Hyperemesis Gravidarum and Nutritional Support

Abstract

INTRODUCTION Nausea and vomiting are common symptoms during pregnancy, with a prevalence of 35%–91% (1). The onset of symptoms occurs as early as after the first missed period, peaking between weeks 8–12 of gestation, with improvement as the second trimester progresses. Nausea and vomiting in pregnancy (NVP) was first described around 2000 BC (2). Hyperemesis gravidarum (HG) is the most severe form of NVP, first described in the late 1800s (3). Patients with HG present with intractable nausea and vomiting in the first trimester that is associated with dehydration, electrolyte disturbances, ketosis, and weight loss. HG is associated with higher risks for adverse pregnancy outcomes including preterm birth and low birth weight infants. Thankfully, the prevalence of HG is much lower than NVP at 1.1% worldwide (1). PHYSIOLOGY OF PREGNANCY AND HYPEREMESIS GRAVIDARUM During pregnancy, a variety of anatomical and physiological changes occur (e.g., cardiovascular, endocrine, hematologic, renal, and gastrointestinal systems), which evolve with gestational age (4). Increased progesterone decreases gastric and intestinal transit, and increased placental gastrin increases gastric acidity. As gestation progresses, the uterus expands and displaces the stomach and intestines, increasing intra-abdominal pressure and decreasing lower esophageal sphincter pressure. Together, these changes can lead to symptoms of reflux, early satiety, nausea, vomiting, bloating, and constipation. However, these changes are not known to be associated with HG. To date, the pathophysiology of HG remains unknown but is presumed to be multifactorial. Although recent advances have suggested variants in specific genes encoding placental proteins or hormone receptor genes may be responsible for HG (e.g., GDF15, IGFBP7, PGR, GFRAL), it is too early to implicate these as definite causes of HG (5). SYMPTOMS HG is associated with severe, persistent vomiting, typically beginning before 16 weeks of gestation, leading to an inability to normally eat or drink and resulting in weight loss of greater than 5% of the pregravid weight and severe limitations in activities (6,7). Although symptoms of NVP often begin around 6 weeks of gestation and improve at the start of the second trimester, the nausea and vomiting associated with HG may start earlier and can extend throughout pregnancy and occasionally into the postpartum state. In addition to nausea, vomiting, and weight loss, dehydration and electrolyte derangements may result in acute kidney injury, cardiac arrhythmia, and neuromuscular symptomatology (8–10). In addition to protein-calorie malnutrition, poor oral intake can lead to vitamin deficiencies. Vitamin K deficiency can lead to coagulopathy and bleeding complications while vitamin B1, B6, and B12 deficiencies can cause neuropathy. Patients with HG are at risk for developing Wernicke encephalopathy (e.g., ataxia, nystagmus, confusion) (11). Other complications associated with HG include, but are not limited to, hematemesis from an esophageal tear (Mallory-Weiss tear), esophageal rupture (Boerhaave syndrome), liver injury, pneumothorax, placental detachment or hemorrhage, splenic avulsion, and preretinal hemorrhage (12). EVALUATION History and physical examination The history should include baseline weight; amount of oral intake; and symptoms of fluid, electrolyte, or metabolic imbalance, paying particular attention to nausea and vomiting that began with pregnancy, which can help to distinguish it from other chronic causes of nausea and vomiting. A history of HG increases the likelihood of HG great than 4-folds in future pregnancies (13). Patients with HG can experience posttraumatic stress symptoms that are associated with higher rates of lactation and psychiatric and social problems compared with those without HG or HG without posttraumatic stress symptoms (14), up to 2 years after delivery. In a survey of patients with HG, rates of reported suicidal ideation were over 32% (25.5% occasional, 6.6% regular) and associated with the severity of illness, poor functional status, and perception of quality of care (15); thus, screening for suicidal ideation and a referral to mental health services is important. The physical examination should focus on assessing hydration status (e.g., orthostatic vital signs, mucous membranes, skin turgor), signs of malnutrition (e.g., weight loss, muscle and fat wasting), electrolyte disturbances (e.g., carpopedal spasm), findings specific to various vitamin and mineral deficiencies, and adequacy of fetal growth. It is important to rule out other causes of nausea and vomiting (Table 1) by assessing for abdominal distention, presence of a succussion splash, bowel sounds, or extraintestinal features of systemic diseases (e.g., erythema nodosum, episcleritis or uveitis seen in Crohn's disease, tremor or tachycardia with thyrotoxicosis). A basic neurologic examination should be performed to assess for vitamin deficiency-related neuropathy or other neurological conditions.Table 1.: Differential diagnosis of nausea and vomiting in pregnancyLaboratory evaluation Several laboratory abnormalities may be found in patients with HG due to severe nausea and vomiting that denote fluid and electrolyte derangement (e.g., elevated creatinine or blood urea nitrogen, hyponatremia, hypokalemia). Urine ketonuria, a marker of lipolysis or starvation, can be used adjunctively with symptoms in the diagnosis of HG. The presence of urinary ketones in pregnancy can be used as a guide to determine when fluid replacement, augmented nutrition, or hospital admission may be warranted. Although recommended by guidelines to screen for HG, ketonuria should not be used to diagnose HG (16). A prolonged international normalized ratio or prothrombin time is seen in those patients who develop vitamin K deficiency (17,18). Patients with HG may be at increased risk for anemia but that should be differentiated from hemolytic anemia seen in the preeclampsia spectrum of disorders (19). Although HG is not considered a primary liver disorder, it can cause elevated liver biochemistries in 50% of cases. Aminotransaminases, if elevated, are typically up to 3 times of normal values but may be up to 20-folds of normal levels (1,000 IU/L). HG can occasionally lead to jaundice from mild cholestasis, but total bilirubin is often <4 mg/dL (20). Imaging considerations and impact Although imaging is not required to make a diagnosis of HG, it may be needed to evaluate for other causes of NVP. In those with elevated liver biochemistries, ultrasonography can rule out biliary stones or vascular thrombosis. Ultrasonography may also be used to assess for fetal growth restriction, particularly in the third trimester and in those with protracted symptoms and concern for malnutrition (20). Other imaging may be required to assess for complications induced by HG (visceral avulsion, hemorrhage, hematoma), and in the urgent/emergent setting, the best test needed to address the clinical concern at hand should be used. In a nonemergent setting, consideration should be given to modalities that minimize exposure to ionizing radiation. Other testing Liver biopsy is rarely needed in those with HG and elevated liver biochemistries. This would typically only be required to definitively exclude other treatable etiologies of liver disease requiring management in pregnancy (e.g., autoimmune hepatitis). DIFFERENTIAL DIAGNOSIS Although nausea and vomiting in a pregnant individual may be due to NVP or HG, the differential diagnosis can be broad (Table 1) and should be considered if symptoms persist beyond the first trimester. Gastrointestinal and systemic conditions should be considered in a pregnant patient with new onset of nausea and vomiting because these can occur anytime in pregnancy. Although HG can cause elevation of liver biochemistries, these findings when seen in the first half of pregnancy require one to consider other potential etiologies, such as acute viral hepatitis, biliary stone disease, autoimmune hepatitis, or hypercoagulable conditions such as Budd-Chiari syndrome. Treatment of hyperemesis gravidarum The treatment of HG depends on the severity of symptoms and focuses on symptom relief, maintenance of hydration, electrolyte balance, and nutrition to prevent serious complications to both the pregnant person and the fetus. Treatment options can be categorized broadly into pharmacologic, nonpharmacologic, and those providing nutritional support. We outline a stepwise approach adapted from the 2018 American College of Obstetrics and Gynecologist (ACOG) guidelines for the treatment of NVP (Figure 1) (10). This approach is not specific for HG. Symptom severity, ability to take oral medications, and nutrition/hydration status should all be taken into account when deciding where along the treatment algorithm to start (10). Patients presenting with severe symptoms and inability to tolerate oral medications may need more intensive therapies with intravenous medications and fluids before stepping down to nonpharmacologic and oral therapies to prevent future flares. Pharmacologic treatment should not be withheld for pregnant people because of fetal safety concerns when needed. Table 2 summarizes therapeutic options, typical dosing, and potential side effects for each treatment.Figure 1.: Proposed treatment and nutritional support algorithm for hyperemesis gravidarum adapted from the ACOG treatment algorithm for the management of nausea and vomiting in pregnancy. ACOG, American College of Obstetrics and Gynecologist; CPN, central parenteral nutrition; EN, enteral nutrition; IM, intramuscular; IV, intravenous; NG, nasogastric, NJ, nasojejunal; PEG, percutaneous endoscopic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; PPN, peripheral parenteral nutrition.Table 2.: Summary of therapies for nausea and vomiting in pregnancy and hyperemesis gravidarumNonpharmacologic therapies. Ginger and acupressure are common first-line nonpharmacologic therapies used during pregnancy. Ginger (Zingiber officinale). The ACOG recommends ginger as the first-line therapy for NVP (21). Ginger is available as a fresh root or powder with several bioactive compounds (e.g., gingerol, shogaol, and zingerone) (22) that act in the gut and central nervous system (Table 2) through serotonin (5HT3), muscarinic (M3), and neurokinin (NK1) receptors. Consumption of up to 1 g per day of ginger has been associated with improvement in NVP symptoms (23). Ginger is not associated with increased fetal malformations; however, it can inhibit platelet function and is not recommended in patients on anticoagulants. Acupressure. Acupressure entails applying pressure to specific points on the body. P6 (Neiguan), an acupoint located 3 finger breaths proximal to the wrist joint, is the most studied acupressure point for nausea and vomiting. This can be applied manually with fingers or by wearing an elastic wristband with an embedded button (Sea-Band; Sea-Band, Leicestershire, England). The efficacy of P6 acupressure for NVP is conflicting; however, the therapy is safe (24). Electroacupressure (Reliefband; Woodside Biomedical Systems, Carlsbad, CA) is a wristband that provides transcutaneous electrical stimulation of the P6 acupoint. Although electroacupressure was effective for motion sickness and postoperative nausea and vomiting, studies in NVP demonstrated mixed results (25). Pharmacologic therapies Pyridoxine (vitamin B6). Pyridoxine is a water-soluble vitamin that is effective in treating NVP either alone or in combination with doxylamine. Although vitamin B6 levels decrease with advancing gestation, B6 deficiency has not been associated with NVP or HG. Pyridoxine alone in doses of 10–25 mg given orally every 8 hours reduces the severity of nausea and decreases vomiting episodes (26). B6 is generally safe; however, sensory neuropathy has been reported in patients taking extremely high doses (>500 mg/d) (27). Doxylamine. Doxylamine is an over-the-counter antihistamine used as a sleep aid. Combination doxylamine/pyridoxine is available in the United States by prescription in 2 doses (10/10 mg and 20/20 mg) for the treatment of NVP not improved with nonpharmacologic therapy. Pyridoxine-doxylamine combination improves nausea and vomiting compared with placebo; however, it is less effective compared with ondansetron (28). Doxylamine is recommended by the ACOG as the first-line pharmacologic therapy for persistent nausea and vomiting refractory to nonpharmacologic therapy (29). If symptoms persist despite combination doxylamine-pyridoxine, promethazine or diphenhydramine can be substituted. Antiemetics. Antiemetics commonly used in pregnancy include metoclopramide, promethazine, trimethobenzamide, and ondansetron. Dopamine (D2) receptor antagonists can be added as second-line therapy in patients with persistent symptoms. Those with severe symptoms and evidence of dehydration should receive antiemetics intravenously (21,28). When compared with metoclopramide, ondansetron demonstrated similar reduction in symptoms with fewer adverse events. However, the data on the safety of ondansetron are conflicting with concern for the potential of increased risk of congenital heart defects if used in the first trimester (30). Thus, the use of ondansetron before 10 weeks should be individualized based on symptoms and availability (or lack thereof) of other options. Corticosteroids. Methylprednisolone is a treatment option in patients with severe symptoms. Corticosteroids demonstrated mixed results in reduction of symptoms in patients with HG (31). When compared with promethazine, there were no differences in symptoms. However, patients receiving methylprednisolone had a lower rate of rehospitalization (30). The ACOG recommends tapering the dose over 2 weeks to the lowest effective dose and limiting the duration to a maximum of 6 weeks (21). Glucocorticoids before 10 weeks of gestation should be avoided because of a potential risk of cleft palate (28,32). NUTRITION SUPPORT Medical nutrition therapy for hyperemesis gravidarum Nutrition support for HG is both challenging and vital to the health of the pregnant person and the fetus. Poor oral intake and fluid losses from persistent emesis are associated with electrolyte derangements, malnutrition, fetal growth restriction, low birth weight, and micronutrient deficiencies (33). Nutrition interventions should be centralized around fluid resuscitation and electrolyte stabilization, followed by nutritional repletion and symptom management, to support adequate fetal growth. More advanced nutrition support (ANS) therapies such as enteral nutrition (EN) and parenteral nutrition (PN) are often needed in those with severe symptoms. EN and PN support ANS should be considered in those not responsive to therapy. Figure 1 expands the adapted ACOG guidelines for treatment of NVP to include an algorithm for determining the appropriate route of ANS for those with HG. EN can be administered by several routes including nasogastric, nasojejunal, percutaneous endoscopy gastrostomy (PEG), or percutaneous endoscopic jejunostomy. Ideally the nasogastric route should be the first-line therapy for ANS in HG (10,33–35). This has the benefits of bypassing the cephalic phase of digestion, maintaining gut integrity, and avoiding infectious and thromboembolic risks of PN (36). EN could potentially lead to improvement in symptoms of nausea and vomiting due to HG: The mean time to resolution of emesis is 4.5 and 3.6 days to stabilize and/or promote weight gain, respectively (37–41). More recent trials have been less promising; however, these were notably underpowered with pronounced limitations (42,43). Nasogastric tube placement is generally preferable over other routes of EN administration because it requires less radiation for placement than nasojejunal tubes and is less invasive than PEG/J tubes. Pitfalls of nasoenteric tubes include inadvertent removal or emesis of the tube (54%) and discomfort, especially with prolonged use (44). In a retrospective study of pregnant individuals with HG requiring EN, the median duration of EN was 5 days (range 0–41), with 54% requiring continued EN on discharge for a median of 5 additional days (range 1–181) (44). For patients requiring prolonged EN or unable to tolerate nasoenteric tubes, PEG/J tubes can be placed safely by experienced endoscopists (45). If there are contraindications to EN or it is ineffective, PN should be considered. If a patient is severely malnourished and well below their pregravid weight, early PN may be prudent as a bridge to EN. Nutrition support route of administration Once nausea and vomiting has stopped and electrolytes are stable, gastric or jejunal feedings may be trialed. Although nasogastric feedings are the preferred route, nasojejunal feedings should be considered for patients with poor tolerance, before pursuing PEG/J and/or PN(33, 41). If EN support is of the anticipated length of need >4–6 weeks, then PEG/J tubes may be considered. These tubes are considered to have a reduced risk of reflux and aspiration when compared with nasoenteric tubes; however, they are more invasive and pose risks of site infection, tube dislodgement, and need for sedation during placement (34). PN can be administered either peripherally with peripheral PN or centrally with central parenteral nutrition (CPN). Although both have risks and benefits, the ultimate decision is based on clinical severity, estimated nutrient needs, and duration of need. Peripheral PN is limited by osmolarity to prevent thrombophlebitis, requiring lower dextrose and amino acid concentrations and larger volumes to ensure nutritional adequacy. CPN can provide the full complement of energy and protein requirements in a smaller, concentrated volume. Peripherally inserted central catheters are the most common central access catheters used because they can be used for 2–12 weeks and are relatively simple to insert at the bedside. By contrast, tunneled catheters or implanted ports require insertion in interventional radiology or the surgical suite. Although peripherally inserted central catheters are the most common access device for CPN infusion, there is greater risk of bacteremia and thrombosis and they interfere with dressing and bathing (46). Pregnancy is associated with increased risk of catheter-related thromboembolism, which further increases PN risk (47). Monitoring of patients on EN and PN support Monitoring the response to EN and PN support is a dynamic component of ANS therapy. A close assessment of malnutrition, refeeding risk, tolerance to interventions, glycemic control, maternal weight gain, and fetal growth are all basic components of the nutrition-monitoring plan. If refeeding risk is identified, it is recommended to check serum potassium, phosphorus, and magnesium before starting ANS and repeat laboratory tests every 12 hours at a minimum for 3 days. Vital signs should be monitored before starting ANS and every 4 hours after initiation. If electrolytes are grossly depleted, ANS should be withheld until these are corrected (48). EN and PN should be initiated at no more than 10–20 kcal/kg and slowly advanced by 33% of goal nutrition needs every 1–2 days (48). It would be prudent to assume that all HG patients are at risk for refeeding syndrome and monitor accordingly. Long-term EN does not require extensive laboratory tracking; however, monitoring of long-term CPN entails biweekly checks of the basic metabolic panel, magnesium, phosphorus, hepatic panel, plasma proteins, and complete blood cell count (33). Trace elements, vitamins, and phospholipid fatty acid profile (triene:tetraene ratio) should be checked at baseline and every 3 months. Oral intake and tolerance should be monitored routinely to assess for appropriateness of EN and PN provisions. Once oral intake meets ≥75% of estimated calorie, protein, and fluid needs, ANS can be discontinued. Calories. Predictive equations available to estimate energy needs in pregnancy vary in complexity. Some account for age, height, weight, and activity level while others are simple weight-based equations (Table 3). While energy needs are not increased for HG alone, predictive equations may underestimate total energy expenditure during times of stress (33). Therefore, frequent monitoring of intrauterine fetal growth and maternal growth is essential to accurately individualize energy provisions.Table 3.: Predictive energy equations for pregnancyProtein. Protein needs range from 1.1 to 1.52 g/kg/d in pregnancy (49,50). There are little data to support increased protein needs with HG. However, additional protein may be necessary during times of increased stress (34). protein can result in poor growth and of the while protein has been associated with fetal and such as and higher in the A minimum of of is suggested for however, amount may not be in patients or in of a risk with HG, can lead to or ketonuria, which has a on as well as and in the While there is no for total fat intake during pregnancy or HG, of total intake as a to start adequate during pregnancy for most fatty are also The is a recommended of the which can be by with mg acid per day in addition to a normal The adequate for fluid in pregnancy is 3 with from and the from in adequate fluid during HG can be especially challenging to fluid losses from persistent is associated with a reduction in fluid which may lead to fetal and if not corrected and for all and during pregnancy (Table Patients with HG have been to less than 50% of the recommended intake for most If a patient with HG requires of parenteral and are not adequate to of pregnancy the PN may be necessary for vitamin magnesium, and if deficiency is laboratory monitoring of electrolytes and should be at baseline and until and then monitored 1–2 times for PN and should be performed at baseline and then every 3 Vitamin and mineral needs in vomiting and poor oral intake can lead to of with risk for Wernicke encephalopathy should be before and along with such as oral dextrose and/or to prevent refeeding syndrome. mg of should be followed by mg for a minimum of days. mg should be continued for maintenance until oral intake is adequate OF of the This as of the on and in Pregnancy and to support the have been to the for from and is a for and and is on the for other have no Hyperemesis gravidarum (HG) may start early in pregnancy and can extend throughout the duration of the pregnancy, occasionally into the postpartum state. A history of HG during pregnancies increases the likelihood of HG with future The examination should focus on assessing hydration status, features of malnutrition, electrolyte disturbances, and adequacy of fetal growth. While HG needs to be considered in pregnant people presenting with protracted nausea and vomiting, other need to be particularly with onset beyond the first trimester. Treatment of HG should focus on symptom and of complications to both the patient and the fetus. Treatment options on the severity of symptoms and should start with nonpharmacologic therapies. Pharmacologic therapies should be used in patients with symptoms. nutrition (EN) support by a gastric route should be followed by jejunal feedings if the is nutrition (PN) support should be the nutrition however, it may be necessary in those who are severely malnourished as a bridge to EN. In those at risk for refeeding mg of should be given before dextrose intravenous EN, and/or PN and for days.

Topics & Concepts