REFERAT

HYPEREMESIS GRAVIDARUM

Preceptor :
dr. Sigit P. Diptoadi, Sp.OG
Written by :
Gita Puspita Anjani (2014-061-152)
Anastasia Michelle (2014-061-155)
Michael Irawan (2014-061-156)
Cindy Feronica (2015-061

KEPANITERAAN KLINIK ILMU KEBIDANAN DAN PENYAKIT KANDUNGAN

FAKULTAS KEDOKTERAN UNIKA ATMA JAYA

Periode

KATA PENGANTAR
Puji dan syukur penulis panjatkan ke hadirat Tuhan Yang Maha Esa, karena atas berkat
dan rahmat-Nya penulis dapat menyelesaikan referat ini sesuai waktu perencanaanya. Penulis
juga berterima kasih kepada semua pihak yang telah membantu penyusunan karya tulis ilmiah
ini, terutama kepada:
1. Dr. dr. Surilena Hasan, Sp.KJ (K) selaku dosen pembimbing utama. Terima kasih untuk
waktu, bimbingan, dan nasihat yang diberikan selama proses penyusunan referat ini.
2. Semua Dokter tim Departemen Jiwa Rumah Sakit Khusus Daerah Duren Sawit.
3. Orang tua, sanak saudara, dan teman-teman penulis yang telah memberikan dukungan
moral dan spiritual selama proses penyusunan referat ini.
4. Serta seluruh pihak yang telah membantu yang tidak dapat penulis sebutkan satu per satu.
Dalam pembuatan referat ini, penulis menyadari masih banyak kekurangan dan
kelemahan akibat terbatasnya kemampuan penulis. Oleh karena itu, dalam kesempatan ini
penulis sangat mengharapkan adanya kritik dan saran yang membangun dari pembaca demi
menyempurnakan referat ini.
Akhir kata, penulis berharap referat ini dapat menjadi referensi yang bermanfaat bagi
para pembaca.
Jakarta,

20

Oktober

2016

Penulis

SECTION I
INTRODUCTION

1.1. BACKGROUND
Nausea and vomiting during pregnancy is a common symptoms that affect 50% to
90% of all women. Nausea and vomiting are usually limited to the first trimester, but 20%
of women have symptoms that continue throughout their pregnancy. The spectrum of
nausea and vomiting in pregnancy can range from mild to severe and can involve persistent
and excessive vomiting.1
Hyperemesis gravidarum (HG) is the most severe form of nausea and vomiting in
pregnancy and is characterized by intractable nausea and vomiting that leads to
dehydration, electrolyte and metabolic disturbances, and nutritional deficiency that may
require hospitalization. Hyperemesis gravidarum has also been defined as severe vomiting
with onset at less than 16 weeks of estimated gestational age.1
Women with Black or Asian ethnicity, of young age, carrying multiple babies or
singleton females, with Type 1 diabetes or with a history of HG were previously reported
to be at higher risk of developing HG; however, most evidence is from small studies. Little
is known about associations with other comorbidities and there is controversy over other
risk factors such as parity. Estimates of HG prevalence vary and there is a little
understanding of the risks of HG readmission in a current pregnancy and reoccurrence
rates in subsequent pregnancies, all of which are needed for planning measures to reduce
onset or worsening of the condition. 2
Hyperemesis gravidarum has an incidence varying from 0.3% to 2% of all
pregnancies. Studies have found an admission rate of 0.8% for hyperemesis gravidarum
and an average of 1.3 hospital admissions per hyperemesis patient, with an average
hospital stay of 2.6-4 days. 3
Hyperemesis Gravidarum is the most common cause of hospitalization in the first
half of pregnancy and is second only to preterm labor for pregnancy overall. Hyperemesis
gravidarum can make a clinical and social impact, and that can be immense. The

socioeconomic impact of the complete spectrum of nausea and vomiting of pregnancy on

time lost from either paid employment or household work is substantial. 1
Hyperemesis Gravidarum can leads to

significant weight loss, malnutrition,

dehydration, dysionemia, and ketonuria. HG contributes to over 375,000 ER/hospital

discharges in the US annually, and

is associated with morbidity such as

pneumomediastinum, renal failure, liver dysfunction, Boerhaaves syndrome, and

Wernickes encephalopathy. HG is

also associated with an increased risk of adverse

outcome including Wernickes encephalopathy, low birth weight, neurodevelopmental

disorders, intrauterine growth restriction, preterm delivery, and fetal and neonatal death. 4
Hyperemesis gravidarum occurs in 0.5-2% of pregnancies, with the variation in incidence
arising from different diagnostic criteria and ethnic variations. 3
Because the high incidence of hyperemesis gravidarum with a lot of impacts in
maternal and fetal, we made these study that will discuss about the etiology, risk factors,
pathophysiology, how to diagnose, and manage hyperemesis gravidarum.

1.2. OBJECTIVES
The purpose of these study is to determine:
1.
2.
3.
4.
5.

Etiologies of hyperemesis gravidarum

Risk factors that can induced hyperemesis gravidarum
The pathophysiologies of hyperemsis gravidarum
How to diagnose hyperemesis gravidarum
How to manage hyperemesis gravidarum

SECTION II
CONTENTS

2.1.

HYPEREMESIS GRAVIDARUM
Hyperemesis Gravidarum is defined as severe unrelenting nausea and vomiting
and defined variably as being sufficiently severe to produce weight loss, dehydration,
ketosis, alkalosis from loss of hydrochloric acid, and hypokalemia. In an attempt to
quantify nausea and vomiting severity, Lacasse and colleagues (2008) have proposed a
pregnancy unique quantification of emesis and nausea (PUQE) scoring index. Other
causes should be considered because hyperemesis gravidarum is a diagnosis of
exclusion.4

2.2.

RISK FACTOR
Various risk factors have been theorized to be associated with HG. These include

increased body weight, multiple gestations, trophoblastic disease, HG in a prior

pregnancy, and nulliparity. In contrast, a decreased risk of HG has been associated with
advanced maternal age and cigarette smoking. Also, metabolic disorders associated with
HG could possibly contribute to an increased risk, including hyperthyroidism,
hyperparathyroidism, altered lipid metabolism, and liver dysfunction.1
Hyperthyroidism has been found to be associated with HG. Decreased thyroid
stimulating hormone (TSH) has been found in patients with HG while levels of free T3
and free T4 have remained within normal limits. It is thought that there may be a
condition known as transient hyperthyroidism of hyperemesis gravidarum (THHG),
which is a self-limiting hyperthyroidism occurring in the context of HG. Another
associated risk factor for hyperemesis gravidarum may be a previous diagnosis of an
eating disorder. Studies have found that occurrence of HG is greater in women with
eating disorders, such as bulimia, than in controls.1

2.3.

ETIOLOGY AND PATHOPHYSIOLOGY

The etiopathogenesis of hyperemesis gravidarum is likely multifactorial. One

popular theory is that nausea and vomiting of pregnancy is related to trophoblastic

activity and gonadotropin production, possibly secondary to elevated serum human
chorionic gonadotropin (hCG) levels. Schoeneck, in the early 1940s, noted that
women with nausea and vomiting of pregnancy had higher concentrations of
urinary hCG than asymptomatic pregnant women. How hCG could cause HG remains

unclear, but proposed mechanisms include a stimulating effect on the secretory processes
in the upper gastrointestinal tract (GIT) or by stimulation of thyroid function because of
its structural similarity to thyroid stimulating hormone (TSH). 5 It also appears to be
related to high or rapidly rising serum levels of other pregnancy-related hormones such as
estrogens, progesterone, leptin, placental growth hormone, prolactin, thyroxine, and
adrenocortical hormones.
The other factors that related to this is biological factor and environmental factor.
In some cases, interrelated psychological components play a major role. There is other
factor that increases the risk for admission such as hyperthyroidism, previous molar
pregnancy, diabetes, gastrointestinal illnesses, some restrictive diets, and asthma and
other allergic disorders.4 Many physicians were thought that psychologic factors are
responsible for nausea and vomiting of pregnancy and hyperemesis gravidarum. In one
well known study, the Cornell Medical Index was administered to 44 pregnant woman
with hyperemesis and 49 pregnant woman without hyperemesis. The pregnant women
with hyperemesis were taking the Minnesota Multiphasic Personality Inventory (MMPI)
and the MMPI data suggested that women with hyperemesis have hysteria, excessive
dependence on their mother, and infantile personalities. However, the study findings were
not conclusive because comparative testing was not performed. Zechnich and Hammer
reported, pregnant women have been shown to have a significantly higher level of
anxiety than nonpregnant women and are known to be readily influenced by
suggestion and by reassurance. Other authors have suggested that HG has been linked
to stress and emotional tension and is found more commonly among immature,

dependent, hysteric, depressed, or anxious women, although this has not been
studied.
Gastrointestinal tract dysfunction also has been suggested as a cause of nausea and
vomiting of pregnancy. In one study, in which progesterone was prescribed to
nonpregnant women, resultant nausea and vomiting suggested that delayed gastric
motility caused by progesterone may be responsible for the condition. Another study said
that potential gastro intestinal causes of nausea and vomiting during pregnancy was the
abnormalities of gastric electrical rhythm (Gastric Dysrhytmias). A recent study
suggested that chronic infection with Helicobacter pylori may play a role in hyperemesis
gravidarum. In this study, 61,8% of pregnant women with hyperemesis were found to be
positive for the H. pylori genome, compared to the 27,6% of pregnant women without
hyperemesis.6
Hyperthyroidism has been found to be associated with HG. In fact, decreased
thyroid stimulating hormone (TSH) has been found in patients with HG while levels of
free T3 and free T4 have remained within normal limits. It is thought that there may be a
condition known as transient hyperthyroidism of hyperemesis gravidarum (THHG),
which is a self-limiting hyperthyroidism occurring in the context of HG. It has been
suggested that the high incidence of transient hyperthyroidism in HG patients is caused
by elevated circulating HCG levels, thyroid hormone receptors hypersensitive for HCG or
the production of a type of HCG that is more potent in stimulating the thyroid gland.
Diagnosis of THHG rests on the following four criteria: (1) abnormal thyroid function
tests developing in the context of hyperemesis gravidarum, (2) no evidence of

prepregnancy hyperthyroidism, (3) absence of physical examination findings consistent

with hyperthyroidism, and (4) negative thyroid antibody titers.

2.4.

DIFFERENTIAL DIAGNOSIS
A thorough history and a complete physical examination are important in the
evaluation of pregnant women who present with persistent vomiting. Nausea and
vomiting in early pregnancy is usually a self-limited condition. When the condition is
more severe, potentially serious causes need to be ruled out.
If the findings of the history and the physical examination suggests a specific
cause, testing is directed toward confirming that cause. Ultrasonography may be helpful
in ruling out gallbladder, liver, and kidney disorders. In addition to hyperemesis
gravidarum, pregnancy-related causes of persistent vomiting include acute fatty liver and
preeclampsia. Non-pregnancy related causes include gastrointestinal, genitourinary,
metabolic, and neurologic disorders.6

2.5.

COMPLICATIONS

Vomiting may be prolonged, frequent, and severe, and there is a list of potentially
fatal complications. Various degrees of acute kidney injury from dehydration are
encountered. Complications from continuous retching include a Mallory-Weiss tear.
Others

are

pneumothorax,

pneumomediastinum,

diaphragmatic

rupture,

and

gastroesophageal rupture (Boerhaave Syndrome).7

In more sever cases, plasma Zinc levels are increased, copper levels decreased,
and magnesium levels unchanged. Two serious vitamin deficiencies have been reported
with hyperemesis in pregnancy. The first one is Thiamine (Vitamin B1) deficiencies that
results in Wernicke encephalopathy. The symptoms that may occur are confusion, ocular
findings, and ataxia, but Chiossi (2006) reported that only half from 49 cases had this
triad. This encephalopathy shows an abnormal electroencephalogram (EEG). The next
one is vitamin K deficiency that cause maternal coagulopathy and fetal intracranial
hemorrhage.8
2.6.
2.6.1.

MANAGEMENT
Diet
Modification of the amount and size of meals consumed throughout the day may

help relieve symptoms. Having smaller amounts of food and fluids more often can help
prevent mild cases of nausea and vomiting from worsening. The meals should contain
more carbohydrate than fat and acid. Protein-rich meals also decrease symptoms. Lighter
snacks, including nuts, dairy products, and beans, are often endorsed. Drinks that contain
electrolytes and other supplements are advised. If certain foods or food preparations
trigger nausea, they should be avoided.
2.6.2. Lifestyle

Women who are affected by this illness should avoid stress and try to get as much
rest as possible. If emotional support is needed, the patient can see a psychologist to help
address the debilitating symptoms. Supportive counseling or crisis intervention may be
necessary.
2.6.3. Intravenous fluid
Intravenous (IV) fluids should be provided to replenish the lost intravascular
volume. Rehydration along with replacement of electrolytes is very important in the
treatment of hyperemesis. Normal saline or Hartmann solution are suitable solutions;
potassium chloride can be added as needed. While replacing electrolytes, the physician
must consider the risks of rapid infusion in order to prevent such conditions as central
pontine myelinolysis.
2.6.4. Thiamine
Thiamine should be a routine supplement in patients with protracted vomiting.
Pregnant women should ingest a total of 1.5 mg/d. If this cannot be taken orally, 100 mg
of thiamine may be diluted in 100 mL of normal saline and infused for 30 minutes to 1
hour weekly.
2.6.5. Antiemetic
Several common drugs are used as antiemetics to control nausea and vomiting
during pregnancy. They should not be used before 12 to 14 weeks of gestation due to
possible detrimental effects to the developing fetus. However, there are data showing lack
of teratogenicity with the use of dopamine antagonists, phenothiazines, and histamine
receptor blockers.
In their 2004 guidelines on vomiting in pregnancy, the American Congress of
Obstetricians and Gynecologists recommended that the first-line antiemetic medications
be IV dimenhydrinate, metoclopramide, or promethazine. In a double-blind study

conducted by Tan and colleagues, promethazine and metoclopramide were found to have
similar therapeutic effects for the treatment of hyperemesis, but there were fewer adverse
effects with metoclopramide. Medications included promethazine 25 mg, or
metoclopramide 10 mg, every 8 hours for 24 hours.6
In a study by Nageotte and colleagues, patients using a combination treatment of
droperidol and diphenhydramine had significantly shorter hospital stays for hyperemesis,
fewer days hospitalized for hyperemesis during pregnancy, and fewer readmissions for
hyperemesis compared with those who were not treated with droperidol or
diphenhydramine as a primary therapy. Droperidol was dosed initially at 1.0 to 2.5 mg,
depending on severity of symptoms, and administered over 15 minutes. A continuous
infusion was then started at 1.0 mg/h. If the symptoms persisted, the amount was
increased to 1.25 mg/h, and increases from that point were made in 0.25mg increments
every 4 hours. Droperidol is structurally related to haloperidol; it did not cause abnormal
fetal or neonatal outcomes, and there were no maternal adverse outcomes, including
hypotension.
Ondansetron is a 5-HT3 antagonist that acts on the CNS and peripheral nervous
system. The primary location of action is in the CNS, but it also increases gastric
emptying. It is very effective for patients who experience the emetic effects of
chemotherapy. It also aids patients with postoperative nausea and vomiting. A study on
ondansetron found it to decrease vomiting after the first dose and decrease nausea
subsequently. The patient studied was able to tolerate a light diet after 2 days of
treatment, and she was discharged 14 days after being admitted on 4 mg of ondansetron
three times daily.
2.6.6. Steroid9

The mechanism of action of steroids is assumed to be a direct effect on the

vomiting center of the brain. Because such high doses are required, it is improbable that
there is a lack of pituitary adrenal reserve in this illness.
One study showed vomiting ceased in all patients within 3 hours after
administration of the first dose of IV hydrocortisone. Maintenance doses ranging between
15 and 45 mg/d helped patients resume eating, reverse muscle wasting, and regain lost
weight from prepregnancy weight. After discharge, maintenance doses of 15 mg/d were
used from 6 to 20 weeks. There is no clear evidence of steroid teratogenicity. It is advised
that steroids only be used after all other causes of vomiting have been excluded, vomiting
has continued for more than 4 weeks and is associated with dehydration, and the risks and
benefits of the treatment have been explained.
A short course of oral methylprednisolone (3 x 16 mg) is more effective than
promethazine (3 x 25 mg) for the treatment of hyperemesis. After 3 days the
methylprednisolone was tapered completely during the course of 2 weeks whereas the
promethazine was continued without change for 2 weeks. Patients were followed up
weekly. The study outcomes were improvement of symptoms within 2 days of starting
therapy and readmission for hyperemesis within 2 weeks of starting the study.
2.6.7.

Ginger10
The root of ginger, Zingiber officinale, has been studied to treat hyperemesis. The

effectiveness of ginger is thought to be dependent on its aromatic, carminative, and

absorbent characteristics. It is thought to act on the GI tract to increase motility, and its
absorbent property may decrease stimuli to the chemoreceptor zone in the medulla that

sends stimuli to the emetic center of the brain stem. Ginger may also block the GI
responses and consequent nausea feedback.
Each woman swallowed capsules containing either 250 mg ginger or lactose q.i.d.
during the first 4 days of the treatment period. Interrupted by a 2 days wash-out period
the alternative medication was given in the second 4-day period. The severity and relief
of symptoms before and after the period were evaluated by two scoring systems.
Subjectively assessed, 19 women (70.4%) stated preference to the period in which ginger,
as was later disclosed, had been given (P = 0.003). More objectively assessed by relief
scores a significantly greater relief of the symptoms was found after ginger treatment
compared to placebo (P = 0.035). No side effects were observed. Powdered root of ginger
in daily doses of 1 g during 4 days was better than placebo in diminishing or eliminating
the symptoms of hyperemesis gravidarum.
2.6.8. Nasogastric enteral feeding11
Nausea and vomiting improved within 24 hours after nasogastric tube placement.
Enteral feedings were well tolerated, and all patients were discharged from the hospital
within 8 days. Enteral feedings were continued, in an outpatient setting, for a mean of 43
days. Ultimately, all patients resumed oral feeding and discontinued enteral feeding.
Subsequently, all patients gave birth to full-term, normal-weight babies.
This treatment has potential complications, such as pneumothorax aspiration,
infection, venous thrombosis, intrahepatic cholestasis, and fatty infiltration of the
placenta. In order to minimize the possibility of aspiration, the feeding tube was placed
past the pylorus. This technique, however, exposes the patient to radiation to check the
position of the tube. Despite its expense, it is considerably cheaper compared with total
parenteral nutrition (TPN). This type of feeding is most useful in patients whose nausea
and vomiting are associated with the consumption of food.

2.6.9. Total Parenteral Nutrition

TPN is a nutrient source that may be used in pregnant women who suffer from
severe hyperemesis or when there is a lack of absorption of adequate nutrients. The
severe nutritional deprivation caused by hyperemesis is preferably treated with enteral
hyperalimentation, but if the patient cannot tolerate this and vomits after feeding, the risk
of aspiration increases. TPN has been used in other conditions to sustain pregnancies,
such as jejunoileal bypass, diabetes, and Crohn disease. TPN is a nonprotein calorie
source, usually glucose or lipid emulsions, that provides utilizable nitrogen, electrolytes,
trace elements, water, and fat-soluble vitamins. This source of calories prevents ketosis,
which develops from fatty acid metabolism and may have adverse effects on the fetus.
In order to study the nutritional effects of hyperemesis, the basal metabolic
expenditure and adjusted metabolic expenditure were defined by indirect calorimetry, and
the appropriate number of calories was calculated for each patient. The group of
hyperemesis patients compared with the two control groups of healthy pregnant women
and healthy women who were not pregnant had significantly different substrate
utilization. The hyperemesis patients used fat, consistent with a catabolic state. The
hyperemesis group also had a mean respiratory quotient that was < 1.00, an indication of
a catabolic state. After treatment with TPN, the respiratory quotient of each hyperemesis
patient was > 1.00, showing a shift to utilization of carbohydrate and protein, indicating
an anabolic state and improvement in nutritional status. The pre- and posttreatment mean
respiratory quotients of the hyperemesis group were significantly different. The birth

weights of the infants surpassed the average birth weights for their respective gestational
ages.
Complications of the TPN catheter include pneumothorax, puncture of nearby
artery, or air embolism. There are also risks when using TPN due to the infusion of such a
large amount of glucose. The consequences are similar to a woman with diabetes during
pregnancy. Hyperglycemia may cause fetal anomalies and complications. Elevations in
the mothers glucose may increase the risk of having a macrosomic baby. An infusion
with a high amount of glucose may compromise respiration if carbon dioxide is
overproduced. Hypertonic dextrose infusions should be started slowly at 40 mL/h or 1
L/d, then increased. If administering solutions containing 25% or more of dextrose, the
infusion should begin at 30 to 45 mL/h and increase in increments of 20 mL/h/d.
Fat emulsions have been shown to induce contractions of the uterine muscle at a
high infusion rate. This may happen at any point in the pregnancy. Placental infarctions
and placental fat deposits are also a risk with fat emulsion infusions, possibly resulting in
placental insufficiency. Fat emulsions should not exceed 3 g/kg/d, or more than 60% of
the total calories, to avoid a fat overload. TPN should be discontinued once the woman is
able to tolerate enteral feedings. Infections are also a risk of TPN and vigilant observation
must be practiced. More severe risks when using TPN include sepsis and cardiac
complications due to electrolyte imbalances.

2.6.10. Acupuncture

In addition to standard treatment, acupuncture to PC6, which is the point 5 cm

proximal to the wrist crease on the palmar side of the forearm, could quicken the
resolution of hyperemesis. In a placebo-controlled, randomized, single-blind, crossover
study, acupuncture treatments were given for 30 minutes three times a day because, in
previous studies, an 8-hour treatment effect had been shown. Women in the active
acupuncture group versus the placebo group had a significantly quicker decrease in the
amount of nausea they experienced. There was also a significant difference in the amount
of vomiting between the two test groups. The active acupuncture group had significantly
fewer patients vomiting. There was no significant difference in food intake between the
two groups, and no side effects were observed.
There are a few possible mechanisms of action for the reduction of hyperemesis
from acupuncture. It seems to inhibit nociceptive transmission and autonomic reflexes. It
also seems to decrease pain in the system from the periaqueductal gray, which partially
works through endorphinergic mechanisms. Because one potential cause of hyperemesis
is reduced gastric emptying, and acupuncture has an effect on the GI tract, another
possible mechanism of action is through somatovisceral reflexes.

Agents
Metoclopramide

Dosage
10 mg every 8 h

Efficacy
Reduces nausea and

Safety
Less drowsiness,

for 24 h

vomiting

dizziness, dystonia
No known

Promethazine

25 mg every 8 h

Reduces nausea and

malformation
No known

Diphenhydramine

for 24 h
12.525 mg

vomiting
Reduces nausea and

malformations
No increased risk of

every 46 h

vomiting

malformations

Droperidol and

1.02.5 mg over

Reduces nausea and

Causes drowsiness
No abnormal

diphenhydramine

15 min, then 1.0

vomiting

outcomes

mg/h
50 mg over 30
Ondansetron

min every 6 h
4 mg every 8 h

Methylprednisolone

16 mg every 8 h

Ginger

1 mg for 4 d

Reduces nausea and

vomiting after first dose
No known
Reduces nausea and

malformations
No known

vomiting

malformations

For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine,

antihistamines, and metoclopramide were associated with greater benefit than placebo.
For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide
were associated with greater benefit than placebo. Ondansetron was associated with
improvement for a range of symptom severity. Corticosteroids may be associated with
benefit in severe cases. Overall the quality of evidence was low.12

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