Medication & Treatments

Recent genetic research has begun to shed light on the aetiology of NVP and HG which has been poorly understood and even stigmatised for generations. While still considered multifactorial involving endocrine, infectious, psychosocial and hereditary factors new research has shown that genetic variants of the Growth and Differentiation Factor 15 protein (GDF15) and insulin-like growth factor-binding protein 7 (IGFBP7) genes were also at play. GDF15 is the same hormone which plays a large part in cancer cachexia which has similar symptoms to HG such as nausea, vomiting and muscle wasting and these findings support the substantial body of research showing familial hereditability of HG. Further research into this area is needed and we are working with the NIHR Bio Resource for Rare Diseases to explore this further at the moment.

When diagnosing NVP and HG it is important to rule out other potential causes of nausea and vomiting particularly where symptoms start after the first trimester or where epigastric pain is present. In such cases investigations may be required to rule out other serious conditions such as peptic ulcer, appendicitis, gastro-intestinal obstruct, urinary tract infection to name but a few.

Ketone analysis has historically been used as a diagnostic criteria and threshold for treatment for HG but this has been shown by systematic review to have no correlation to severity of symptoms and is not an indicator of dehydration. Additionally, some pregnant women will have ketones present in their urine throughout pregnancy even when their carbohydrate intake is sufficient. Therefore, in addition to a lack of ketones being a barrier to treatment, ketosis has sometimes been a barrier to discharge in women who have been well enough to go home from hospital.

Based on the best available evidence we do not recommend the use of ketoanalysis in assessing women with pregnancy sickness of hyperemesis gravidarum.

 

The most important feature of any treatment for nausea and vomiting in pregnancy are:-

1. Does it work (efficacy)?
2. Does it do any harm to the developing foetus (safety)?
3. Does it have significant side effects on the mother to be?

In 2016 the Royal College of Obstetricians and Gynaecologists (RCOG) published national guidelines for the treatment of nausea and vomiting of pregnancy and hyperemesis gravidarum. Clinicians can feel confident that these guidelines are based on the best available evidence at the moment. You can access the guidelines here.

Early recognition and management of NVP could have a profound effect on women’s health and quality of life during pregnancy, as well as a financial impact on the healthcare system

Two systematic reviews on treatments for NVP and HG (O'Donnell et al, 2016 and Boelig et al, 2016) both concluded that further research is required and research to date has been hampered by a lack of international definition and consensus on outcomes. Therefore, currently, treatment is largely based on clinical experience and expertise.

 

Mild to moderate NVP can often be managed without the need for pharmacological intervention, however where symptoms are impacting a women's ability to eat and/or drink and weight loss is occurring the need for treatment increases. The treatments listed below and supported by the RCOG for use in pregnancy have not been found to cause harmful effects for the fetus. However, increasingly evidence is showing the potentially harmful effects of malnutrition and dehydration during pregnancy, including the first trimester. Malnutrition in early pregnancy has been found to have lifelong cardiometabolic consequences for the offspring.

Historically, HG was the leading cause of death in early pregnancy and although mortality is now rare for this condition, it is not unheard of. This 2015 case report highlights the issues surrounding a death directly due to hyperemesis gravidarum. There were six deaths in the UK between 2006-2012 due to complications arising from HG and of particular note is where co-morbidities are exacerbated by an inability to take medication due to HG, for example for epileptic patients and those with mental health condition.

Additionally, the physical and psychological effects of profound and prolonged nausea and/or vomiting on the mother should not be underestimated and quality of life should be a factor in decision making about treatments. A recent systematic review of qualitative evidence found that even moderate NVP could have a serious detrimental effect on women's lives and mental health.

Intravenous (IV, meaning directly into the vein) fluids are given to correct dehydration, and medication can be given through the IV port when oral medication is unable to be tolerated.

Assessment for the need of IV fluids should not include ketoanalysis, which has been shown by systematic review to not correlate with the severity of HG and is not an indicator of dehydration. Signs and symptoms of dehydration should be assessed as they would for any non-pregnant or pregnant patient with any other condition.

For example, assessing fluid intake and urine output, skin turgor, dry mucous membranes, dizziness, tachycardia, reduced blood pressure and so on. Women with HG who are showing signs of dehydration are unlikely to be able to rehydrate themselves sufficiently due to the ongoing and constant nature of the condition, therefore the threshold for IV fluid rehydration should be low. 

Although IV therapy is common and some doctors would prefer to repeatedly prescribe IV fluids rather than medication for pregnant women, they are not without risk. The main risk associated with IV therapy lies at the site of cannulation. Blood and fluids can leak in to surrounding tissues causing damage and pain. Repeated cannulations can lead to destruction of the vein by scar tissue making future cannulations impossible. Infection is a risk, and in the days of antibiotic-resistant strains of bacteria such as MRSA,treating infection can be difficult. Therefore, women who require IV rehydration should also be treated with appropriate anti sickness medication to reduce the need for repeated IVs.

However, IV fluid replacement remains an effective treatment for dehydration, which actually can cause nausea and vomiting. Women often feel temporary but effective relief from a few bags of IV fluids.

Recently, in rural areas around the United Kingdom, there is an increasing service provision for IV fluids to be administered at home which is an exciting development for HG sufferers who can find the trip to and from hospital and the ward environment quite distressing and exacerbating of symptoms. In particular, a pioneering service led by community nurse Emma Moxham, near Bath in the south west of England, has been successfully providing IV at home for women with HG for about 3 years now and interest in the service is increasing in other areas too.

In inner city areas there is an increasing move towards IV day clinics where hyperemesis patients can be rapidly rehydrated during the day and go home in the evening. 

Dr Marjory Maclean, consultant obstetrician at Ayrshire Maternity Unit in Scotland, suggests a suitable regime for fluid replacement as follows:

Fluid Replacement

• If significant ketonuria, 1000 ml 0.9% sodium chloride intravenously over 2 to 4 hours. Hartmann’s can also be used.

• Thereafter fluids should be reduced to 500 ml 4–6 hourly, the regime being guided by U&E results, which should be performed daily, particularly for monitoring potassium levels.

• Avoid glucose initially as it contains insufficient sodium and especially as Wernicke’s encephalopathy may be precipitated unless thiamine is given first.

 

A wide body of evidence suggests that H1 receptor antagonist antihistamines have no human teratogenic potential. Pooled data from 7 randomised controlled trials indicate that these antihistamines are effective in the treatment of NVP. Some of the H1 receptor antagonist antihistamines that are available in the UK include Promethazine (Avomine) and Cyclizine (Valoid) These antihistamines can cause drowsiness and should not be taken without medical advice.

 

Prospective and retrospective cohort studies, case-control, and record linkage studies of patients with exposure to various and multiple phenothiazines have failed to demonstrate an increased risk of major malformations. Significant therapeutic effect on NVP was demonstrated in 3 randomised controlled trials in severe NVP. One of the phenothiazines available in the UK is prochlorperazine (Stemetil) and it is also available as Buccastem which melts in between the gum and lip and may therefore be more suitable for women struggling to swallow tablets. Side effects include drowsiness, restlessness and occasional extra pyramidal effects. These are prescription only medications.

 

There is only limited information on its safety in pregnancy, although the little that has been published is reassuring. There are a very limited number of studies that indicate the effectiveness of metoclopramide in the treatment of NVP. Side effects include drowsiness, restlessness and occasionally extra pyramidal effects. This is a prescription only medication.

In 2015 the European Medicines Agency recommended that maxolon/metoclopramide should only be given for 5 days. This is because it is felt that longer courses are more likely to produce side effects in the person taking this therapy, although this mostly relates to children and older patients. Specifically, there is concern that beyond 5 days there is more chance of oculogyric crisis and dystonia developing, which put into more understandable terms is facial and skeletal muscle spasms and dizziness.

Please note, there is no new concern about foetal problems this recommendation refers only to side effects for the mother.

 

Domperidone works by speeding up the passage of food through the stomach into the intestine, which then prevents nausea and vomiting. It also prevents food from flowing the wrong way through the stomach and so can prevent reflux. Domperidone blocks dopamine receptors found in an area of the brain known as the chemoreceptor trigger zone (CTZ). The CTZ is activated by nerve messages from the stomach when an irritant is present or when certain chemicals are in the blood stream, such as pregnancy hormones. Once activated, messages are sent to the vomiting centre which sends messages to the gut and triggers vomiting. By blocking the dopamine receptors in the CTZ, domperidone prevents nausea messages from being sent to the vomiting centre and in turn reduces the nausea and vomiting.

As with many of the treatments mentioned here, the safety of Domperidone has not been established in proper medical trials. It has, however, been used for a number of years in pregnancy and as yet no adverse effect on the foetus has been reported. As with all these treatments, their use should be restricted to cases where first line treatment has failed to suppress symptoms and the benefits of further treatment would outweigh the risks to the foetus.

Like with metoclopramide, domperidone may only be suitable for short term use due to European Medicines Agency guidance regarding prolonged use and an association with heart problems, however this advice mostly relates to people over 60 or those already taking certain heart medications. 

Domperidone can be given as a suppository (in your rectum) which some women may find easier then swallowing orally. 

 

This is a powerful anti sickness tablet used to treat people who have severe sickness when being treated with chemotherapy for cancer.
There are a few studies published in the world literature of it being used to treat severe hyperemesis gravidarum when other therapies have failed.
One fairly small observational study in around 170 pregnancies in which the Mums had taken ondansetron showed no increase in foetal abnormalities. A 2013 study of 1,849 women exposed to ondansetron found no increased risk of adverse fetal outcomes.

Side effects for ondansetron include constipation and headaches. Bowel management and laxative options should be discussed with patients when prescribing. 

 

There may be a small increased risk of oral clefting associated with the use of corticosteroids and many authorities say that they should not be used to treat NVP in the first 12 weeks of pregnancy. There is emerging data on the effectiveness of corticosteroids to treat severe and persistent NVP. Corticosteroids need to be given under medical supervision and assessment.

Dr Roy Taylor from Newcastle University published a paper in 2009 regarding the use of steroids as the treatment of choice in severe Hyperemesis Gravidarum.

 

The conclusion from 6 randomised controlled trials with a total of 675 participants was that ginger extract at 1000 mgs per day may be effective treatment for NVP. However the small number of patients in these studies allocated to receive ginger (n=303) may have been insufficient to properly test the safety of ginger with regards to pregnancy outcome. Ginger is a non regulated food product and most preparations available are of variable purity and composition so dose is uncertain. Side effects include heartburn and thromboxane synthetase inhibition i.e. inhibits platelet aggregation.

Survey work conducted via our charity of over 500 women's experience of being offered and taking ginger for hyperemesis gravidarum found that it was ineffective and could cause harm. Not only did ginger produce unpleasant side effects which could exacerbate symptoms but the psychological impact of being told to take ginger repeatedly was very detrimental to well-being. Where healthcare professionals recommended ginger to women with HG trust and confidence in the professional was eroded and women were left feeling dismissed and not believed.

 

Stimulation of the P6 point, located three fingers breadth above the wrist, has been used for many years to treat nausea from a variety of causes. Trials of a non-blinded randomised nature have shown a decrease of persisting nausea by at least 50%. Bands worn at the wrist (e.g. Sea Bands) that apply pressure may be a simple way of stimulating the P6 point. There are no theoretical concerns about the safety of acupressure in pregnancy. Long term use throughout pregnancy may cause minor scaring on the wrists.