ABSTRACT

Nausea and vomiting are commonly experienced symptoms in pregnancy, especially in early pregnancy. There are considerable risks and effects on pregnant women who experience this condition. Nausea and vomiting affect up to 70–85% of all women during gestation and for the majority self-management suffices. For the remainder, symptoms are more severe, clinical conditions may become critical and lead to hyperemesis gravidarum (0.3–1.0% of pregnant women). Moreover, differential diagnosis with pathological conditions characterized by nausea and vomiting is required to exclude other specific diseases. Overall, the morbidity in pregnant women with nausea and vomiting in pregnancy (NVP) is significant, although it tends to be underestimated. The pathogenesis remains unclear, but there is unanimous consensus that the disorder is multifactorial and that several genetic, endocrine, infectious, psychological and social factors may be variably involved. The treatment of NVP can be challenging and the optimal targets for therapy are not known. Currently, the therapy used depends on the severity of the disorder and is focused on improving the symptoms, while minimizing risks to mother and fetus. Therapies range from dietary changes, hydration advice, lifestyle behaviors, pharmacologic and non-pharmacologic treatments, to hospitalization with intravenous fluid replacement and nutrition therapy when needed. All these interventions can also be used, in combination, with a personalized scheme of management.

DEFINITIONS AND EPIDEMIOLOGY

Nausea and vomiting in pregnancy (NVP) is one of the most common symptoms of pregnancy affecting up to 70–85% 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 adequate 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 characterized by severe vomiting, dehydration, ketosis, electrolyte imbalance, nutritional deficiencies and weight loss (usually defined as >5% of pre-pregnancy weight decrease). However, there is no absolute accepted cut-off 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 well 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.

PATHOGENESIS

The underlying pathophysiology of NVP and HG is poorly understood, but it is recognized as being of multifactorial origin and it is thought to involve a combination of biological, endocrine, physiological, and psychological and sociocultural factors.⁴ In addition, a genetic predisposition and placentally mediated mechanisms are described as potential causes of these symptoms. Table 1 lists the main conditions probably involved in the pathogenesis of NVP and HG disorders.

Genetic predisposition

Genetic factors are associated with an increased risk of NVP occurrence. In the 1990s Corey et al. observed a higher use of nausea medication in pregnancy among women with female monozygotic twins compared to female dizygotic twins.⁵ In a recent study on twins, NPV is found to be a highly hereditable condition and a genetic correlation accounting for 73% of the variance, 51% for duration of NVP and 53% for severity of NVP.⁶ In addition, family history of HG is also a risk factor with approximately 28% of women reporting a history of HG in their mothers and 19% reporting their sisters had HG symptoms.^7,8 In accordance with these findings, it has been reported that the risk of HG in a pregnant woman is increased threefold if the woman’s mother had ever experienced hyperemesis in a pregnancy.⁹ Furthermore, women who experienced HG in their first pregnancy have a significant risk of recurrence when compared to women who did not experience the condition in their first pregnancy.¹⁰

Ethnicity

The incidence of NVP also appears to vary with ethnicity and ranges between 3 and 20 per 1000 pregnancies.^11,12 It is more commonly diagnosed in women in India, Pakistan, other parts of Asia, and New Zealand compared to European, American Indian, and Eskimo populations.¹³

Placentally mediated mechanisms

A possible role of the placenta in the pathogenesis of NVP has been suggested by Niebyl. The evidence in support of this is based on the observation that pregnancies with no fetus (complete hydatidiform mole) are associated with clinically relevant and severe NVP disorder, suggesting that these symptoms derived by the placenta, not the fetus. According to this hypothesis, nausea and vomiting are less common in multiparous women, older women, and smokers due to the smaller placental volume.¹⁴

Studies have found an association between HG and placental dysfunction disorders like pre-eclampsia and placental abruption in patients where the HG diagnosis was made in the second trimester of pregnancy.¹⁵ However, Vandraas et al. found a positive association between HG and high placental weight-to-birth weight ratio limited to female offspring.¹⁶ Based on these reports, it is possible that changes in placenta characteristics and function in HG patients may be related to changes in the production of hormones by this organ.

Endocrine factors

Endocrine factors are recognized as largely involved in NVP and HG pathogenesis. Higher levels of human chorionic gonadotropin (hCG), as is the case in multiple or molar pregnancies, have been associated with more severe forms of NVP and HG. A recent observational study found that free hCG and pappalysin-1 (also known as pregnancy-associated plasma protein A) levels were higher in women suffering from HG than in non-sufferers.¹⁷

Gestational transient thyrotoxicosis, has been reported in 60% of women suffering from HG¹⁸ and thyroid-stimulating hormone levels are raised in women with HG.¹⁹ Certain hCG 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.²⁰ Higher levels of estrogen, progesterone and leptin, and lower levels of adrenocorticotropic hormone and prolactin have also been associated with HG.²¹ Progesterone and estrogen levels seem to be related with increased hCG serum concentrations and also with changes in gastric motility and emptying. Overall, thyroid hormones, hCG and sex hormones were variably involved in the mechanisms determining nausea and vomiting in pregnancy as a sort of “vicious circle”.

Gastrointestinal factors

Delayed gastric emptying related to relaxation of smooth muscle during pregnancy may influence NVP symptoms. This theory was first suggested in early 1990s. Data are controversial, but in support of gastrointestinal dysmotility as part of pathogenesis of NVP, several studies reported that normal slow wave activity was less likely associated with this condition.²² In addition, pregnant women with NVP showed more unstable elastogastrography activity compared with women after pregnancy termination and non-pregnant controls.²³ Other studies have found no difference in the timing of gastric emptying of pregnant women with nausea and vomiting.^24,25 Furthermore, higher rates of Helicobacter pylori infection have been noted in women suffering from HG.²⁶ Data related to this topic are controversial. H. pylori is more common identified in the stomach of women with HG than women without HG.^12,27 Frigo et al. reported that more than 90% of women with HG were positive for H. pylori compared to 46.5% of controls.²⁸ Similarly, a study that used the gold standard of testing, histological examination of the mucosal biopsy, found that 95% of HG patients tested positive for H. pylori compared with about 50% in the control group.²⁹ In addition, several systematic reviews described a significant association between maternal H. pylori infection and HG. 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.³⁰ In contrast, other researchers did not report a significant association and most infected women were asymptomatic.^31,32 The conflicting data could be explained by methodological evaluations such as serologic testing for H. pylori not being able to distinguish between active and past infection, and active versus past infection may cause different symptoms.^12,30 In terms of the pathogenetic mechanism, it has been suggested that H. pylori may exacerbate hormone-induced modifications in the electrical and nerve functioning of the stomach.^30,33 Screening for H. pylori could be an option in patients with HG, especially those with prolonged and severe conditions that are refractory to conventional management.^27,30

Serotonin

Another interesting theory on NVP/HG origin is related to serotonin. It is a key factor in the regulation of autonomic gastrointestinal functions including dysmotility, secretion and visceral sensitivity.³⁴ The role of serotonin in NVP and HG is still controversial. Several studies did not find any difference in serotonin levels between pregnant women with or without these symptoms. Other researchers focused on the response to pharmacological therapy with serotonin receptor antagonists molecules suggested a role of higher serotonin levels in NVP and HG patients.³⁰

Psychological theories

Lack of a definitive and absolute physiological trigger for NVP and 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.³⁵ Symptoms of nausea and vomiting are commonly experienced during early pregnancy and have been often associated with stress, anxiety, and depression mood. However, nausea and vomiting in late pregnancy is less frequently studied. At this regard, Kramer et al. examined the prevalence, severity, and psychosocial determinants of NVP during early and late pregnancy.³⁶ From their analysis it emerged that the prevalence of NVP was 63.3% in early pregnancy and 45.4% in late pregnancy. Severity of symptoms was associated with earlier gestation, antiemetic medication use, employment status, and symptoms of major depression. Maternal smoking and having the support of three or more persons were protective for NVP. Nevertheless, it is now more commonly accepted that psychological afflictions are a consequence of the condition rather than a cause.

ASSESSMENT AND DIAGNOSIS

The diagnosis of NVP/HG is made after excluding differential diagnoses, including gastrointestinal disorders, urinary tract infections, metabolic and endocrine disorders, drugs, psychological disorders (such as eating disorders) and other pregnancy-associated conditions (in particular molar pregnancy) (Table 2).³⁷ Timing of onset and cessation of symptoms, accurate history, physical examination and additional investigations (if needed) are imperative in order to consider all underlying and potentially contributing medical conditions. There is currently no widely accepted approach to measuring the severity of symptoms in pregnant women; several methods have been proposed over the years and are now available. The most commonly used tools for the assessment of NVP/HG severity are presented in Table 3. In 2002, the Pregnancy-Unique Quantification of Emesis (PUQE) scoring system based on three symptoms (nausea, vomiting and retching) over the previous 12 hours was proposed; later an extension of the original PUQE by assessing NVP over 24 hours was validated. PUQE-24 showed strong correlation with NVP and resulted in better direct management and prediction of maternal-fetal outcomes.³⁸ Overall, PUQE scale is one of the most known and used tools to assess NVP severity worldwide.

MANAGEMENT

Currently, the management of NVP/HG is focused on improving symptoms, while minimizing risks to mother and fetus. The optimal strategy is a multilevel and personalized approach: treatment modalities depend on the severity of the symptoms and their medical consequences. Therapies range from nutritional changes, rehydration (including intravenous if needed), non-pharmacological options (ginger, acupressure/acupuncture, psychological interventions), pharmacological treatments and hospitalization.

Dietary changes

Dietary changes and nutritional advise are basic for the initial management for NVP. Eating small amounts of food several times a day instead of large meals has been recommended.³⁹ The meals should be light and low in fat; fatty foods may further delay gastric emptying and spicy foods may trigger nausea.³⁰ Drinking small volumes of fluids including beverages with electrolytes is also advisable.³⁹ The smell of hot foods is reported as a possible trigger for NVP, thus cold foods should be preferred.³⁰

Ginger

Ginger's effects on improving NVP have been reported for many years. The American College of Obstetrics and Gynecology (ACOG) recommends ginger as a useful non-pharmacological strategy to treat NVP.⁴⁰ More recently, Viljoen et al. found that ginger improved nausea compared to placebo, but did not decrease the episode of emesis.⁴¹

Ginger seems to relieve symptoms influencing the gastric motility (by means of a dopamine and serotonin antagonist function); in addition gingerols inhibit the growth of H. pylori, which is considered to play a possible role in NVP/HG pathogenesis as previously mentioned.⁴² Ginger use is safe in pregnancy; only in patients on anticoagulant therapy is it not recommended because it may inhibit platelet function.^30,43

Alternative medicine

Alternative medicine based on acupressure/acupuncture practice has been reported by several researchers to significantly decrease the occurrence of nausea, vomiting and retching in women with NVP.³⁰ Not all studies are unanimous. In a systematic review of randomized trials, P6 (Neiguan) point acupuncture or an acupressure wristband was not significantly more effective than placebo.⁴⁴ On the other hand, recently Galeshi et al. compared the effects of pressure on P6 and KID21 (Youmen) points on the severity of nausea and vomiting in pregnancy. This study showed decreased NVP in both groups (p <0.001) and there was no significant difference between the two groups in terms of the severity of NVP, although the reduction in nausea was greater in the P6 group than the KID21 group, and the reduction in vomiting was better in the KID21 group than the P6 group. No side-effects were observed, confirming this procedure as a possible safe option to relief NVP.⁴⁵ Aromatherapy is another type of complementary medicine that is variably used in NVP and consists of the inhalation of peppermint oil and lemon for example.^46,47 Kia et al. observed that there was a statistically significant difference between two study groups in the mean scores of nausea and vomiting on the second and fourth days of lemon inhalation (p = 0.017 and p = 0.039, respectively). The mean of nausea and vomiting intensity in the second and fourth days in the intervention group were significantly lower than the control group, demonstrating that lemon scent can be effective in reducing nausea and vomiting of pregnancy.⁴⁷

Thiamine supplementation

An important early intervention in NVP and especially HG is the thiamine supplementation. Thiamine pyrophosphate is the biological active form of vitamin B1. It is an essential co-enzyme in several biochemical pathways, many in the brain. The daily requirement of thiamine increases to 1.5 mg/day during pregnancy and can be even more owing to impaired absorption due to HG (daily thiamine requirement is around 1.1 mg/day for non-pregnant females).⁴⁸ Early thiamine replacement is helpful to reduce maternal morbidity, especially Wernicke's encephalopathy in severe cases.⁴⁹

Fluid rehydration

Prompt maternal hydration is crucial to relieve many of the symptoms of NVP and HG. In mild–moderate cases, healthcare providers should advise adequate fluid intake during the day. In moderate–severe cases, intravenous fluid rehydration could be required. In these patients, in addition to fluid replacement, parental nutrition and vitamin and mineral supplementation will help to correct any electrolyte imbalance.³⁰

Pharmacologic interventions

Antihistamines

These drugs are commonly used during early pregnancy for nausea and vomiting. First generation H1-receptors antagonists act by decreasing stimulation of the vomiting center (diphenhydramine, dimenhydrinate, meclizine, doxylamine). The majority of reviews report a lack of negative association between prenatal antihistamine exposure and birth defects.⁵⁰ These drugs are classified as pregnancy category B. Of special interest is the use of doxylamine, with or without pyridoxine, to control NVP. The ACOG recommends that these agents, singly or in combination, can be used as first line treatment.⁵¹ Pyridoxine (vitamin B6, pregnancy category A) is a water soluble vitamin involved in the metabolism of aminoacids, lipid and carbohydrates. Doxylamine-pyridoxine combination has been widely used around the world; studies and meta-analysis support their efficacy on nausea and vomiting, as well as their maternal and fetal safety.^30,52

Antiemetics

Dopamine antagonists (chlorpromazine, prochlorperazine maleate) reduce symptoms in NVP and HG, but fall in pregnancy category C. Their use in early pregnancy has been associated with a slightly increased risk of birth defects. Another member of this group, promethazine (used in pregnancy despite the classification in category C) was not found to be associated with teratogenic effects. Nevertheless, it is considered as a second line option for NVP, especially as an alternative of doxylamine.³⁰

Benzamides

Metoclopramide is a dopamine and serotonin receptor antagonist, largely used for NVP. It improves gastric transit and motility. It is a pregnancy category B and seems to be free of risks for congenital malformations or other adverse pregnancy outcomes. Its chronic use is associated with maternal drowsiness, dizziness, dystonia and tardive dyskinesia. Owing to these possible maternal side-effects it is considered as a third-line therapy for NVP.^30,51

Serotonin receptor antagonists

These molecules are considered to be the most effective antiemetic drugs available on the market and are commonly prescribed, even if there are controversial opinions and conflicting data between experts. Ondansetron, one of the most known and used, is classified as pregnancy category B. It works both centrally and peripherally by blocking serotonin receptors in the small bowel and medullary vomiting center. The scientific literature is divided regarding the risks derived from its use in pregnancy. Several studies reported a low major teratogenic risk with ondansetron, but that an increased risk for a cardiac septum defect is likely.⁵³ Several studies described a small increased risk of orofacial clefts.^54,55 Picot et al. recently reported that no statistically significant association was observed for major congenital malformations, overall cardiac malformations, atrial septal defects and cleft lip with or without cleft palate. Exploratory investigations of other malformations showed an increased and dose-dependent risks of diaphragmatic hernia, respiratory system anomalies, hypoplastic left heart, ventricular septal defect and renal agenesis/dysgenesis.^56,57 Recent reviews about ondansetron safety during pregnancy concluded that there is no strong evidence of harm to preclude its use in pregnancy.⁵⁸

In the past, researchers had evaluated the pharmacodynamics of granisetron (pregnancy category B) as another option for treating NVP. Caritis et al. studied the effects of granisetron administered with a transdermal patch to women with NVP. The study demonstrated a good profile in improving symptoms of nausea and vomiting. Moreover, this patch was useful in women who can not tolerate oral medications.⁵⁹ More recently, Shapira et al. observed that granisetron exposure was not associated with increased risk for minor or major fetal anomalies, providing preliminary reassurance regarding the safety of in utero exposure, but further studies are needed.⁶⁰

Corticosteroids

Corticosteroids seem to exert an antiemetic effect on the trigger zone in the brainstem. This resulted in the consideration and use this medication in refractory cases of HG. There are conflicting data (regarding fetal safety) and opinions on this option; currently there are no established guidelines for its use. ACOG includes it in its algorithm of therapeutic treatment of NVP methylprednisolone as a latest option in cases of persistent symptoms.⁵¹

Psychological interventions

Several studies have investigated the potential role of psychological factors in the etiology of NVP/HG. There are controversial positions on this topic. Experts who believe in the theory of a psychological origin of NVP suggest specific interventions that can be variably associated to other pharmacological and non-pharmacological strategies in order to relieve symptoms. Overall, psychological interventions for nausea and vomiting during pregnancy fall into four categories:

• Behavioral therapy;
• Mindfulness-based cognitive therapy;
• Hypnosis;
• Progressive muscle relaxing.

A systematic review of studies on this topic evaluated them as being of poor methodological quality. Further research is needed to provide strong evidence on the effectiveness of psychological therapies for women suffering from NVP.⁶¹

Table 4 lists the available interventions in case of NVP and HG.

NVP FROM THE PERSPECTIVE OF THE FETUS-NEWBORN

The existing scientific literature has examined NVP mainly from the perspective of the mother, and less is known about the fetus and newborn aspects. Possible offspring outcomes in a multi-ethnic Asian cohort have been researched. Results showed that compared to children of mothers who had no or mild–moderate NVP, children with exposure to severe NVP exhibited more externalizing behaviors and social communication difficulties before 2 years, both externalizing and internalizing behaviors at 2 years, and only internalizing behaviors after 2 years.⁶² Similarly, Parker et al. observed that NVP was associated with slightly worse visual motor performance, and prolonged NVP and NVP extending late into pregnancy were associated with poorer scores on several neurodevelopmental measures.⁶³ NVP is also cited as a possible cardiovascular risk factor at school age: maternal daily vomiting during early pregnancy is associated with higher childhood total body fat mass and abdominal fat mass levels, but not with other cardiovascular risk factors.⁶⁴ Whitehouse et al. investigated whether the presence and severity of NVP may be related to symptom severity in offspring with autism spectrum disorders (ASD).  A large sample of children with ASD was investigated (227 males and 60 females, aged 2–18 years). The frequency and severity of nausea and vomiting during the pregnancy of the child was assessed on a 5-point scale the frequency and severity of nausea and vomiting during the pregnancy of the child being assessed: no NVP during the pregnancy, occasional nausea, but no vomiting, daily nausea, but no vomiting. The strong, positive association between increasing frequency and severity of NVP and ASD severity in offspring provides evidence that exposure to an atypical hormonal environment during prenatal life may affect neurodevelopment and contribute to the ASD phenotype.

CONCLUSIONS

Nausea and vomiting of pregnancy are frequent conditions that healthcare professionals often face in daily clinical practice. An accurate differential diagnosis and a careful measurement of the severity of the condition over time are important for management decisions, as well as for research into different therapeutic modalities.

PRACTICE RECOMMENDATIONS