Heartburn, Nausea, and Vomiting During Pregnancy

Abstract

INTRODUCTION Heartburn, nausea, and vomiting are very common upper gastrointestinal (GI) symptoms during pregnancy. Prevalence estimates for heartburn during pregnancy range from 30% to 80%, and regurgitation can also occur (1). Heartburn and regurgitation are the main symptoms of gastroesophageal reflux disease (GERD). GERD symptoms can progress throughout pregnancy but typically resolve after delivery (1,2). The effect of GERD on pregnancy outcomes has been examined in several studies, with no significant differences in birth outcomes for women with GERD (2). Reported rates of nausea and vomiting during pregnancy are 35%–91%, with approximately 69% of women reporting symptoms (3). Traditionally labeled “morning sickness,” this is a misnomer because nausea and vomiting can persist throughout the day. One study examining this found that of 1,000 pregnant patients, only 18% had nausea solely in the morning, with 31% reporting vomiting restricted to the morning (4). Nausea and vomiting are most common in the first trimester, with prevalence rates of 50%–80% for nausea and 50% for vomiting (5). Nausea and vomiting of pregnancy (NVP) has few effects on pregnancy outcome when symptoms are mild or moderate. Severe nausea and vomiting resulting in poor oral intake, weight loss, and limitations on normal activity can contribute to prematurity and low birth weight and should raise suspicion for hyperemesis gravidarum (6). See Elkins et al article in this monograph on Hyperemesis Gravidarum for additional details (7). PATHOPHYSIOLOGY There are multiple risk factors and physiological changes that occur during pregnancy which contribute to heartburn, regurgitation, nausea, and vomiting. A history of GERD increases the chance of heartburn occurring during pregnancy (2,8–11). Multiparity and advancing gestational progression have also been implicated (11). Although some studies have reported an association between weight gain, body mass index, and heartburn during pregnancy, other studies have not (2,11). GERD symptoms can occur very early in pregnancy because of elevation of progesterone, which relaxes smooth muscle, including the lower esophageal sphincter (LES). Progesterone decreases lower esophageal sphincter pressure (LESP), which can contribute to gastroesophageal reflux (12,13). Estrogen elevations in pregnancy do not directly affect LESP but are related to progesterone levels so may indirectly contribute to LESP (13,14). LESP returns to normal after delivery (12,13). Although intra-abdominal pressure does increase because of the growth of the fetus, it is not clear that this significantly contributes to reflux symptoms during pregnancy (12). Gastric emptying during pregnancy is not significantly reduced, so this is unlikely to contribute to reflux symptoms (15,16). There are multiple factors that affect NVP. Prepregnancy nausea and vomiting, younger age, and multiple gestation are risk factors for NVP (2,17). NVP is more common in women who have a history of migraines, motion sickness, or nausea with estrogen-containing medications (4). Gastric emptying is unchanged during pregnancy, and intra-abdominal pressure from the fetus is unlikely to contribute to NVP. Changes in hormone levels during pregnancy may contribute to NVP, although studies are mixed. Human chorionic gonadotropin (HCG) increases during pregnancy and correlates with the symptoms of nausea and vomiting, with higher levels of HCG associated with increased nausea and vomiting (18). Estradiol levels are also associated with NVP, with more frequent nausea and vomiting, when estradiol levels are increased (19). Recent genetic studies suggest variations in hormone receptors and the placental proteins GDF15 and IGFBP7 possibly contribute to NVP (20). SYMPTOMS GERD symptoms during pregnancy include heartburn and regurgitation. Atypical symptoms of reflux may include dysphagia, chest pain, belching, and hiccups. GERD symptoms become more common as the pregnancy progresses. In one study of 510 pregnant patients using a validated GERD symptom questionnaire, 26% had GERD symptoms during the first trimester, which increased to 36% in the second trimester, and 51% in the third trimester, compared with 9.3% of nonpregnant women (1). Symptoms are often worse in the third trimester, with 10.1% of women having daily heartburn and 40.7% with weekly regurgitation (1). GERD symptoms often occur after meals and in the supine position. GERD symptoms have a negative impact and progressive reduction in overall quality of life during pregnancy, impacting sleep, eating, and social function (21–23). Symptoms often attributed to extraesophageal GERD, such as cough and asthma, are uncommon manifestations of GERD during pregnancy (24). GERD symptoms may be worsened by spicy food or meals with higher fat content (7,23). NVP often begins between around 6 weeks of gestation, with most pregnant patients developing symptoms by 9 weeks and improving by 16 weeks. In one study of NPV, the mean number of days of nausea was 35, with 90% of pregnant patients having resolution of symptoms by 22 weeks (25). Symptoms of nausea and vomiting can occur throughout the day. NVP symptom severity can be graded using the Motherisk-pregnancy-unique quantification of emesis and nausea score (26). This score includes questions about the duration of nausea, number of episodes of vomiting, and frequency of retching during the day and has been correlated with quality of life in pregnant patients (27). Severe nausea and vomiting that leads to weight loss (>5% of prepregnancy weight), affects eating and drinking, and limits normal activities should raise concern for hyperemesis gravidarum. Nausea and vomiting due to hyperemesis gravidarum may begin before 6 weeks of gestation and continue through the third trimester and delivery (7). EVALUATION History and physical examination The diagnosis of GERD is primarily based on symptom report, typically including symptoms of heartburn and/or regurgitation. When patients present with symptoms of nausea and/or vomiting, they should be assessed for dehydration. Fevers, headaches, and persistent epigastric pain should raise concerns for other etiologies because they are rarely present in NVP. Eliciting the timing of symptoms because it relates to the pregnancy may be useful. NVP onset is often during the first trimester before 9 weeks of gestation, and symptoms often improve after the first trimester. The presence of nausea or vomiting before pregnancy or later than 9 weeks raises concern that there may be another etiology for the symptoms (18). Since reflux often increases in frequency later in pregnancy with increased weight gain, overall trends in weight should be reviewed in patients with reflux or NVP. In most cases, the physical examination is unremarkable. Examination should evaluate for signs of dehydration, such as orthostatic hypotension and dry mucous membranes, which can be a sign of hyperemesis gravidarum. Fever or abdominal tenderness may raise concern that symptoms are due to another etiology. An abnormal neurological examination may reflect nutritional complications of hyperemesis gravidarum or other etiologies. A goiter may also reveal primary thyroid disease as a cause of the vomiting. Laboratory evaluation Typically, no laboratory tests are warranted if symptoms are suggestive of GERD or mild or self-limited NVP, the examination is unremarkable, and there are no concerns for dehydration. If there is late onset (past 9 weeks), persistent (past 20 weeks) or severe NVP, atypical symptoms, or a suspicion that there could be another etiology, laboratory testing can include a complete blood count; urine analysis including ketones; complete metabolic panel including blood urea nitrogen, creatinine, and transaminases; amylase; HCG; and possible thyroid function tests. Dehydration, acute kidney injury, electrolyte abnormalities, and urinary ketones are suggestive of hyperemesis gravidarum and should prompt additional evaluation. See chapter on Hyperemesis Gravidarum for additional laboratory evaluation of suspected HG. A quantitative HCG level may be used in conjunction with early pregnancy ultrasound to determine whether a molar pregnancy or multiple gestations may be present. If a goiter is present on examination, thyroid testing should be obtained. If there is no goiter or suspicion of prior thyroid disease and vomiting is self-limited, then thyroid testing is not indicated (18). Thyroid testing, if obtained, could reflect an elevated free T4 and suppressed thyroid stimulating hormone (TSH) during first half of pregnancy, which may represent gestational transient thyrotoxicosis and may be monitored with a repeat test around 20 weeks and is typically managed supportively (28). New onset GERD symptoms in the third trimester, particularly if associated with epigastric pain, should trigger an evaluation for preeclampsia. Imaging In cases of NVP, an abdominal ultrasound can be considered to evaluate for gallbladder disease. Barium and computed tomography (CT) radiologic studies should be avoided to minimize radiation exposure. Other tests An upper endoscopy is not typically indicated unless there is concern for a complication of reflux disease (e.g., esophageal stricture). Most patients with GERD during pregnancy may have mild esophagitis and rarely experience complications such as erosive esophagitis or stricture. If needed, endoscopy may safely be performed ideally after the first trimester. See the article by Sethi et al in this monograph for more information on advanced endoscopy during pregnancy (30). Esophageal manometry and reflux testing can also safely be performed but are rarely necessary because GERD management during pregnancy is typically focused on symptom control (not surgical evaluation) and the physiologic changes seen during pregnancy typically resolve after delivery. DIFFERENTIAL DIAGNOSIS Although GERD and NVP are common, other causes should be considered when atypical presentations are encountered. Peptic ulcer disease may be considered with intractable dyspeptic symptoms or after nonresponse with initial management. Achalasia may be considered in cases of regurgitation or vomiting, especially if the symptoms predate the pregnancy. Typical abdominal etiologies of nausea and vomiting should also be considered such as gallbladder and biliary disease, gastroparesis, intestinal obstruction, hepatitis, pancreatitis, and appendicitis. In the third trimester, new GERD symptoms with epigastric pain should prompt an evaluation for preeclampsia. Liver disease of pregnancy should also be considered. Additional consideration may be given to genitourinary conditions such as pyelonephritis and metabolic conditions related to thyroid disease, diabetic ketoacidosis, porphyria, or Addison disease (18). TREATMENT A step-up approach is used for both GERD and NVP management. Figure 1 displays the recommendations for managing reflux symptoms and nausea and vomiting. Mild symptoms are often treated with diet and lifestyle modification and consideration of over-the-counter acid neutralizers. Medication therapy of GERD, nausea, and vomiting should include a discussion with the patient and communication with the obstetrician. For management of reflux, appreciation of the benefits, risks, and individual priorities for each patient and informed consent are recommended before embarking on medical therapy. This discussion should also include an understanding as to when testing may be required before escalation of pharmacologic therapy. For NVP, initiation of treatment is encouraged early with diet, lifestyle modification and consideration of nutritional supplementation, and escalation of therapy may be required in severe cases. Antiemetics may be indicated in some cases. Persistent nausea and vomiting with high concentrations of urinary ketones may require intravenous hydration with multivitamins (including thiamine) with monitoring of ketones and serum electrolytes. Severe and refractory cases of NVP may be due to hyperemesis gravidarum and require escalation of care including hospitalization and nutritional support. See chapter on Hyperemesis Gravidarum for additional details.Figure 1.: Suggested approach to reflux symptoms and nausea and vomiting during pregnancy. A step-up approach can be considered, starting with diet and lifestyle changes, initial pharmacotherapy and treatment with supplements, and escalation of pharmacotherapy with additional counseling. Communication between the gastroenterologist, obstetrician, and patient is important when managing GERD and NVP. For persistent, severe symptoms, additional testing is needed. The blue arrows on the sides of the pyramid illustrate increasing severity and persistence of symptoms.Diet and lifestyle modification Diet and lifestyle optimization is the foundation of initial management. Patients should be encouraged to eat smaller and more frequent meals. For reflux management, avoiding eating late at night or within 3 hours of laying down and raising the head of the bed or sleeping on a wedge pillow maybe helpful particularly when nocturnal regurgitation is present. Reduction of fatty foods is recommended. Polyunsaturated fats may be associated with reflux (23). Meats and carbonated beverages may be associated with reflux during pregnancy (29,31). Alcohol and nicotine should be avoided to both control symptoms and to minimize maternal and fetal harm. Specific food triggers, such as spicy foods, that correlate with symptoms should be minimized or avoided if they are troublesome. For patients with NVP, bland, dry, and high-protein and carbohydrate foods may be easier to tolerate. Increasing liquid intake between meals is also encouraged. Moreover, there may be specific foods or smells that carry appeal or aversion during pregnancy; these should be noted in either case. Additional considerations to improve NVP symptoms and coping with the symptoms include identification and minimization of triggers, such as sight, smell or taste of certain foods, minimizing pressure on the abdomen, or stimulation of the gag reflex (29). Lifestyle mitigation strategies for patients with NVP include avoiding crowded or warm areas with limited airflow, avoiding prominent odors, brushing teeth after meals (instead of the first thing in the morning), laying down with onset of symptoms, getting out of bed slowly, and minimizing stress (29). Alternative strategies such as acupuncture, acupressure, and acustimulation have been investigated but with inconsistent overall results (29,32). Heartburn and GERD pharmacotherapy As described above, lifestyle modification is key in treating mild symptoms, given potential teratogenic concerns with common pharmacologic therapies. Nonetheless, if needed, safe and effective pharmacologic and supplemental therapeutic options are available for reflux, nausea, and vomiting (33). Table 1 summarizes the available pharmacotherapy for GERD symptoms in pregnancy and lactation.Table 1.: Medications used to treat GERD symptoms and risk during pregnancy and breastfeedingAntacids Antacids effectively and immediately relieve heartburn symptoms. Magnesium-containing, aluminum-containing, or calcium-containing antacids have not been found to be teratogenic in animal studies (34). Some antacids containing sodium bicarbonate also contain aspirin, which should be avoided during pregnancy, unless recommended by the patient's obstetrician (33). Sodium alginate antacids form a barrier in the stomach to prevent reflux of gastric contents into the esophagus, in addition to antacid effects from their magnesium and calcium content, and are effective in pregnancy. There are few recent studies of alginates (such as Gaviscon) in pregnant patients, and the alginate formulations currently available have evolved over time. In a 2017 study of 100 pregnant patients, treatment with an alginate provided similar control of heartburn compared with a magnesium-aluminum antacid, with significant improvement in heartburn frequency and intensity in both groups, with no effect on pregnancy or neonatal outcomes (35). Alginates are generally considered safe during pregnancy (36). Sucralfate Sucralfate exerts local mucosal protection and is used in the management of gastric ulcers. In a randomized controlled trial during pregnancy, sucralfate-treated patients had higher frequency of remission of heartburn and regurgitation compared with controls, and there were no maternal or fetal adverse events reported (37). Although not generally recommended for the management of upper GI symptoms, sucralfate is a generally safe option during pregnancy. Histamine-2 receptor antagonists. Histamine-2 receptor antagonists (H2RAs) are the most common antireflux medication used during pregnancy. A meta-analysis of 2,398 exposed and 119,892 nonexposed pregnant patients did not identify a difference in fetal safety for congenital malformations, spontaneous abortions, preterm delivery, and small for gestational age or fetal growth (38). For specific H2RAs, the few reports available suggest that famotidine and cimetidine are safe during pregnancy. Initial studies of very high doses of nizatidine in pregnant rabbits identified spontaneous abortions, low fetal weight, and fewer live fetuses. Risks in humans are low, but other H2RAs are preferred (39). Ranitidine (brand name Zantac) was recalled from the market in 2020 because of concerns about a contaminant known as N-nitrosodimethylamine. More recently, Zantac reemerged on the market but now contains famotidine instead of ranitidine (Zantac 360). Proton pump inhibitors. Proton pump inhibitors (PPIs) are considered the most effective antireflux medications. In a large cohort study examining 5,082 live births with exposure to PPIs between 4 weeks before conception and the end of the first trimester of pregnancy, the authors identified that there was no increased risk of major birth defects compared with the cohort of live births without PPI exposure (40). One systematic review and meta-analysis assessed 26 observational studies and similarly found no association between PPI and abortions, stillbirth, neonatal death, preterm birth, or low-birth weight. However, the meta-analysis identified an increased risk of congenital malformations (odds ratio 1.28, 95% confidence interval 1.09–1.52) (38). Another meta-analysis of PPI use in pregnancy found no increased risk of spontaneous abortion, preterm delivery, or major malformations (41). This study also specifically examined the risk of major malformations with omeprazole use during pregnancy, which was not elevated. Based on real world experiences and limited available data, PPIs are generally considered safe during pregnancy. Heartburn and GERD pharmacotherapy during lactation Antacid use during breastfeeding is considered acceptable because magnesium and calcium salts are poorly absorbed orally, with negligible levels in the blood, so when taken by the mother are unlikely to produce harmful levels in milk (42). Famotidine is the preferred H2RA during breastfeeding because it has the least excretion into milk and least effect on the CYP450 enzymes. Cimetidine has the greatest excretion into breast milk among the H2RAs and the greatest number of documented drug interactions, although no harmful effects in breastfed infants have been reported with maternal cimetidine use (42). Despite their popularity, very few studies of PPI use during lactation are available. Based on these limited data, pantoprazole and omeprazole seem to be present in extremely low amounts in human milk and are not a reason to discontinue milk feeding (42). Antiemetic therapy during pregnancy A multitude of oral antiemetic therapies are available for first-line use during pregnancy (43). Doxylamine is among the few US FDA-approved drugs for the treatment of NVP (44). Other commonly used antiemetics considered low risk during pregnancy include diphenhydramine, cyclizine, promethazine, prochlorperazine, ondansetron, and metoclopramide (45). Additional information and tables pertaining to pharmacotherapy of nausea and vomiting during pregnancy can be found in the chapter on Hyperemesis Gravidarum (7). Nutritional supplements for NVP Ginger and vitamin B6 are considered safe and potentially effective treatment options for NVP during pregnancy. A systematic review and meta-analysis of 12 randomized controlled trials identified significant improvement in symptoms of nausea compared with placebo. Furthermore, there was not an increased risk of spontaneous abortion with ginger compared with placebo or vitamin B6 (46). One randomized double-blind controlled trial of 123 pregnant women compared vitamin B6 25 mg and ginger 650 mg 3 times per day for 4 days. Significant reduction of nausea and vomiting was identified with both ginger and vitamin B6, with greater symptom reduction among the ginger group (47). CONFLICTS OF INTEREST Guarantor of the article: Kerry Dunbar, MD, PhD, AGAF, FASGE. Financial support: This article appeared as part of the ACG Monograph on GI Diseases and Endoscopy in Pregnancy and Postpartum Period. Unrestricted educational grants to support the monograph have been provided to the ACG Institute for Clinical Research & Education from UCB, Inc., Ferring Pharmaceuticals, Inc., and Janssen Biotech, Inc. Additional support: NIH K23 DK125266 (PI: Yadlapati). VA CSR&D Merit Award I01CX001668-01 (PI: Dunbar). This material is the result of work supported with resources at the Dallas VA Medical Center. Potential competing interests: K.D.: none declared. R.Y.: consultant for Medtronic, Phathom Pharmaceuticals, StatLinkMD; Research support: Ironwood Pharmaceuticals; Advisory Board with Stock Options: RJS Mediagnostix. V.K.: consultant for Medtronic, Ambu; Advisory Board for Exact, Research support: Lucid. VA/US Government Disclaimer: the contents do not represent the views of the US Department of Veterans Affairs or the US Government.BEST PRACTICE RECOMMENDATIONS ✓ GERD, nausea, and vomiting during pregnancy significantly affect quality of life and should be treated. ✓ Diet and lifestyle modification are the initial foundation for managing these symptoms in pregnancy. ✓ When necessary, pharmacotherapy should not be avoided because numerous safe and well-established options for medical therapy are available. ✓ Most cases of GERD do not require testing and may be managed with diet and lifestyle optimization. A step-up approach is generally encouraged. ✓ Proton pump inhibitors are generally considered safe to use during pregnancy. ✓ NVP ideally should be treated early and can be managed with diet and lifestyle modification and with vitamin B6 or ginger supplementation. ✓ For patients with late onset, persistent, and/or severe NVP, laboratory testing and additional evaluation may be indicated.

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