Nausea and Vomiting in Pregnancy

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AUTHORS

Valentina Tosto

Center of Perinatal and Reproductive Medicine, Department of Obstetrics and Gynecology, University of Perugia, Italy Valentina Tsibizova

Almazov National Medical Research Center, Health Ministry of Russian Federation, Saint Petersburg, Russia Gian Carlo Di Renzo

Center of Perinatal and Reproductive Medicine, Department of Obstetrics and Gynecology, University of Perugia, Italy

ABSTRACT

Nausea and vomiting are commonly experienced symptoms in pregnancy, especially in early pregnancy. There are considerable risks and e ects on pregnant women who experience this condition. Nausea and vomiting a ect up to 70– 85% of all women during gestation and for the majority self-management su ces. 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, di erential diagnosis with pathological conditions characterized by nausea and vomiting is required to

exclude other speci c diseases. Overall, the morbidity in pregnant women with nausea and vomiting in pregnancy (NVP) is signi cant, 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 uid 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 a ecting up to 70–85% of all women during the rst half of pregnancy.1_{Symptoms usually start between 6 and 8 weeks of gestation, rise to a peak} This chapter should be cited as follows:

Tosto V, Tsibizova V, et al, Glob. libr. women's med., ISSN: 1756-2228; DOI 10.3843/GLOWM.415723

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 6

PREGNANCY COMPLAINTS AND COMPLICATIONS: CLINICAL

PRESENTATIONS

Volume Editor: Professor Gian Carlo Di Renzo, University of Perugia, Italy

Chapter

Nausea and Vomiting in

Pregnancy

First published: February 2021

The Continuous Textbook of Women\'s Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.415723 30/06/2021

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before the end of the rst 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 e ects on relationships with family and friends.3_{The most severe form} of NVP is referred to as hyperemesis gravidarum (HG), and is reported to a ect 0.3–1.0% of pregnant women.1_{It is} characterized by severe vomiting, dehydration, ketosis, electrolyte imbalance, nutritional de ciencies and weight loss (usually de ned as >5% of pre-pregnancy weight decrease). However, there is no absolute accepted cut-o 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 insu cient to make a diagnosis of HG. For these reasons, study populations are seldom described as having HG, and are more frequently de ned 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.

Table 1 Nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) origin: a multifactorial genesis. Genetic

predisposition

Twins5,6 Family history:

NVP/HG in mothers and sisters7,8,9 Increased risk of recurrence10

Ethnicity Geographical heterogeneity11,12

More commonly reported in Indian, Pakistan, Asian and New Zealand populations13

Placentally mediated mechanisms

Possible linear correlation with placental volume14 Correlation with pre-eclampsia, abruption placentae15 Placental weight-to-birth weight ratio16

Correlation with hormonal changes

Endocrine factors and hormones

Human chorionic gonadotropin17 Thyroid hormones18,19,20

Estrogen, progesterone, leptin, prolactin, adrenocorticotropin hormone20,21

Gastrointestinal dysmotility

Differences in reported data

Gastric emptying timing, elastogastrography activity study22,23,24,25 Helicobacter

pylori infection

Controversial data

Numerous studies support a relevant correlation between H. pylori infection and NP/HG27,28,29,30 H. pylori may exacerbate hormone-induced modifications in the electric and nerve functioning of the stomach30,33

Serotonin Influences autonomic gastrointestinal functions including gastric dysmotility, secretion and visceral sensitivity34

Pharmacological effects of serotonin receptor antagonists molecules suggested a role of higher serotonin levels in NVP/HG patients30

Psychological

Lack of studies and conflicting opinions • • – • • • • • • • • • • • • • • • • •

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theories Lack of studies and conflicting opinions

Psychosomatic and psychological theories include resentment or ambivalence towards the pregnancy, immaturity, conversion disorder, symptom of hysteria, neurosis or depression, stress, anxiety, and depression mood, employment status, family support35

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 ndings, 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 rst pregnancy have a signi cant risk of recurrence when compared to women who did not experience the condition in their rst 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 o spring.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 su ering from HG than in non-su erers.17

Gestational transient thyrotoxicosis, has been reported in 60% of women su ering 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”.

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Gastrointestinal factors

Delayed gastric emptying related to relaxation of smooth muscle during pregnancy may in uence NVP symptoms. This theory was rst 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 di erence 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 su ering from HG.26_{Data related to this topic are controversial. H. pylori is more} common identi ed 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 signi cant 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 signi cant association and most infected women were asymptomatic.31,32 The con icting 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 di erent symptoms.12,30_{In terms of the pathogenetic mechanism, it has been suggested that H.} pylori may exacerbate hormone-induced modi cations 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 nd any di erence 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 de nitive 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 a ictions are a consequence of the condition rather than a cause.

ASSESSMENT AND DIAGNOSIS

The diagnosis of NVP/HG is made after excluding di erential 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,}

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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 Quanti cation 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.

Table 2 Di erential diagnosis: non pregnancy-related diseases and disorders associated with NVP.37

Mechanical obstruction Stomach, duodenum, small bowel, colon, hepatobiliary duct disease, pancreatic duct disease

Intestinal pseudo-obstruction

(visceral neuropathy, myopathy)

Scleroderma, amyloidosis, idiopathic

Gastroparesis Post-operative, diabetic gastroparesis

Peptic disease Esophagus: re ux

Stomach: gastritis, ulcer, H. pylori Duodenum: duodenitis, ulcer

Vagotomy Post-operative

Peritoneal irritation Peritonitis, cancer, irradiation

Carcinoma Gastric, ovarian, hypernephroma, paraneoplastic syndrome

Metabolic-hormonal Diabetes mellitus, hyperthyroidism, hypothyroidism, hypercalcemia, uremia, Addison's disease

Drugs

Central nervous system disease Migraine, infections, tumors, raised intracranial pressure, vestibular nerve-brain stem lesions

Psychological – psychiatric disorders Eating disorders

Table 3 Scales to assess the severity of nausea and vomiting in pregnancy/hyperemesis gravidarum (NVP/HG). Scale Description

PUQE score Three questions regarding nausea, vomiting and retching during previous 12 hours (or PUQE-24 = previous PUQE-24 hours)

For each component: 0 = no symptoms, 5 = worst possible symptoms Maximum score = 15

Scores of ≥13 indicate severe symptoms

RINVR Eight questions about duration/amount, frequency and distress caused by symptoms of nausea, vomiting and retching

For each component: 0 = no symptoms, 5 = worst possible symptoms Maximum score = 40

Scores of ≥33 indicated severe symptoms

McGill Nausea

Contains a nausea rating index (nine sets of words which describe sensory, affective, evaluative • • • • • • • • •

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questionnaire

(considers nausea only)

Contains a nausea rating index (nine sets of words which describe sensory, affective, evaluative and miscellaneous afferent feelings related to nausea that patients rank)

An overall nausea index (0–5, where 0 = no symptoms, 5 = excruciating symptoms) Plus a VAS: 0 cm = no nausea, 10 cm = extreme nausea

NVPI Three questions relating to nausea, retching and vomiting over the past 7 days For each component: 0 = no symptoms, 5 = worst possible symptoms

Maximum score = 15

A score of ≥8 indicates severe symptoms

VAS Patients rate their symptoms on a scale of 0–10, where 0 = no symptoms, 10 = extreme symptoms

Scale Description

NVPI, Nausea and Vomiting of Pregnancy Instrument; PUQE, Pregnancy-Unique Quanti cation of Emesis and Nausea; RINVR, Rhodes Index of Nausea, Vomiting and Retching; VAS, visual analog scale.

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 uids} 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 e ects 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 in uencing 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 signi cantly 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 signi cantly more e ective than placebo.44 On the other hand, recently Galeshi et al. compared the e ects 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 signi cant di erence 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-e ects were observed, con rming this procedure as a possible

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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 signi cant di erence 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 signi cantly lower than the control group, demonstrating that lemon scent can be e ective 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 uid intake during the day. In moderate–severe cases, intravenous uid rehydration could be required. In these patients, in addition to uid 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 classi ed 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

rst 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 e cacy 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 classi cation in category C) was not found to be associated with teratogenic e ects. 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-e ects it is considered as a third-line therapy for NVP.30,51

Serotonin receptor antagonists

These molecules are considered to be the most e ective antiemetic drugs available on the market and are commonly prescribed, even if there are controversial opinions and con icting data between experts. Ondansetron, one of the most known and used, is classi ed as pregnancy category B. It works both centrally and peripherally by blocking serotonin

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receptors in the small bowel and medullary vomiting center. The scienti c 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 signi cant 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 e ects of granisetron administered with a transdermal patch to women with NVP. The study demonstrated a good pro le 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 e ect on the trigger zone in the brainstem. This resulted in the

consideration and use this medication in refractory cases of HG. There are con icting 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 speci c 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:

1) Behavioral therapy;

2) Mindfulness-based cognitive therapy; 3) Hypnosis;

4) 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 e ectiveness of psychological therapies for women su ering from NVP.61 Table 4 lists the available interventions in case of NVP and HG.

Table 4 Nausea and vomiting in pregnancy/hyperemesis gravidarum (NVP/HG) available interventions. Key elements of

care

Usually multistep level of care according to medical conditions:

primary care (general practice – GP appointment; midwife consultation, gynecologist consultation)

secondary care (inpatient admission, emergency attendances, ambulance service call) Several options available:

non-pharmacological and pharmacological off label use for several drugs

combination of interventions if needed

Consider hospitalization in severe and refractory cases

Interventions

Conservative measures – first line

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Conservative measures – first line

diet and fluid intake advice (small and more frequent amounts) thiamine supplementation ginger leaflet rest no treatment First-line pharmacotherapy antihistamines

antihistamines + vit B6 (doxylamine + pyridoxine)

Second-line pharmacotherapy

antiemetics benzamides

serotonin receptor antagonists (ondansetron, granisetron; off label use)

Third-line therapy (severe and refractory cases/persistent symptoms)

corticosteroids (methylprednisolone orally or intramuscularly)49

Alternative medicine

acupuncture/acupressure (P6 and KID21 points) aromatherapy (inhalation of peppermint oil, lemon)

Psychological interventions:

behavioral therapy

mindfulness-based cognitive therapy hypnosis

progressive muscle relaxing

NVP FROM THE PERSPECTIVE OF THE FETUS-NEWBORN

The existing scienti c literature has examined NVP mainly from the perspective of the mother, and less is known about the fetus and newborn aspects. Possible o spring 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 di culties 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 o spring 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 o spring provides evidence that exposure to an atypical hormonal environment during prenatal life may a ect 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 di erential diagnosis and a careful measurement of the severity of the condition over time are important for management decisions, as well as for research into di erent therapeutic modalities.

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PRACTICE RECOMMENDATIONS

Consider differential diagnosis: nausea and vomiting in pregnancy (NVP) are very frequent. Remember NPV can be part of the clinical expression of severe pathologies.

Definition of the level of severity of NVP guides adequate management.

Multistep level of care should guide available interventions: multidisciplinary management if needed, combination of interventions if required, close monitoring of maternal-fetal wellbeing.

CONFLICTS OF INTEREST

The authors of this chapter declare that they have no interests that con ict with the contents of the chapter. •

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REFERENCES

1 Ellila P, Laitinen L, Nurmi M, et al. Nausea and vomiting of pregnancy: A study with pregnancy-unique quanti cation of emesis

questionnaire. Eur J Obstet Gynecol Reprod Biol 2018;230–60–67.

2 Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy. BMJ 2011;342:d3606. 10.1136/bmj.d3606.

3 Attard CL, Kohli MA, Coleman S, et al. The burden of illness of severe nausea and vomiting of pregnancy in the United States. Am J

Obstet Gynecol 2002;186:S220–7. 10.1067/mob.2002.122605.

4 Jueckstock JK, Kaestner R, Mylonas I. Managing hyperemesis gravidarum: a multimodal challenge. BMC Med 2010;8:46.

10.1186/1741-7015-8-46.

5 Corey LA, Berg K, Solaas MH, et al. The epidemiology of pregnancy complications and outcome in a Norwegian twin population. Obstet

Gynecol 1992;80:989–94

6 Colodro-Conde L, Jern P, Johansson A, et al. Nausea and Vomiting During Pregnancy is Highly Heritable. Behav Genet 2016.

7 Fejzo MS, Poursharif B, Korst LM, et al. Symptoms and pregnancy outcomes associated with extreme weight loss among women with

hyperemesis gravidarum. J Womens Health (Larchmt) 2009;18:1981–7.

8 Zhang Y, Cantor RM, MacGibbon K, et al. Familial aggregation of hyperemesis gravidarum. Am J Obstet Gynecol 2011;204:230, e231–237.

9 Vikanes AV, Skjaerven R, Grijibovski AM, et al. Recurrence of hyperemesis gravidarum across generations: population based cohort

study. BMJ 2010;340:c2050. 10.1097/ogx.0b013e3182021d24.

10 Trogstad LIS, Stoltenberg C, Magnus P, et al. Recurrence risk in hyperemesis gravidarum. Br J Obstet Gynaecol 2005;112:1641–5. 10.1111/j.1471-0528.2005.00765.x

11 Bashiri A, Neumann L, Maymon E, et al. Hyperemesis gravidarum: epidemiologic features, complications and outcome. Eur J Obstet Gynecol Reprod Biol 1995;63:135–8.

12 Lee NM, Saha S. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am 2011;40:309–34.

13 Verberg MF, Gillott DJ, Al-Fardan N, et al. Hyperemesis gravidarum, a literature review. Hum Reprod Update 2005;11:527–39. 14 Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med 2010;363(16):1544–50.

15 Wood A. Second trimester hypermesis gravidarum is associated with increased risk of preterm pre-eclampsia, placental abruption and small for gestational age birth. Evid Based Nurs 2014;17:74.

16 Vandraas KF, Vikanes AV, Stoer NC, et al. Is hypermesis gravidarum associated with placental weight and the placental weight-to-birth weight ratio? A population-based Norwegian cohort study. Placenta 2013;34:990–4.

17 Derbent AU, Yanik FF, Simavli S, et al. First trimester maternal serum PAPP-A and free beta-HCG levels in hyperemesis gravidarum. Prenat Diagn 2011;31:450–3. 10.1002/pd.2715.

18 Goodwin TM, Poursharif B, Korst LM, et al. Secular trends in the treatment of hyperemesis gravidarum. Am J Perinatol 2008;25:141–7. 10.1055/s-2008-1040344.

19 Ismail SK, Kenny L. Review on hyperemesis gravidarum. Baillieres Best Pract Res Clin Gastroenterol 2007;21:755–69. 10.1016/j.bpg.2007.05.008.

20 Yamazaki K, Sato K, Shizume K, et al. Potent thyrotropic activity of human chorionic gonadotrophin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab 1995;80:473–9. 21 Verberg MF, Gillott DJ, Al-Fardan N, et al. Hyperemesis gravidarum, a literature review. Hum Reprod Update 2005;11:527–39.

10.1093/humupd/dmi021.

22 Koch KL, Frissore CL. Nausea and vomiting during pregnancy. Gastroenterol Clin North Am 2003;32:201–34.

23 Riezzo G, Pezzolla F, Darconza G, et al. Gastric myoelectrical activity in the rst trimester of pregnancy: a cutaneous electrogastrographic study. Am J Gastroenterol 1992;87:702–7.

24 Maes BD, Spitz B, Ghoos YF, et al. Gastric emptying in hyperemesis gravidarum and non-dyspeptic pregnancy. Aliment Pharmacol Ther 1999;13237–243.

25 Mac e AG, Magides AD, Richmond MN, et al. Gastric emptying in pregnancy. Br J Anaesth 1991;67:54–7.

26 Sandven I, Abdelnoor M, Nesheim B-I, et al. Helicobacter pylori infection and hyperemesis gravidarum: a systematic review and meta-analysis of case–control studies. Acta Obstet Gynecol Scand 2009;88:1190–200. 10.3109/00016340903284927.

27 Shaban MM, Kandil HO, Elshafei AH. Helicobacter pylori seropositivity in patients with hypermesisi gravidarum. Am J Med Sci 2014;347:101–5.

28 Frigo P, Lang C, Reisenberger K, et al. Hyperemesis gravidarum associated with Helicobacter pylori seropositivity. Obstet Gynecol 1998;91:615–7.

29 Bagis T, Gumurdulu Y, Kayaselcuk F, et al. Endoscopy in hyperemesis gravidarum and Helicobacter pylori infection. Int J Gynaecol Obstet 2002;79:105–9.

30 Bustos M, Venkataramanan R, Caritis S. Nausea and Vomiting of Pregnancy-What's New? Auton Neurosci 2017;202:62–72. 31 Verberg MF, Gillott DJ, Al-Fardan N, et al. Hyperemesis gravidarum, a literature review. Human Reprod Update 2005;11:527–39. 32 Weyermann M, Brenner H, Adler G, et al. Helicobacter pylori infection and the occurrence and severity of gastrointestinal symptoms

during pregnancy. Am J Obstet Gynecol 2003;189:526–31.

33 Goldberg D, Szilagyi A, Graves L. Hyperemesis gravidarum and Helicobacter pylori infection: a systematic review. Obstet Gynecol 2007;110:695–703.

34 Browning KN. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015;9:413. 35 Saberi F, Sadat Z, Abedzadeh-Kalahroudi M, et al. Acupressure and ginger to relieve nausea and vomiting in pregnancy: a randomized

study. Iran Red Crescent Med J 2013;15:854–61. 10.5812/ircmj.12984.

36 Kramer J, Bowen A, Stewart N, et al. Nausea and vomiting of pregnancy: prevalence, severity and relation to psychosocial health. MCN Am J Matern Child Nurs 2013;38(1):21–7.

37 Firoz T, Maltepe C, Einarson A. Nausea and Vomiting in Pregnancy is not always Nausea and Vomiting of Pregnancy. J Obstet Gynaecol 2010;(10):970–2.

38 Ebrahimi N, Maltepe C, Garcia Bournissen F, et al. Nausea and vomiting of pregnancy: using the 24-hour Pregnancy-Unique Quanti cation of Emesis (PUQE-24) scale. J Obstet Gynaecol Can 2009;31(9):803–7.

(12)

39 Bischo SC, Renzer C. Nausea and nutrition. Auton Neurosci 2006;129:22–7.

40 ACOG (American College of Obstetrics and Gynecology). Practice Bullettin: nausea and vomiting of pregnancy. Obstet Gynecol 2004;103:803–4.

41 Viljoen E, Visser J, Koen N, et al. A systematic review and meta-analysis of the e ect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J 2014;13:20.

42 Mahady GB, Pendland SL, Yun GS, et al. Ginger (Zingiber o cinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer Res 2003;23:3699–702.

43 Backon J. Ginger in preventing nausea and vomiting of pregnancy: a caveat due to its thromboxane synthetase activity and e ect on testosterone binding. Eur J Obstet Gynecol Reprod Biol 1991;42:163–4.

44 Matthews A, Haas DM, O'Mathuna DP, et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst rev 2015;9:CD007575.

45 Galeshi M, Ghanbarpour A, Rad MN, et al. A comparison of the e ect of pressure on the KID21 (Youmen) and P6 (Neiguan) points on the severity of nausea and vomiting of pregnancy. J Complement Integr Med 2020;17(2):/j/jcim.2020.17.issue-2/jcim-2019-0035/jcim-2019-0035.xml.

46 Joulaeerad N, Ozgoli G, Hajimehdipoor H, et al. E ect of Aromatherapy with Peppermint Oil on the Severity of Nausea and Vomiting in Pregnancy: A Single-blind, Randomized, Placebo-controlled trial. J Reprod Infert 2018;19(1):32–8.

47 Kia PY, Safajou F, Shahnazi M, et al. The e ect of lemon inhalation aromatherapy on nausea and vomiting of pregnancy: a double-blinded, randomized, controlled clinical trial. Iran Red Crescent Med J 2014;16(3):e14360.

48 Chiossi G, Neri I, Cavazzuti , et al. Hyperemesis gravidarum complicated by Wernicke encephalopathy: background, case report, and review of literature. Obstet Gynecol Surv 2006;61:255–68.

49 Berdai MA, Labib S, Harandou M, et al. Wernicke'a Encephalopathy Complicating Hypermesis during pregnancy. Case Rep Crit Care 2016;2016:8783932.

50 Gilboa SM, Ailes EC, Rai RP, et al. Antihistamines and birth defects: a systematic review of the literature. Expert Opin Drug Saf 2014;13:1667–98.

51 ACOG (American College of Obstetrics and Gynecology). Practice Bullettin: nausea and vomiting of pregnancy. No.189. Obstet Gynecol. 2018;131(1):190–3.

52 Koren G, Clarck S, Hankins GD, et al. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC Pregnancy Childbirth 2015;15:59.

53 Charstairs SD. Ondansetron Use in Pregnancy and Birth defects: a Systematic Review. Obstet Gynecol 2016;127:878–83.

54 Huybrechts KH, hernandez-Diaz S, Straub L, et al. Association of maternal rst-trimester ondansetron use with cardiac malformations and oral clefts in o spring. JAMA 2018;320(23):2429–37.

55 Parker SE, Van Bennekom C, Anderka M, et al. Ondansetron for Treatment of Nausea and Vomiting of Pregnancy and the Risk of Speci c Birth Defects. Obstet Gynecol 2018;132(2):385–94.

56 Picot C, Berard A, Grenet G, et al. Risk of malformation after ondansetron in pregnancy: an updated systematic review and meta-analysis. Birth Defects Res 2020;112(13):996–1013.

57 Lemon LS, Bodnar LM, garrard W, et al. Ondansetron use in the rst trimester of pregnancy and the risk of neonatal ventricular septal defect. Int J Epidemiol 2020;49(2):648–56.

58 Siminerio LL, Bodnar LM, Venkataramanan R, et al. Ondansetron Use in Pregnancy. Obstetrics & Gynecology 2016;127:1–7.

59 Caritis S, Zhao Y, Chen HJ, et al. Pharmacodynamics of transdermal granistetron in women with nausea and vomiting of pregnancy. Am J Obstet Gynecol 2016.

60 Shapira M, Avrahami I, Mazaki-Tovi S, et al. The safety of early pregnancy exposure to granisetron. Eur J Obstet Gynecol Reprod Biol 2020;245:35–8.

61 Emami-Sahebi A, Elyasi F, Yazdani-Charati J, et al. Psychological interventions for nausea and vomiting of pregnancy: A systematic review. Taiwan J Obstet Gynecol 2018;57(5):644–9.

62 Syn NL, Chan SY, Chia EWY, et al. Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: The Growing Up in Singapore Towards Healthy Outcomes study. Paediatr Perinat Epidemiol 2020. doi: 10.1111/ppe.12703.

63 Parker SE, Starr JR, Collett BR, et al. Nausea and vomiting during pregnancy and neurodevelopmental outcomes in o spring. Paediatr Perinat Epidemiol 2014;28(6):527–35.

64 Poeran-Bahadoer S, Jaddoe VWV, Gishti O, et al. Maternal vomiting during early pregnancy and cardiovascular risk factors at school age: the Generation R Study. J Dev Orig Health Dis 2020;11(2):118–26.

65 Whitehouse AJO, Alvares GA, Cleary D, et al. Symptom severity in autism spectrum disorder is related to the frequency and severity of nausea and vomiting during pregnancy: a retrospective case-control study. Mol Autism 2018;9:37.