A condition of severe, prolonged, and persistent vomiting during pregnancy is called

Nausea, Vomiting, and Hyperemesis Gravidarum (SeeChapter 15)

In their first trimester, 60% to 70% of pregnant women report having some nausea, and more than 40% report vomiting.51,52 Onset of these symptoms is typically in the 4th to 6th week of gestation, with a peak occurrence in the 8th to 12th week and resolution by week 20. Although nausea and vomiting may vary from mild to severe, most affected individuals are still able to obtain adequate oral nutrition and hydration, in some cases by eating frequent small meals of dry starchy foods. Hp infection in pregnant women may contribute to the development of vomiting.53

Severe persistent vomiting demanding medical intervention, orhyperemesis gravidarum, is less common, occurring in 2% or less of pregnancies.54,55 Hyperemesis is accompanied by fluid, electrolyte, and acid-base imbalances, nutritional deficiency, and weight loss and is defined by the presence of ketonuria and a 5% decrease from pre-pregnancy weight. It may be associated with pyrosis, hematemesis, and hypersalivation (ptyalism).56 Although the prognosis of hyperemesis gravidarum is generally favorable, severe untreated disease may lead to significant maternal and fetal morbidity. Symptoms usually begin at weeks 4 to 5 and improve by weeks 14 to 16 of gestation. In up to 20% of affected patients, however, vomiting persists until delivery.57 Hyperemesis frequently recurs in subsequent pregnancies. Reported risk factors for hyperemesis include a personal or family history of the disorder,58 a female fetus or multiple gestation, gestational trophoblastic disease, fetal trisomy 21, hydrops fetalis, and maternal Hp infection.59

The etiology of hyperemesis gravidarum is likely multifactorial, including contributions by hormonal changes, GI dysmotility, Hp infection, and psychosocial factors. A genetic predisposition is suggested by familial clusters of the disease. Pregnancy-related hormones, specifically HCG and estrogen, have been implicated as important causes of hyperemesis.60 Symptoms worsen during periods of peak HCG concentrations, and conditions associated with higher serum HCG levels, such as multiple gestation, trophoblastic disease, and trisomy 21, are associated with an increased incidence of hyperemesis.61 Elevated serum estrogen concentrations, as seen in obese patients, have also been associated with this disorder.62 Estrogen and progesterone are thought to cause nausea and vomiting by altering gastric motility and slowing GI transit time.63 Other hormones implicated in the pathogenesis of hyperemesis include thyroid hormones and gut-derived hormones, ghrelin, and leptin.64,65 Abnormal thyroid function test results are found in two thirds of patients with hyperemesis gravidarum.66 The alpha subunit of HCG has thyroid-stimulating hormone-like activity that suppresses endogenous thyroid-stimulating hormone release and causes a slight rise in free thyroxine (T4) levels.67 Despite these findings, this transient gestational thyrotoxicosis is not associated with unfavorable pregnancy outcomes and does not usually require treatment. An increased risk of hyperemesis has been found in 2 meta-analyses of Hp infection during pregnancy.68,69 Some authors have documented symptomatic improvement in pregnant patients with vomiting after Hp eradication.70,71

Clinical Features and Pathophysiologic Considerations

Women with multiple fetuses or with molar pregnancies (i.e., hydatidiform mole) tend to have extremely high concentrations of human chorionic gonadotropin (hCG) and have a higher incidence of hyperemesis gravidarum; however, the causal relationship between elevated hCG levels and hyperemesis gravidarum has not been firmly established. Patients with hyperemesis gravidarum also have abnormal thyroid function tests, and they may exhibit signs and symptoms of hyperthyroidism. Because hCG has intrinsic thyroid-stimulating activity and hyperthyroidism is a known cause of vomiting, these observations deserve further investigations. Mild abnormalities of liver chemistry tests are often present. The role of psychological derangements in the pathogenesis of hyperemesis gravidarum is controversial.

Wernicke Encephalopathy and Hyperemesis Gravidarum

More than three-fourths of women experience nausea and vomiting during pregnancy, most commonly between 6 and 16 weeks’ gestation. When vomiting becomes severe enough to result in weight loss (5% of prepregnancy weight), metabolic derangement, or dehydration (high urine specific gravity), the condition is termedhyperemesis gravidarum. There is no international consensus on a definition, making studies on this entity difficult to conduct and interpret (Koot et al., 2018). Commonly, hyperemesis is isolated and idiopathic, affecting less than 1% of pregnancies. Molar pregnancy, hyperthyroidism, and hepatitis are differential diagnostic considerations. Hypokalemia associated with hyperemesis gravidarum is blamed for rare cardiac arrest, respiratory arrest, and fetal loss (Walch et al., 2018). Studies on treatment with vitamin B6 (pyridoxine), 10–25 mg three times daily for 5 days DMS, showed little benefit, but enthusiasts continue to recommend this treatment, sometimes with ginger. However, a meta-analysis found that affected women taking vitamin B6 spend more days in hospital (Boelig et al., 2018). Antihistamines, metoclopramide, and steroids have been recommended in an approach proportionate to the severity of the medical condition (Niebyl, 2010). A literature review found no difference in efficacy among the use of metoclopramide, ondansetron, and promethazine, recommending that a choice may be determined based on cost and side effects of these medications (Boelig et al., 2018). Other authors suggest further investigation into the use of mirtazapine (Abramowitz et al., 2017). National guidelines describing a treatment approach have been updated (Committee on Obstetric Practice, 2018). Although US national guidelines recommend against gestational marijuana use (Committee on Obstetric Practice, Committee opinion, 2017), the practice is common in states where consumption is legal. In Northern California researchers find that use of marijuana for severe, mild, and no nausea and vomiting were 11.3%, 8.4%, and 4.5% respectively, despite lack of demonstrated efficacy or safety (Young-Wolff et al., 2018).

In the context of hyperemesis gravidarum, apathy, drowsiness, memory loss, catatonia, ophthalmoplegia, nystagmus, ataxia, and optic neuropathy, with or without optic disc edema, may result individually or together, typically between 14 and 20 weeks’ gestation. These clinical features are emblematic ofWernicke encephalopathy (seeChapter 85). A subtle presentation can delay prompt diagnosis. This condition is sometimes associated with gestational polyneuropathy and central pontine myelinolysis. Exacerbating factors include persistence of thehyperemesis over at least 2 weeks and the administration of intravenous glucose without other nutrients.

Death or severe morbidity results when this condition is not treated. In a small study, only half of women with this condition delivered normal children. The amount and duration of parenteral thiamine supplementation required is unknown and must be titrated to the clinical state. The Royal College of Physicians endorses a protocol employing intravenous Thiamine 500 mg three times daily for 2-3 days followed by 250 mg daily for 3-5 days, then oral thiamine 100 mg three times daily. Treatment with multiple vitamins IV, correcting hypomagesemia, and potentially fatal hypokalemia remain elements essential to maternal and fetal recovery (Thomson, A, 2012). Despite therapy, some women continue to have ataxia and visual difficulties months to years afterward. Several researchers suggest treating any patient with prolonged nausea and vomiting with oral thiamine, 100 mg daily, and those admitted to the hospital with 150 mg daily DMS (Jarvis and Nelson-Piercy, 2011) (Fig. 112.3).

Diagnosis

Hyperemesis gravidarum is a diagnosis of exclusion. All other causes of nausea and vomiting must be ruled out before the diagnosis of hyperemesis gravidarum is made. Hyperemesis gravidarum is a diagnosis of the first trimester of the pregnancy. After the first trimester of pregnancy, a different diagnosis should be entertained for any pregnant patient with severe, persistent vomiting and dehydration. Pancreatitis, cholecystitis, hepatitis, thyroid disease, gastroenteritis, peptic ulcer disease, fatty liver of pregnancy, appendicitis, diabetic autonomic dysfunction, pyelonephritis, and gestational trophoblastic disease (i.e., complete/partial molar pregnancy) can also mimic hyperemesis gravidarum.

Hyperemesis Gravidarum

HG is a severe pathologic form of NVP characterized by a greater than 5% loss of prepregnancy weight and otherwise unexplained ketonuria. HG is much less common than NVP and occurs in only about 0.5% of pregnancies. Like NVP, HG typically begins early in pregnancy; severe vomiting that begins after the first trimester is unlikely from HG and additional workup should be considered in such cases, including serum liver function tests, lipase levels, and imaging studies.

Aside from severe nausea and vomiting, symptoms of HG may include xerostomia, sialorrhea or ptyalism, and dysgeusia. Physical findings reflective of hypovolemia include dry mucous membranes, poor skin turgor, and orthostatic hypotension or hypotension. Serum electrolyte abnormalities include hyponatremia, hypocalcemia, and hypokalemia. Patients may demonstrate prerenal azotemia, and chronic vomiting of gastric contents may cause hypochloremic metabolic alkalosis. An increased hematocrit reflects hemoconcentration from hypovolemia. Patients with severe vomiting may develop abnormal liver function tests, particularly elevations of the serum aminotransferases. Patients may exhibit mild biochemical hyperthyroidism that manifests as low thyroid-stimulating hormone (TSH) levels as a result of elevated serum hCG levels, and inadequate nutrition may lead to vitamin or micronutrient deficiencies.

Patients with more severe NVP may benefit from drug therapy. Bendectin—which contains vitamin B6 and doxylamine, an antihistamine—was once commonly administered for NVP but was withdrawn in 1983 due to unproven allegations of teratogenicity.35 A subsequent meta-analysis reported no increase in the incidence of birth defects after in utero exposure to Bendectin.36 A delayed-release form ofdoxylamine-pyridoxine (Diclegis in the United States or Diclectin in Canada) is currently approved to treat NVP, and it has been shown in multiple randomized, controlled trials to be more effective than placebo in treating NVP.35 However, it is important to note that no studies have been performed to compare its effectiveness with the combination of doxylamine and pyridoxine taken concurrently as separate pills, and the cost of this option is likely to be significantly less than the combined delayed-release form.

If the initial approach with doxylamine and pyridoxine is ineffective, consideration can be given to an alternate antihistamine or to adding a dopamine antagonist.Dopamine antagonists—such as promethazine, prochlorperazine, and metoclopramide—are thought to work both by increasing gastric motility and by centrally suppressing emetic signaling, and they have been used with success. Fetal data are reassuring, with no increased rates of spontaneous abortion or malformation. Maternal side effects are rare but can include dystonic reactions or tardive dyskinesia, which may be irreversible even after discontinuation of the medication.37

Hyperemesis Gravidarum

Hyperemesis gravidarum is an uncommon condition associated with pregnancy. It is defined as severe nausea and vomiting in women at less than 16 weeks’ gestation, resulting in more than 5% weight loss, dehydration, and large ketonuria. Patients may present with hyponatremia, hypokalemia, hypochloremic acidosis, and abnormal liver function. This condition generally begins early in pregnancy (6 to 9 weeks of gestation) and full resolution is usually seen by weeks 18 to 20. Patients often require hospitalization for intravenous fluid hydration, electrolyte repletion, treatment with sedatives, antiemetics, and, depending on severity, corticosteroids.

The prevalence of hyperemesis gravidarum is not known exactly, with reports varying from 0.5% to 1.5% of pregnancies.40-45 The variations in prevalence are partly caused by the different definitions of hyperemesis gravidarum. The severity of the nausea and vomiting may also be overlooked and considered normal morning sickness. There is a higher prevalence among Asians than whites, and one study has reported that 4.5% of pregnancies in Kuwait were complicated by hyperemesis gravidarum.46

The cause of hyperemesis gravidarum is unknown. Excess hCG has been a proposed mechanism, and serum hCG has been found in higher concentrations in patients with increasing severity of vomiting (Fig. 16-5).47 However, in some reports, hCG concentrations have also been found to be no different in patients with hyperemesis gravidarum when compared with nonhyperemetic patients.21,48 In patients with hyperemesis gravidarum, hCG isoforms with higher thyrotropic activity have been isolated.37 Whether there may be some other associated action of hCG in hyperemetic patients is unknown. Some patients with very high concentrations of hCG do not have hyperemesis. A higher estrogen concentration has been suggested as the cause of the vomiting, because there was a direct relationship between the degree of vomiting and estrogen concentration,47,49 and high levels of estrogen have been known to induce nausea and vomiting. However, the exact cause of hyperemesis gravidarum has yet to be established.

Hyperemesis Gravidarum

Hyperemesis gravidarum (HG) occurs in less than 2% of pregnancies, starting in the first trimester and resolving by week 20 of gestation. It is characterized by severe nausea and vomiting, with electrolyte disturbances that can require hospitalization. Weight loss exceeds 5% of prepregnancy body weight. HG is more common in primiparous women and may be associated with mild elevation of transaminase levels. The cause of HG is unclear, but predisposing factors might include female gender of the fetus. Rehydration and antiemetics are useful. The outcome for the mother is benign except when severe vomiting causes esophageal rupture, vascular depletion, and renal damage. Adverse infant outcomes such as prematurity and low birth weight are rare and seem to occur because of poor maternal weight gain later in the pregnancy.

Hyperemesis Gravidarum (HG)

HG is a severe form of morning sickness, where persistent vomiting is associated with weight loss exceeding 5% of pre-pregnancy body weight. Ketonuria, unrelated to other causes, may be present. Liver dysfunction can occur in women with HG and usually occurs within 1–3 weeks after the onset of severe vomiting. Moderate increases in the serum aminotransferases can occur in approximately 50% of hospitalized patients, usually with values in the low hundreds, and rarely as high as 1000 IU/l.11 The ALT is typically elevated to a greater extent than the AST. Hyperbilirubinemia can occur, but rarely exceeds 3–4 mg/dl.12

HG is not a liver disease per se, and the cause of the hepatic enzyme abnormalities is unknown. The degree of abnormality in the blood tests correlates with the severity of the vomiting; the highest elevations are seen in patients with the most severe or protracted vomiting. It is suspected that the liver abnormalities may be related to dehydration and relative malnutrition. Abnormal liver biochemical tests resolve promptly upon resolution of the vomiting; however, hyperemesis gravidarum, along with liver enzyme abnormalities, often recurs in subsequent pregnancies.12

Clinical Features and Diagnosis

Hyperemesis gravidarum (HG) is intractable vomiting of such severity as to necessitate intravenous hydration. HG occurs in the first trimester of pregnancy, typically between 4 and 10 weeks of gestation, with risk factors being adolescent pregnancy, multiparity, twins, and hydatiform mole. Patients become severely dehydrated and may lose >5% of prepregnancy weight. High transaminase levels (up to a 20-fold increase) occur in 25–50% of cases and occasionally patients have mild jaundice. A clinical diagnosis is made based on the severity and timing of vomiting; mild to moderate vomiting in pregnancy does not cause liver dysfunction. Viral hepatitis must be considered but liver biopsy is necessary only to exclude other serious diagnoses.

Hyperemesis Gravidarum

Hyperemesis gravidarum is characterized by prolonged and severe nausea and vomiting in early pregnancy and is associated with a loss of 5% body weight, dehydration, and ketosis. It occurs in approximately 1–1.5% of pregnancies, is more prevalent in Asian women than in Caucasians, and is more common with multiple gestations. Abnormalities of serum chemistries include hyponatremia, hypokalemia, hypochloremic alkalosis, and abnormalities of liver function. There is a positive correlation between the severity of vomiting and serum hCG level.

The majority of hyperemesis patients have a suppressed serum TSH level and increased free thyroxine concentration. Free thyroxine and TSH levels normalize when the hyperemesis resolves in the second trimester. In general, these patients do not have clinical features of hyperthyroidism or goiter. The hyperthyroidism is most likely due to a less sialylated hCG, which stimulates the TSH receptor to a greater extent, although it has a reduced serum half-life.

In most patients, the increased thyroid function of hyperemesis gravidarum is self-limited and subsides with the disappearance of vomiting. In a small percentage of patients, however, there is clear clinical evidence of hyperthyroidism; this has been termed transient hyperthyroidism of hyperemesis gravidarum or gestational thyrotoxicosis. In these situations, the diagnosis of Graves׳ disease should be excluded. Treatment with antithyroid drugs does not influence the course of hyperemesis gravidarum, even when associated with elevated thyroid function tests. If they are used, these drugs should be discontinued as soon as thyroid function tests return to normal and the vomiting subsides.