Discussion

I.Introduction
Hyperemesis gravidarum is defined as persistent and excessive vomiting starting
before the end of the 22nd week of gestation and further subdivides the condition into mild
and severe, with severe being associated with metabolic disturbances such as carbohydrate
depletion, dehydration, or electrolyte imbalance. HG is a diagnosis of exclusion,
characterized by prolonged and severe nausea and vomiting, dehydration, large ketonuria,
and more than 5% body weight loss.
II.

Etiology
The cause of HG is not well understood but appears to have both physiologic and

psychologic components. Estrogen, prosgesterone, adrenal and pituitary hormones have been
proposed as causes but currently there is no conclusive evidence. It is said that nausea and
vomiting in preganancy is related to trophoblastic activity and gonadotropin production,
possible secondary to elevated serum human chorionic gonadotropin(hCG) levels. Women
with molar pregnancy and trisomy gestation are associated with elevated human chorionic
gonadatropin (HCG) levels. These levels peak at about 8 weeks gestation with increasing
symptoms of nausea and vomiting. However, HCG levels do not correlate well with the
severity of hyperemesis. Serum progesterone levels also peak in first trimester of pregnancy;
progesterone alone or in combination with estrogen may cause gastric dysrhythmias by
decreasing the gastric smooth muscles contractility. Serum prostaglandin E2 CPGE2) levels
were found to be higher during symptomatic period of hyperemesis gravidarum. Placental
PGE2 synthesis is stimulated by HCG, the latter usually peaking between 9th to 12 weeks of
gestations, which may explain the symptoms of hyperemesis gravidarum. HCG has a
thyrotropic action and hyperemesis gravidarum is more common in pregnancies with high
HCG and exhibiting transient self-limiting hyperthyroidism. Anti thyroid drugs in this
situation is usually unnecessary.
Recent studies suggested that chronic Helicobacter pylori infection might play a role
in hyperemesis, H. pylori seropositivity was present in up to 60% of pregnant mothers
compared with 50% in the general population, However, the seropositivity did not correlate
with gastrointestinal symptoms. H. pylori infection has been found in cases of persistent
vomiting in pregnancy not responding to supportive treatment. Psychological factors

associated with hyperemesis gravidarum is by far the oldest theory. Some researchers also
postulated that psychological factors might be responsible for hyperemesis gravidarum. In
one study, it was suggested that women with hyperemesis have hysteria, excessive
dependence on their mothers and infantile personalities. Psychoanalytic theories describe
hyperemesis as a conversion or somatization disorder or inability of the mother to cope with
excessive life stress. However these findings are not conclusive due to a lack of robust data to
support these associations. Persistent nausea and vomiting has been associated with food
substances. Hyperemesis gravidarum is more common in populations where meat, fish,
poultry and eggs are commonly consumed; in contrast nausea and vomiting is less common
in cultures where plant foods such as corn are consumed. High risk for recurrence is observed
in women with hyperemesis in the first pregnancy. The risk is reduced by a change in
paternity. For women with no previous hyperemesis, a long interval between births slightly
increases the risk of hyperemesis in the second pregnancy. So, relative impact of genetic and
environmental factors and their possible interactions in seen in hyperemesis. A low
prepregnancy weight : height ratio may predispose women to the development of
hyperemesis. Low maternal age and parity more than one independently increases the risk for
nausea and vomiting in pregnancy. Smoking before pregnancy and using vitamins in early
pregnancy are associated with a decreased risk for nausea and vomiting. Therefore, the
pathogenesis of hyperemesis gravidarum seems to be multifactorial. Women with vomiting in
pregnancy are also found more commonly have history of oral contraceptive sickness, motion
sickness, migraine, a positive family history of hyperemesis and canying a female fetus.
III.

Clinical Evaluation

History
Hyperemesis gravidarum more commonly occurs in primigravida. Most of these
patients present at the maternal antenatal clinic or emergency department depending on the
severity of the symptoms. When a multipara presents with hyperemesis gravidarum, they may
have had previous pregnancies complicated with a similar problem. In history taking, the
attending doctor must document clearly the period of amenorrhoea, symptoms of pregnancy,
the time of onset of nausea and vomiting and history of any co-morbid disease. History of
fever, chills and rigors, headache and visual disturbance are not seen in hyperemesis
gravidarum. If these symptoms present, other acute medical or surgical conditions should be
excluded.

Physical examination
The general condition of the mother including blood pressure, pulse, and hydrational
status must be examined. Features suggestive of dehydration such as dry lips and tongue,
decreased skin turgor and reduced urine output warrant admission to hospital and
resuscitation. Besides the usual signs of pregnancy, one must examine the thyroid to look for
goitre and to elicit clinical signs of thyrotoxicosis. Abdominal examination to look for uterine
size is important. An uterus larger than gestational age and absence of fetal parts may suggest
a molar pregnancy. The pregnancy is best confirmed by ultrasonography. Acute
pyelonephritis and acute surgical condition such as appendicitis or renal colic must be
excluded.
Investigations
The most important immediate blood test is serum urea and electrolytes. Hypokalemia
and hyponatremia are well known complications in severe hyperemesis gravidarum, which
may lead to metabolic alkalosis. Urine test for specific gravity and ketone is done daily till
negative for at least for 2 days. Daily weight measurement and input-output records should be
maintained. Other baseline investigations for pregnancy if have not been done must be
included such as haemoglobin level, ABO grouping and Rhesus, VDRL and HIV serology
test. In cases where the diagnosis is unclear or symptoms persists for more than three days
despite treatment, other blood tests may be helpful. These include thyroid function test, liver
function test, serum amylase and a complete renal function test.

Table 1. Differential Diagnosis of Persistent or Prolonged Vomiting in Pregnancy

Condition
Infections

Disease
Acute pyelonephritis
Acute gastroenteritis
Viral fever
Encephalitis
Viral hepatitis
Malaria

Metabolic disorders

Diabetic ketoacidosis
Hyperthyroidism
Hyperparathyroidism
Hypercalcemia
Uraemia

Gastrointestinal disorders

Addisons disease
Pancreatitis
Appendicitis
Peptic ulcer disease

Neurological disorders

Biliary tract disease

Benign intracranial; hypertension
Tumour
Severe migraine
Vestibular disease
Drugs induced

Others

IV.

Management
Treatment approaches include dietary/lifestyle changes, oral or rectal medication, and

hospitalization for parenteral fluids and therapies in women who fail to respond to outpatient
management and continue to lose weight. Enteral or parenteral nutrition may be required.
Diet
Meals and snacks should be eaten slowly and in small amounts every one to two
hours to avoid a full stomach. Women with nausea should eat before, or as soon as, they feel
hungry to avoid an empty stomach, which can aggravate nausea. A snack before getting out
of bed in the morning can be helpful. Woman should figure out what foods they tolerate best
and try to eat those foods. Dietary manipulations that help some women include eliminating
coffee

and

spicy,

odorous,

high

fat,

acidic,

and

very

sweet

foods,

and

substituting snacks/meals that are protein dominant, salty, low fat, bland, and/or dry (eg, nuts,
pretzels, crackers, cereal, toast). Patients whose symptoms are related to delayed gastric
emptying should improve with a diet comprised of liquids and low fat solids since these
foods are more readily emptied by the stomach; however, it is not known to what degree
gastric emptying and dysfunction account for symptoms in women with nausea and vomiting
of pregnancy. Drinking peppermint tea or sucking peppermint candies can reduce

postprandial nausea. The GI symptoms of motion sickness and hyperemesis are similar;
therefore, 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.

Pharmacology Intervention
Pyridoxine is a water-soluble B-complex vitamin that is a necessary coenzyme in the
metabolism of lipids, carbohydrates, and amino acids. It can be used as a single agent or in
conjunction with doxylamine succinate for the treatment of nausea of pregnancy. The
combination doxylamine-pyridoxine appears to improve efficacy. Initially, two delayed
release tablets (a total of doxylamine 20 mg and pyridoxine 20 mg) are taken at bedtime. The
dose may be increased to four tablets per day as needed for more severe nausea (one tablet in
the morning, one tablet in the afternoon, two tablets at bedtime).
Only a few antihistamines have been studied for the treatment of nausea and vomiting
of pregnancy. The most commonly used antihistamine is doxylamine in combination with
pyridoxine. Other antihistamines that have been used independently to treat nausea and
vomiting of pregnancy include meclizine, dimenhydrinate, and diphenhydramine. The
primary mechanism of antihistamines in treatment of nausea and vomiting of pregnancy is
direct inhibition of histamine at the histamine 1 (H1) receptor; the secondary mechanism is an
indirect effect on the vestibular system by decreasing stimulation of the vomiting center. In
addition, these agents inhibit the muscarinic receptor, which may mediate the emetic
response. Side effects include sedation, dry mouth, lightheadedness, and constipation.
Hyperemesis is a common unlabeled indication for use of ondansetron. Ondansetron 4
mg can be taken orally every eight hours, as needed, or administered intravenously by bolus
injection every eight hours, as needed. The dose is increased only if necessary, and limited to
16 mg/dose. Headache, fatigue, constipation, and drowsiness are the most common drugrelated side effects. Ondansetron can cause QT prolongation, particularly in patients with

underlying arrhythmia risk factors, such as a personal or family history of long QT syndrome,
hypokalemia or hypomagnesemia, heart failure, administration of concomitant medications
that lead to QT prolongation, and use of multiple doses or intravenous ondansetron.
Electrocardiographic and electrolyte monitoring is recommended in these patients. Serotonin
syndrome is a potentially life-threatening condition associated with use of serotonergic agents
and manifested by increased serotonergic activity in the central nervous system. Therefore the
use of ondansetron should be limited in refractory or unresponsive cases.
Glucocorticoids have been used in women with severe and refractory hyperemesis,
although the mechanism of action is not well understood. There is a paucity of evidence that
glucocorticoids are effective. Glucocorticoid use has been associated with a slightly increased
risk of oral clefts when the drug is administered before 10 weeks of gestation; therefore,
ideally, use of glucocorticoids should be avoided in the first trimester.
Glucocorticoids should be avoided in the first trimester. If administered after 10
weeks, the palate has formed and is not at risk for developing defects. An effective dose
is methylprednisolone (16 mg) intravenously every 8 hours for 48 to 72 hours .
Methylprednisolone can be stopped abruptly if there is no response, and tapered over two
weeks in women who experience relief of symptoms. After intravenous therapy, we use an
oral prednisone taper regimen of 40 mg oral prednisone per day for one day, followed by 20
mg per day for three days, followed by 10 mg per day for three days, and then 5 mg per day
for seven days. This regimen may be repeated up to three times over a six week period.
Glucocorticoids should be reserved for treatment of refractory nausea and vomiting of
pregnancy or hyperemesis gravidarum, given the risk of maternal side effects and uncertain
efficacy

Table 2. Anti-emetic used in Hyperemesis Gravidarum

Drug

Recommended

Route

dose
1st line

Promethazine

25 mg t.d.s

PO/IM

And/or

2nd line

Cyclizine

50 mg t.d.s

PO/IM/IV

Prochlorperazine

12.5mg t.d.s.

IM

10mg t.d.s.

PO

3-6 mg b.d.

Buccal

And/or

3rd line

Metoclopramide

10mg t.d.s.

PO/IM/IV

Ondansetron

4-8mg then

IM/ slow IV

4-8mg b.d.

PO

Fluid Therapy
Dehydration occurs when fluid output exceeds fluid intake and is often associated
with electrolyte abnormalities, fatigue, dizziness, and weakness. We correct dehydration with
up to 2 L intravenous Ringers lactate/Hartmanns/Nacl infused over three to five hours,
supplemented with appropriate electrolytes and vitamins. Subsequently, the infusion rate is
adjusted to maintain a urine output of at least 100 mL/hour and the solution is changed to
dextrose 5% in 0.45% saline. The optimum replacement fluid regimen has not been studied.
It is prudent to avoid use of dextrose in the initial rehydration fluid because of the theoretical

concern of Wernickes encephalopathy with dextrose infusion in a thiamine-deficient state.

We delay dextrose infusion until after the patient has received thiamine in her initial
rehydration fluid.

OA us tep sa time ne tn tMaD inaaggneoms ie nstu go f evsot m hity pn eg rienm perseig n a n c y ( H y p e r e m e s i )

C y c liz n e 5 0 mg I M /I V ( is t lin e ) o r P r o c h lo r p e ra z in e 1 2 .5 mg I M ( 2 n d lin e ) o r me to c lo p r a m id e 1 0
uK pe ttoo n1u4r iwa e3 +k os r le s
Cmga l I Me m/IeVrg(e2 n cdyl inf ev)o m it n g p e rs i t b e y o n d 2 4 h o u r s
DI nivsec shtaigr a etiowsit-hMSo u tUp a, tUie&n tE p, rFe Bs cCr i,pLtiFn Tf,o Ur oS ra l a n tie m e tic s
1A snt li-n em ceytic liz n e 5 0 mg T D S a n d /o r 2 n d lin e P r o c h lo rp e ra z in e 1 2 ,5 mg T D S o r
meH y dtorca ltoi pnra-mHida retm1 0a nmg's T1 DliStr e s ta fo l o w e d b y 1 litre o v e r 2 h o u rs
K e to n u r ia 13 + o r le s
D ie t a d v ic e

Figure 1 shows outpatient management in hyperemesis patients

Check for urine ketones

and review blood
results

V.

If urine ketones 2+ or more

or patiebt unwell Admit to
hospital

Complications

Maternal Complications
Persistent severe vomiting of mother can lead to dehydration, electrolyte imbalance
and ketosis. More serious conditions include esophageal tear or rupture, splenic avulsion,
pneumothorax and peripheral neuropathy due to B6 and B12 deficiency, Wernicke's
encephalopathy has been associated with treatment of hyperemesis gravidarum with
intravenous dextrose replacement without thiamine supplement. Central pontine myelinolysis
associated with Wernicke's encephalopathy has been reported. The incidence of maternal
death due to hyperemesis gravidarum is rare but has been reported.
Fetal complications
Uncomplicated nausea and vomiting have been noted to have more favourable
outcome of pregnancy than those without vomiting, these includes less cases of miscarriages,
preterm deliveries and stillbirths. However uncontrolled hyperemesis gravidarum has been
associated with fetal growth retardation and fetal death, In one report it was stated that up to
32% of infants whose mothers experienced weight loss due to hyperemesis were less than
10th percentile for the gestational weight at birth. A low risk of central nervous system and
skeletal malformations was noted in children born of mothers with hyperemesis gravidaru.
Hyperemesis gravidarum may also be a risk factor for testicular cancer in the male offspring.
VI.

Prevention
Ideally, all women of child-bearing age should be advised to take a daily multivitamin

with folic acid beginning in the preconception period; this reduces the risk of congenital
anomalies, particularly neural tube defects, and may help to decrease the frequency and
severity of nausea and vomiting during pregnancy The positive effects of multivitamins are
likely due to the general optimization of nutritional status and metabolism. In addition,
heartburn and acid reflux have been associated with increased severity of nausea and
vomiting of pregnancy, which suggests that managing these disorders prior to pregnancy
might prevent or reduce the severity of symptoms.

VII.

Conclusion

Hyperemesis gravidarum is a multifactorial neurohormornal disorder of early

pregnancy. It can lead to potential complications to both mother and fetus if it is not
controlled. Important acute medical and surgical conditions, which present with vomiting
must be excluded before making the diagnosis of hyperemesis gravidarum. A complete
history, physical examination and investigations are important to establish the diagnosis.
Prompt treatment is essential to prevent complications. Pharmacotherapy complement with
non-pharmacological treatment successfully controlling most symptoms of hyperemesis
gravidarum.

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