Hyperemesis Gravidarum

Introduction

Nausea and vomiting of pregnancy (NVP) is so common that it is often treated as an inevitable inconvenience. Up to 80% of pregnant women experience it, and the term morning sickness is a misnomer because symptoms occur at any time of day. Hyperemesis gravidarum sits at the severe end of the same spectrum, affecting approximately 0.3-3.6% of pregnancies, and is the commonest reason for hospital admission in the first half of pregnancy.¹

The distinction matters because hyperemesis is a diagnosis with defined consequences. It is conventionally defined by a triad: weight loss of more than 5% of pre-pregnancy weight, dehydration, and electrolyte imbalance. It is a diagnosis of exclusion, made only once other causes of vomiting have been considered, and it carries a genuine mortality risk through Wernicke's encephalopathy, thromboembolism and, historically, hepatic and renal failure.^1,2

It is also a condition that has been repeatedly minimised. Women with hyperemesis report high rates of psychological morbidity, and a proportion request termination of an otherwise wanted pregnancy because their symptoms are not adequately controlled. Effective early treatment is not merely symptomatic care; it changes outcomes.¹

Pathophysiology

No single mechanism explains hyperemesis, but several strands of evidence converge on the placenta.

Human chorionic gonadotrophin

The temporal pattern of symptoms follows the hCG curve closely: onset at 4-7 weeks, peak at 9-12 weeks, resolution by 16-20 weeks. Conditions with high hCG, notably multiple pregnancy and complete molar pregnancy, carry a markedly increased risk. hCG shares an alpha subunit with TSH and cross-reacts weakly with the TSH receptor, producing gestational transient thyrotoxicosis in around two-thirds of women with severe hyperemesis.

GDF15

Growth differentiation factor 15 is a placentally derived hormone acting on the GFRAL receptor in the area postrema, the brainstem chemoreceptor trigger zone. Women with genetically determined low pre-pregnancy GDF15 exposure, and fetuses producing high GDF15, are at greatest risk, which explains both the familial clustering and why the condition tends to recur.³

Other contributors

Oestrogen delays gastric emptying and reduces intestinal transit; progesterone relaxes the lower oesophageal sphincter and worsens reflux. Helicobacter pylori infection is more prevalent in women with hyperemesis, although a causal role is unproven and eradication is not routine.

Risk factors

• Previous hyperemesis gravidarum - the single strongest predictor, with recurrence in a substantial minority
• Family history in a mother or sister
• Multiple pregnancy
• Molar pregnancy or other trophoblastic disease
• Nulliparity
• Raised BMI
• History of motion sickness or migraine
• Female fetus

Clinical features

The history should establish when symptoms started, how frequently the woman is vomiting, what she is able to keep down, how much weight she has lost, and how it is affecting her daily function. Ptyalism, the inability to swallow saliva, is characteristic and unpleasant. Many women also report intense food and smell aversions, heartburn and constipation.

Timing is the most useful discriminator. Symptoms of NVP begin between 4 and 7 weeks in most women, and virtually always before 9 weeks. Vomiting starting after 11 weeks is not hyperemesis and should prompt a deliberate search for another cause.¹

Examination

Assess volume status: pulse, blood pressure including postural drop, capillary refill, mucous membranes, skin turgor and urine output. Weigh the woman and compare with her booking or pre-pregnancy weight. Examine the abdomen, which should be non-tender; significant abdominal pain is not a feature of hyperemesis. Check for a uterus large for dates, which raises the possibility of multiple or molar pregnancy, and look specifically for signs of thyrotoxicosis and for the neurological signs of thiamine deficiency.

The PUQE score

The Pregnancy-Unique Quantification of Emesis score grades severity from three questions covering the last 24 hours: hours of nausea, number of vomits, and number of retching episodes. It gives a reproducible number that can be tracked across a treatment episode, and is used to decide the setting of care.¹

Differential diagnosis

Hyperemesis is a diagnosis of exclusion. The differential is broad and the consequences of missing an alternative are serious.^1,2

• Gastrointestinal: gastroenteritis, gastritis, peptic ulcer, appendicitis, cholecystitis, pancreatitis, bowel obstruction
• Urinary: urinary tract infection and pyelonephritis - always dipstick and culture
• Metabolic and endocrine: diabetic ketoacidosis, hypercalcaemia, Addison's disease, thyrotoxicosis
• Neurological: raised intracranial pressure, vestibular disease, migraine
• Obstetric: molar pregnancy and multiple pregnancy, both of which cause severe symptoms in their own right
• Iatrogenic: iron supplements, opioids, antibiotics

Investigations

Management

Fluid and electrolyte replacement

Normal saline (0.9% sodium chloride) with added potassium chloride, titrated to the daily U&E, is the fluid of choice. Potassium requirements are frequently underestimated: prolonged vomiting produces substantial losses and the deficit must be replaced before the vomiting will settle. Fluid balance and daily weights guide the volume required.

Thiamine

All women admitted with hyperemesis, and any woman vomiting for more than three weeks, should receive thiamine supplementation. Oral thiamine 100 mg three times daily is adequate for most; intravenous vitamin B complex (Pabrinex) is used where oral intake is impossible. Body stores of thiamine last only two to three weeks, which is why Wernicke's encephalopathy appears in this population and not in patients with brief vomiting illnesses.

Thromboprophylaxis

Pregnancy is prothrombotic, and dehydration and immobility compound the risk. Low molecular weight heparin and anti-embolic stockings should be prescribed for the duration of any admission with hyperemesis, and continued until the woman is mobile and no longer dehydrated.¹

Antiemetics

Antiemetics are used in a stepwise fashion. There is no benefit in withholding treatment out of vague concern about teratogenicity: the first-line agents have decades of safety data, and untreated hyperemesis is itself harmful. Where oral treatment cannot be retained, give the drug by intramuscular, intravenous or rectal route.

Adjuncts and supportive care

• Ranitidine has been withdrawn; use omeprazole or another proton pump inhibitor for associated reflux and to protect against oesophagitis
• Small, frequent, dry, bland, carbohydrate-based meals with fluids taken separately from food
• Ginger and acupressure at the P6 point have modest evidence and are reasonable to offer in mild disease
• Stop or substitute iron-containing preparations, which aggravate nausea; folic acid alone can be continued
• Screen for and treat low mood, and signpost to support organisations such as Pregnancy Sickness Support
• Consider enteral or, exceptionally, parenteral nutrition where weight loss is progressive despite maximal therapy

Complications

Maternal

• Wernicke's encephalopathy - the classic triad of confusion, ataxia and ophthalmoplegia; often incomplete, so treat on suspicion
• Mallory-Weiss tear - haematemesis after forceful retching
• Venous thromboembolism - from dehydration, immobility and the pregnant state
• Acute kidney injury - pre-renal, from sustained hypovolaemia
• Central pontine myelinolysis - from over-rapid correction of hyponatraemia
• Refeeding syndrome - hypophosphataemia, hypomagnesaemia and hypokalaemia on reintroducing nutrition after prolonged starvation
• Psychological morbidity - anxiety, depression, post-traumatic symptoms, and requests for termination of a wanted pregnancy

Fetal

Most pregnancies complicated by hyperemesis have normal outcomes. Where the mother has substantial and sustained weight loss, there is an increased risk of a small-for-gestational-age infant and of preterm birth. Interestingly, mild to moderate NVP is associated with a lower miscarriage rate, reflecting robust trophoblastic function rather than any protective effect of vomiting itself.

Red flags

Prognosis and future pregnancies

In most women symptoms improve substantially by 16-20 weeks, in parallel with falling hCG. A minority, around 10%, continue to have symptoms until delivery. Symptoms almost always resolve completely within hours to days of the birth, including delivery of a molar pregnancy, which is itself a diagnostic clue to the placental origin of the condition.

Recurrence in a subsequent pregnancy is common, with reported rates ranging widely but consistently much higher than the background risk. Women should be counselled to seek help early rather than waiting until they are dehydrated, and to start an antiemetic as soon as symptoms begin rather than escalating stepwise from scratch. A pre-pregnancy or early-pregnancy plan agreed with the obstetric team, specifying which antiemetic worked previously and the threshold for day-case fluids, materially reduces admissions.^1,5