Background
Nausea and vomiting in pregnancy (NVP) is one of the most common symptoms of pregnancy affecting 50–85% of all women during the first half of pregnancy.1 Symptoms usually start between 6 and 8 weeks of gestation, rise to a peak before the end of the first trimester and, in the majority of women, resolve by 20 weeks.2 Most women (65–70%) self-manage their symptoms with avoidance of dietary triggers and oral hydration.2 However, in the remainder, symptoms are more severe and/or protracted, leading to physical and psychosocial sequelae. These can include reduced quality of life (QoL), lost work time and negative effects on relationships with family and friends.3
The most severe form of NVP is referred to as hyperemesis gravidarum (HG), and is reported to affect 0.3–1.0% of pregnant women.1 It is characterised by intractable vomiting, dehydration, ketosis, electrolyte imbalance, nutritional deficiencies and weight loss (usually defined as > 5% of pre-pregnancy weight). However, there is no widely accepted point at which NVP becomes HG. Likewise, the distinction between studies of women with NVP and HG is generally not possible as the degree of dehydration and weight loss prior to the intervention are rarely reported. Furthermore, although some studies report baseline symptom severity using a validated scale, this is insufficient to make a diagnosis of HG. For these reasons, study populations are seldom described as having HG, and are more frequently defined in terms of the severity of NVP. Therefore, for the purposes of this review, studies on interventions for both NVP and HG have been included.
Aetiology
The underlying pathophysiology of NVP/HG is poorly understood but is thought to involve a combination of biological, physiological, psychological and sociocultural factors.4
Genetic factors increase the risk of occurrence: results from a Norwegian study which included over 500,000 women found that the risk of HG was 15.2% in the second pregnancy of women who had a previous history of HG compared with 0.7% in women who did not [odds ratio (OR) 26.4, 95% confidence interval (CI) 24.2 to 28.7].5 The risk of developing HG is also increased threefold in the daughters of women who suffered from HG (unadjusted OR 2.9, 95% CI 2.4 to 3.6).6
Endocrine factors, especially higher levels of human chorionic gonadotropin, as is the case in multiple or molar pregnancies, have been associated with more severe forms of NVP/HG. A recent observational study found that free human chorionic gonadotropin and pappalysin-1 (also known as pregnancy-associated plasma protein A) were higher in women suffering from HG than in non-sufferers.7
Gestational transient thyrotoxicosis, has been reported in 60% of women suffering from HG8 and thyroid-stimulating hormone levels are raised in women with HG.9 Certain human chorionic gonadotropin subtypes can stimulate thyroid-stimulating hormone receptors and so contribute to the hyperthyroidism. The degree of hyperthyroidism has been found to correlate with the severity of NVP/HG.10 Higher levels of oestrogen, progesterone and leptin, and lower levels of adrenocorticotrophic hormone and prolactin have also been associated with HG.11
Delayed gastric emptying related to relaxation of smooth muscle during pregnancy may influence NVP symptoms. Furthermore, higher rates of Helicobacter pylori infection have been noted in women suffering from HG:11 in a meta-analysis of 25 studies investigating the association of H. pylori and HG, 14 studies demonstrated an increased risk of HG in infected women (with OR between 2.42 and 109.3), and 11 studies found no association.12
Lack of a definitive physiological trigger for HG has, in the past, led to numerous psychosomatic and psychological theories such as resentment or ambivalence towards the pregnancy, immaturity, conversion disorder, symptom of hysteria, neurosis or depression.13 It is now more commonly accepted that psychological afflictions are a consequence of the condition rather than a cause.4,9
Impact on patients
Severe NVP causes emotional and psychological distress and can have a profound effect on a women’s QoL, behavioural and cognitive function, affecting work capacity, household activities and interaction with children.14–16 Women with HG report feeling isolated, depressed and lonely, unable to cope with routine daily interactions or simple tasks. Two recent observational studies found higher incidences of depression, anxiety and stress in women diagnosed with HG compared with controls.17,18 Following cessation of symptoms the depression, anxiety and stress scores took several weeks to resolve,18 not returning to control values until the third trimester.17 However, in some women these psychological symptoms do not fully resolve and can result in post-traumatic stress disorder.19
As a result women make greater use of health-care resources. Based on Hospital Episode Statistics data for England, there were nearly 26,000 admissions for NVP/HG in 2010–11 with an average length of stay of 2 days.20 These NHS costs are likely to underestimate the full costs as women may purchase a variety of products over the counter, pay for alternative therapies, receive treatment in primary care settings or as a hospital outpatient, and may incur extra child care, living costs and lost earnings. In addition, the associated increased risk of cognitive, behavioural and emotional dysfunction in pregnancy18 may prompt the use of further services and resources.
In the absence of a definitive cause, management of NVP/HG tends to focus on the alleviation of symptoms and prevention of serious morbidity. Typically, women are admitted to hospital, prescribed intravenous (i.v.) fluid therapy and antiemetic medication, but there is little time spent dealing with their psychological, social and emotional needs or providing information and guidance about the condition. The result is that women can feel unsupported, dissatisfied with care and experience negative interpersonal interactions with health-care providers.21
Finally, severe NVP/HG has implications for offspring. A recent systematic review and meta-analysis reported that women with HG were more likely to deliver preterm (OR 1.32, 95% CI 1.04 to 1.68) and to have a baby that was small for gestational age (OR 1.28, 95% CI 1.02 to 1.60), although there was no evidence of an association with congenital anomalies (pooled results from three studies: OR 1.17, 95% CI 0.68 to 2.03) or perinatal death (OR 0.92, 95% CI 0.61 to 1.41).22 A large Swedish birth cohort reported that women with HG who had their first admission in the second trimester were at increased risk of preterm pre-eclampsia (OR 2.09, 95% CI 1.38 to 3.16), placental abruption (OR 3.07, 95% CI 1.88 to 5.00) and to have a baby that was small for gestational age (OR 1.39, 95% CI 1.06 to 1.83), suggesting an association between HG and placental-mediated disease.23
Assessment and diagnosis
The diagnosis of NVP/HG is made after excluding differential diagnoses, including gastrointestinal disorders, urinary tract infection, metabolic and endocrine disorders, drugs, psychological disorders (such as eating disorders) and other pregnancy-associated conditions (in particular molar pregnancy). However, there is currently no widely accepted approach to measuring the severity of symptoms in women. The most commonly used tools for the assessment of NVP/HG severity are presented in , with actual examples of the tools provided in Appendix 1.
Tools used to measure the severity of NVP
However, although the measurement of NVP/HG symptom severity is the main aim for women and practitioners, other wider outcomes are also relevant when assessing the broader effectiveness of interventions. Thus, key secondary outcomes in studies to date have included both measures related to maternal physical and psychosocial health, and fetal or neonatal outcomes ().
Secondary outcome measures
Current interventions for nausea and vomiting in pregnancy/hyperemesis gravidarum
For the purposes of this report, interventions are considered in three broad groups:
First-line interventions, usually initiated by women before seeking medical care and hence tend to be used in less severe NVP.
Second-line interventions, typically prescribed when a women presents to medical care. Initially this is likely to be a general practitioner (GP) in primary care but may involve referral of women with more severe symptoms for inpatient, outpatient or day case care in hospital.
Third-line interventions, reserved for women in hospital with persistent or recurrent symptoms despite second-line therapies.
The relationship between these three intervention groups is described in , with key individual interventions described in detail in the following sections.
Treatments for NVP. a, Care may also involve urine ± blood tests, weight and maternal observations; and b, care will involve urine and blood tests, weight, maternal observations and pelvic ultrasound. i.m., intramuscular.
Patient-initiated first-line interventions
When first experiencing the symptoms of NVP, women often access information, advice and services from a variety of sources. Information is readily available regarding simple lifestyle changes, dietary modifications and alternative therapies via the internet and in pregnancy magazines. ‘Self-help’ interventions also include a range of supplements that are available ‘over the counter’. Many women try one or more of these before seeking medical advice.
Dietary/lifestyle interventions
Women report using a range of dietary/lifestyle interventions (e.g. increasing oral fluid intake, eating small frequent meals, eating bland foods/protein-predominant meals and avoiding spicy, odorous and fatty foods, and stopping iron-containing multivitamins).2,34
Vitamins
Vitamins are vital nutrients. They are available over the counter as single vitamin or multivitamin preparations.
Vitamin B6 (pyridoxine) A water-soluble vitamin essential for many metabolic processes within the body. Usually taken in doses of 10–50 mg up to four times daily to treat NVP.
Vitamin B12 (cyanocobalamin) A water-soluble vitamin essential for normal function of the nervous system, red blood cell formation and many other metabolic processes.
Ginger
Ginger (Zingiber officinale) is considered a food supplement (not a drug) and is available in several preparations; powdered fresh root, tablets, capsules and syrup. Its antinausea properties were first described in traditional Chinese medicine.35
Acupressure/acupuncture
Acupressure involves the application of physical pressure to specific acupuncture points; with respect to NVP this involves the pericardium 6 (P6) point near the wrist.
Acupuncture involves the manipulation of thin needles inserted into acupuncture points in the skin.
Hypnotherapy
Hypnotherapy employs direct suggestion of symptom removal with the subject under hypnosis.
Aromatherapy
Aromatherapy was first used by ancient civilisations for cosmetics, perfumes and drugs. It involves the use of plant materials, aromatic plant and essential oils to alter mood, cognitive, psychological or physical well-being. Oils can either be applied topically via massage, via inhalation or via emersion mixed with water. Common uses include stress and anxiety relief, to uplift mood or counter depression. Evidence surrounding efficacy and safety remains unclear for some treatments.
Clinician-prescribed second-line interventions
Second-line interventions tend to be used for more severe symptoms either instead of or, less frequently, in addition to, first-line interventions. These may be initiated either in primary care by the GP or in a secondary care hospital setting.
Antiemetic drugs
Antiemetic drugs include antagonists to histamine, acetylcholine, dopamine and 5-hydroxytryptamine (5-HT3) receptors in the chemoreceptor trigger zone, vestibular apparatus and visceral afferents. Dyspepsia symptoms which often accompany NVP are also often treated with H2 receptor blockers (e.g. ranitidine) or proton pump inhibitors (e.g. omeprazole).2
Antihistamines (H1 receptor blockers) are probably the most widely used antiemetics and include doxylamine, meclizine, diphenhydramine, hydroxyzine, dimenhydrinate and cyclizine. Doxylamine is sometimes used in combination with vitamin B6 (pyridoxine). This combined therapy could be used as a treatment option in countries where Diclectin® (Duchesnay Inc.; delayed release doxylamine, 10 mg, plus pyridoxine, 10 mg, available in Canada and the USA but not the UK) is not available.36
Dopamine antagonists are known to stimulate gastrointestinal motility, so encouraging the transit of substances through the stomach. They also work centrally by antagonising the action on D2 receptors in the chemoreceptor trigger zone. Several phenothiazines including promethazine and prochlorperazine have been used to treat NVP/HG. Other drugs in this class used to treat NVP/HG include metoclopramide, domperidone, droperidol and trimethobenzamide.
5-HT3
receptor antagonists (selective serotonin receptor antagonists) are commonly used to treat chemotherapy and post-operative induced nausea and vomiting which is caused by release of 5-HT3 from the upper small intestine. The action of 5-HT3 receptor antagonists are mediated through the central chemoreceptor trigger zone and peripheral (intestinal and spinal) 5-HT3 receptors.
Intravenous fluids
Administration of i.v. fluids treats the consequences of NVP/HG rather than the symptoms. Women who are severely dehydrated and ketotic need hospital admission and i.v. fluid and electrolyte replacement. This is routinely carried out in either a day care ‘outpatient’ setting or on an inpatient ward.
Clinician-prescribed third-line interventions
Third-line interventions are reserved for women who have severe and persisting symptoms and associated weight loss and dehydration (although latter may have been corrected). Although commenced while the women are in hospital, some of these interventions may be continued on an outpatient basis.
Corticosteroids
Steroids are being increasingly used in refractory cases of NVP/HG which have been unresponsive to other treatments (i.v. hydrocortisone 100 mg twice daily, followed by oral prednisolone 40–50 mg, reducing to a maintenance dose).
Enteral feeding and total parenteral nutrition
Enteral feeding refers to the delivery of nutrients directly into the stomach, duodenum or jejunum. For women who cannot tolerate enteral nutrition, the use of total parenteral nutrition (TPN) has been reported in case series but use is associated with significant maternal morbidity.37
Interventions presented in the report but not routinely used to treat nausea and vomiting in pregnancy
Diazepam
Diazepam in a benzodiazepine drug used to treat, for example, anxiety, panic attacks, insomnia and seizures. It enhances the effects of the neurotransmitter gamma-aminobutyric acid which leads to central nervous system depression. Its use results in sedation, long-term use results in physical dependence.
Clonidine
Clonidine is a centrally acting α2 adrenergic agonist and imidazoline receptor agonist. It is usually used to treat hypertension, attention deficit hyperactivity disorder and, less commonly, anxiety disorders, withdrawal, migraine and certain chronic pain conditions. Observational data suggests that it may be effective in the treatment of refractory nausea and vomiting.38
Gabapentin
Gabapentin was originally synthesised to mimic the action of the neurotransmitter gamma-aminobutyric acid, but acts on various brain receptors. It is generally used to treat seizures and neuropathic pain, with less common uses including the treatment of generalised anxiety disorders, restless leg syndrome and itching caused by various aetiologies. It has previously been associated with improvements in refractory nausea in a small study of breast cancer patients.39
Current guidance and use of therapies within the NHS
Currently there are no national guidelines within the NHS pertaining to NVP/HG; however, the Royal College of Obstetricians and Gynaecologists are in the process of producing said guidelines which should be published in early 2016. Initially, GPs may try different antiemetics before referring women to hospital. Traditionally, secondary care would involve admission to either an antenatal or gynaecology ward for treatment with i.v. fluids, antiemetics and vitamin supplements. Oral intake would gradually be resumed followed by discharge back into the community. Resumption of symptoms would result in readmission and a repeat of previous care, possibly trying different antiemetics or a combination thereof.
Increasingly, more obstetric and gynaecology units are using ‘day case’ management as the first option for initial referrals. Care usually involves some form of rapid rehydration and treatment with an i.v. antiemetic, followed by discharge with oral antiemetics, ideally with advice, support and guidance regarding self-help measures. However, assessing symptom severity, as well as the packages of care, vary substantially and lack a strong evidence base.
When available, day case, outpatient management does result in fewer admissions to hospital. Consequently, women who are admitted tend to be suffering from more severe symptoms. These women are likely to have had repeated hospital attendances and to have tried a number of different combinations of interventions. This latter group of women are likely to experience persistent severe symptoms, weight loss, electrolyte imbalance and failure to cope. In some of these women corticosteroid therapy may be considered an appropriate option when more conventional options have failed. In rare circumstances where this proves unsuccessful, enteral or parenteral nutrition may be instigated and, as a last resort, some women will opt for termination of pregnancy.
Aims and objectives
This study aimed to:
review systematically the evidence of the clinical effectiveness and cost-effectiveness of each treatment for NVP/HG
determine which therapies are most likely to be cost-effective for implementation into the UK NHS
identify and prioritise future research needs.
Structure of the report
The following chapter (see Chapter 2) describes the methods employed for the systematic review and synthesis of evidence for interventions for HG and/or NVP. Chapter 3 provides an overview of the identified evidence, including the quality of the included studies, and a brief discussion of the issues that arose in attempting to synthesise the emergent data. Chapters 4–17 detail the findings for each individual intervention, focussing on the evidence for their effectiveness in terms of nausea, vomiting and retching. Chapter 18 presents the methods and results of the economic evaluation. Key issues considered likely to be important from the perspective of both patients and health-care practitioners are described in Chapters 19 and 20. The implications of the results of this review are discussed in depth in Chapter 21, with the final conclusions outlined in Chapter 22.
