygastria or both) or gastroparesis and
abnormalities in gastric neural activity and smooth muscle
function . This is predominantly due to the influences of
progesterone and estrogen on the GI tract. In addition, the
enlarging uterus and displacement of the abdominal organs
can lead to adjustment of the gastroesophageal junction and
reflux or nausea and vomiting. These changes in the GI tract
are more significant in women with preexisting GI disease
including diabetic gastroparesis, gastroesophageal reflux
disease (GERD), gastric bypass surgery, and inflammatory
bowel disease, potentially resulting in more severe symptoms
[35–37]. If the patient has a preexisting GI condition, the
approach to management and potential pharmacotherapeu-
Helicobacter pylori (H. Pylori) is a gram-negative flag-
ellated spiral bacterium found in the stomach. It has long
been established that prolonged infection with this organism
causes chronic gastritis, duodenal and gastric ulceration, and
gastric cancer. It is commonly treated with triple therapy
consisting of two antibiotics and a proton pump inhibitor or
H2 blocker . More recently, H. pylori infection has been
associated with more severe HG and NVP, with some studies
showing a higher incidence of infection with H. pylori in
women with HG than in normal pregnant controls . In
4 Obstetrics and Gynecology International
by Sandven et al. examining the association between H.
pylori infection and HG, 25 case-control studies were iden-
tified . They found that exposure to H. pylori is as-
sociated with an increased risk of HG. Another study by
Guven et al. investigated the relationship between H. pylori
infection and HG in early pregnancy through serologic and
stool antigen tests in a prospective cross-sectional study
on 40 women with HG and 40 controls at 7–12 weeks of
pregnancy . They found that the rate of serology-specific
H. pylori IgG positivity was 80% in subjects with HG and
35% in controls—a significant difference. There was also a
significant difference in the rate of H. pylori stool antigen
test positivity, with a rate of 87.5% in subjects with HG
and 62.5% in controls. They concluded that both serologic
and stool antigen testing were good screening methods to
identify those subjects in early pregnancy with H. pylori
infection and HG . If a patient presents with excessive
symptoms of nausea and vomiting that persist beyond the
second trimester, greater or longer than expected symptoms
of nausea and vomiting and/or weight loss, testing for the
presence of H. pylori may be indicated .
Much attention has been given to the role that genetics
plays in the development and severity of NVP and HG.
Not only are NVP and HG likely heritable diseases, but the
severity of the disease appears to be associated with a genetic
predisposition . It appears that women are at the greatest
risk if their mother or sister had NVP or HG, or if the
patient herself had severe disease in a previous pregnancy
[4, 33]. In a study by Fejzo et al. 2008, the prevalence of
severe NVP and HG among relatives of affected individuals
was explored . 1224 self-reported cases of HG along with
their family histories were used for the purpose of the study.
Hyperemesis Education and Research Foundation between
2003 and 2006. Approximately 28% of cases reported that
their mother had severe NVP or HG while pregnant with
them and of the 721 sisters with pregnancy history, 137
(19%) had HG. In severe cases requiring total parenteral
nutrition (TPN) or nasogastric tube (NGT) feeds, the
proportion of affected sisters was 25% . With these re-
sults, strong preliminary evidence for a genetic component
to extreme NVP or HG was established.
Several risk factors have been associated with NVP and
HG, with the most recognized being multiple gestation,
molar pregnancy, positive family history. It also appears that
women. In those who have NVP later in pregnancy (after 20
weeks), the women are older, have higher parity and BMI,
and are more likely to develop gestational diabetes .
Factorsthat worsen NVP include stress, lack of sleep, chronic
H. pylori infection, peptic or duodenal ulcers, migraines
[25, 44]. Prenatal vitamins are often cited by women as
initiating exacerbating symptoms of NVP and HG . A
study by Louik et al. in 2006 investigated the potential risk
factors for NVP occurrence, time of onset, and duration of
disease . They found that the overall risk of NVP was
67%, with the risk, timing of onset, and duration of NVP
nearly identical for mothers of both normal and malformed
Table 2: Early pharmacotherapies for NVP/HG.
Pyridoxine hydrochloride monotherapy 10–25 mg po tid-qid
-or-Pyridoxine hydrochloride 10–25mg po tid or qid plus Doxy-
lamine succinate 25mg 1/2 tablet po tid-qid
-or-Diclectin (pyridoxine hydrochloride 10mg plus doxylamine
succinate 10mg) 4 tablets qd given 1qam, 1 at lunch, and 2qhs
with a maximum of 8–12 tablets qd if increased BMI
Dimenhydrinate 50–100mg po/iv q 4–6 hours
Promethazine 12.5–25mg po/iv/pr q 4–6 hours
Metoclopramide 5–10mg po/iv tid
Ondansetron 4–8mg iv/po tid
infants. They also found that younger women, multiparas,
and multiple gestations had increased risk for NVP. They
did not find an association between NVP and increased
prepregnancy weight, black race, or low education, or sex of
the infant. Finally, a longer duration of NVP increased with
were more likely to be less educated and have lower incomes
It is estimated that up to 10% of women will require
pharmacotherapy to treat the symptoms of nausea and
vomiting despite changes in lifestyle and nutrition [15, 47].
The American College of Obstetricians and Gynecologists
(ACOG) currently recommends that a combination of oral
pyridoxine hydrochloride (vitamin B6) and doxylamine
succinate be used as first-line treatment for NVP if pyri-
doxine monotherapy does not relieve symptoms (Table 2)
. Pyridoxine is a water soluble vitamin that is involved
in the metabolism of amino acids, lipids, and carbohydrates
. Doxylamine is a histamine-1 (H1) receptor antagonist
marketed in the USA as Unisom Night Time Sleep Aid
(25mg) that is typically given with pyridoxine. Doxylamine
directly inhibits the action of histamine at the H1-receptor,
acts indirectly at the vestibular system, and exhibits some
inhibition of muscarinic receptors to decrease stimulation
of the vomiting center [49, 50]. Although these medications
are available individually over-the-counter in the United
States (USA), in Canada the combination is available as
Diclectin (Duchesnay, Inc., Lava QC, Canada), a sustained-
release formulation of 10 mg of pyridoxine and 10 mg
doxylamine . It is currently recommended that 4 tablets
of Diclectin be given a day. This dosage can be adjusted for
severity of symptoms and/or maternal BMI. If the patient
has a higher BMI, she may take up to 8–12 tablets a day
without increasing maternal adverse effects, fetal risk, degree
of tiredness, and birth defects . These higher doses
appear to be more efficacious. As symptoms improve and
recurrence of symptoms .
Obstetrics and Gynecology International5
The combination of pyridoxine and doxylamine has the
most data on safety and efficacy, including data in the
first trimester [4, 7, 52, 53]. It was originally available in
both the USA and Canada as Bendectin, a delayed-release
combination of doxylamine and pyridoxine. Bendectin had
a similar formulation to Diclectin in that they contained
the same active ingredients, but Diclectin utilizes modern
manufacturing technology for a delayed-release tablet .
Bendectin was removed from the US market in 1983 due
to allegations of teratogenicity, including fetal heart and
limb reduction defects [1, 13, 55]. This left no available
FDA-approved medication for the treatment of NVP in the
USA Since its removal from the US market, the incidence
of hospitalization for HG has increased 2-3-fold while the
available, that is, namely Canada and Europe, and the rate of
birth defectsin the USA hasnot changed since its withdrawal
[1, 4, 56, 57]. Despite the controversy and the fact that it
is no longer available, Bendectin is still the most studied
drug in pregnancy and no evidence shows a relationship
between Bendectin use in the first trimester and congenital
anomalies . In Canada, Diclectin has been associated
with a decreased incidence of hospitalization for NVP in
observational studies [57, 59]. Furthermore, the combina-
tion of over-the-counter oral vitamin B6 and Unisom in the
USA has been studied in over 6000 patients and controls
with no evidence of teratogenicity, and in randomized trials
it has been associated with a 70% reduction in nausea and
vomiting [4, 60]. Many case-control and cohort studies,
including over 170000 exposures, have demonstrated the
safety of doxylamine and pyridoxine .
Despite the fact that allegations of teratogenicity have
been unsubstantiated, no randomized controlled trial on the
effectiveness of Diclectin for the treatment of NVP had been
done in order to support its reintroduction back into the US
market until recently. In 2010, Koren et al. took this first step
by evaluating the effectiveness of Diclectin as compared with
placebo for NVP in a randomized, double-blind, multicenter
133) or placebo (n = 128) for 14 days, with symptoms
of NVP evaluated using the 2-part PUQE score (clinical
and quality of life). The subjects were instructed to take
two tablets of Diclectin at bedtime on Day 1. If symptoms
persisted into the afternoon of Day 2, the subject was
an additional tablet in the morning of Day 3. If assessment of
evening symptoms, a fourth tablet was added in the mid-
afternoon. The minimum dosage was 2 tablets at bedtime
and the maximum was 4 tablets a day. Results showed
that women receiving Diclectin had a significant greater
improvement in symptoms when compared to placebo when
considering the PUQE score and assessment of quality of
life from day 1 to 15, as well as in day-to-day improvement
in symptoms and well-being. In addition, approximately
48.9% of women opted to continue compassionate use of
Diclectin in comparison to 32.8% of placebos, and women
receiving placebo were 50% more likely to report use of
alternative therapies to relieve symptoms when compared to
with an increased risk of any adverse effects when compared
to placebo. They concluded that Diclectin delayed-release
formulation was both effective and well tolerated in the
treatment of NVP.
After initiating treatment of NVP with a combination
of doxylamine and pyridoxine, breakthrough nausea and
vomiting can be treated with the addition of a different an-
tihistamine or a dopamine antagonist. Dimenhydrinate is
an H1-receptor antagonist that is widely used for the
treatment of NVP. In addition, it is often useful to initiate
treatment with an H2-receptor antagonist as their safety and
efficacy are evident when using these agents for treating
the reflux and heartburn symptoms associated with NVP
. Cimetidine, ranitidine, or famotidine are H2-receptor
blockers that can be used especially if the patient has a
history GERD, gastroduodenal ulcers, or other GI disease.
Another second-line choice of therapy for NVP and HG in
addition to dimenhydrinate is promethazine. Promethazine
belongs to a class of dopamine (D2) receptor antagonists
called phenothiazines that exhibit antiemetic properties by
inhibiting gastric motility through the D2 receptors located
in the GI tract and by inhibiting the chemoreceptor trigger
zone [23, 49, 50]. Numerous human and animal studies,
including those in the first trimester, show a lack of associa-
tion between the use of promethazine during pregnancy and
an increased risk for malformations . Metoclopramide
is another dopamine receptor antagonist that works as both
an antiemetic and prokinetic by decreasing gastrointestinal
emptying time and acting on the central chemoreceptor
trigger zone [15, 23, 50]. Metoclopramide is particularly
are factor, that is, diabetic patients . Both promethazine
of dehydration when antihistamines fail to treat the nausea
and vomiting. Although data is limited, no animal or human
studies have shown an increased risk for birth defects in
animals and humans with these dopamine receptor antago-
nists. Matok et al. investigated the safety of metoclopramide
during the first trimester in a retrospective cohort study of
3458 infants exposed to metoclopramide . They found
that exposure to metoclopramide in the first trimester was
not associated with a significantly increased risk of adverse
outcomes, including major congenital malformations, low
birth weight, preterm delivery, and perinatal death.
Serotonin 5-hydroxytryptamine3-receptor (5-HT3) an-
tagonists have been primarily used for the treatment of
chemotherapy-induced nausea and vomiting. However, the
use of ondansetron for NVP and HG is widely accepted.
5-HT3 antagonists as a third-line pharmacotherapeutic
intervention for NVP and HG, ondansetron is commonly
used earlier in treatment due to less sedating effects when
compared to promethazine . Ondansetron works both
centrally and peripherally at the 5-HT3 receptors located
in the small bowel, vagus nerve, and at the chemoreceptor
trigger zone, resulting in decreased stimulation of the
its use in pregnancy, data to date have been favorable. There
6 Obstetrics and Gynecology International
has been no evidence of teratogenicity in animal studies even
at doses significantly higher than that used in humans or
in case reports of use in the first trimester [63–65]. In
a prospective comparative observational study involving 169
infants exposed to ondansetron in the first trimester, 3.6%
had major malformations, which was not significantly dif-
ferent from the rates in 2 control groups .
Although NVP and HG are two of the most common
medical conditions of pregnancy, management can be very
challenging for the clinician. Not only is appropriate diag-
nosis essential in order to initiate treatment, but timing of
diagnosis is just as crucial to avoid delay in management.
There are multiple pharmacotherapies available today, and
each treatment regimen should be tapered to the particular
patient. Due to the favorable effectiveness and safety profiles
of the over-the-counter combination of pyridoxine and dox-
ylamine in the USA and Diclectin in Canada, initiation with
these medications early on is reasonable and recommended.
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