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Gastrointestinal disorders
23.1
Gastroesophageal reflux disease
Gastroesophageal reflux disease (GERD), most commonly manifested as heartburn, is estimated to affect 40%–85% of pregnant women [ ]. Risk factors for GERD in pregnancy include increasing gestational age, parity, and a history of heartburn [ ]. In addition to heartburn, pregnant women may experience other GERD-related symptoms such as regurgitation and epigastric pain. Less likely manifestations of GERD include chest pain, hoarseness, sore throat, chronic cough, and asthma [ ].
The pathophysiology of GERD is believed to be multifactorial. Decreased resting lower esophageal sphincter (LES) pressure due to the effects of estrogen and progesterone are thought to be important contributors to gestational GERD along with decreased sensitivity of the LES to physiologic stimuli [ ]. Other proposed factors include decreased esophageal peristalsis, esophageal dysmotility, and delayed gastric emptying due to hormonal and mechanical changes [ ].
Most patients have a benign disease course, with only a few experiencing GERD-related complications such as gastrointestinal (GI) bleeding or stricture formation. In general, symptoms begin at the end of the first trimester, worsen through the remainder of pregnancy, and then resolve promptly after delivery. Diagnosis is made based on symptoms, and more invasive measures such as endoscopy and esophageal pH studies are generally not indicated. Barium studies such as esophagrams should be avoided in pregnancy due to the risks of radiation exposure to the fetus.
23.1.1
Treatment
23.1.1.1
Therapeutic lifestyle modifications
Treatment of GERD in pregnancy should follow a “step-up” approach. Treatment should begin with therapeutic lifestyle modifications including strict abstinence from tobacco and alcohol and avoiding late-night meals, recumbency after eating, and trigger foods (e.g., spicy or sour foods, carbonated beverages, coffee, and chocolate). Eating several small meals throughout the day, elevating the head of the bed by 6 inches, and sleeping on the left side may provide additional benefit [ ]. In addition, medications known to provoke GERD such as anticholinergics, sedatives, theophylline, prostaglandins, and calcium channel blockers should be discontinued, when possible. It is estimated that 25% of patients with uncomplicated GERD have symptom resolution after making these modifications [ ].
23.1.2
Antacids
For patients who fail to respond to conservative measures, antacids and alginic acid constitute first-line pharmacologic therapy. Aluminum, magnesium, and calcium-based antacids are generally considered safe in pregnancy. Calcium-based antacids have the added benefit of increasing calcium intake which has been associated with the prevention of preeclampsia [ ].
Patients taking antacids, however, should be aware of the possibility of aluminum-containing antacids causing constipation and magnesium-containing antacids causing diarrhea [ ]. Furthermore, magnesium-containing antacids should be avoided later in pregnancy, due to their ability to arrest labor and precipitate seizures. Magnesium trisilicate has potentially teratogenic properties in high doses and should be avoided throughout pregnancy [ ]. Also patients on iron should be advised not to take iron and antacids together in order to maximize iron absorption by an acidic gastric pH. Sodium bicarbonate should not be taken due to the risk of metabolic alkalosis and fluid overload in the mother and fetus [ ].
Alginic acid is considered effective and fast acting in most pregnant patients. Although it has not been studied extensively, it should be safe because it is not absorbed systemically. An open-label trial reported “very good” or “good” symptom relief in the majority of women taking alginic acid within 10 min [ ].
23.1.3
Sucralfate
Sucralfate is an aluminum salt of a sulfated disaccharide. As it is poorly absorbed from the GI tract, it acts mainly as a local mucosal protectant. Sucralfate has been shown in a randomized controlled trial in pregnancy to provide greater relief from heartburn and regurgitation than lifestyle and dietary modifications alone [ ].
23.1.4
Promotility agents
Metoclopramide is a prokinetic, dopamine antagonist which may be useful in the treatment of GERD by increasing LES pressure, improving esophageal acid clearance, and promoting gastric emptying. Use of metoclopramide is often limited by its poor tolerability and the risk for extrapyramidal side effects. Due to the rare risk of tardive dyskinesia, a black-box warning was issued in 2009. The risk of tardive dyskinesia increases with high dose or long-term use of the drug (use greater than 3 months) and continues even after the drug has been discontinued. It has been reported that the risk of tardive dyskinesia is likely <1% [ ].
23.1.5
H 2 -receptor antagonists
The H 2 -receptor antagonists (H 2 -RAs) form the next tier of therapy. H 2 -RAs are considered safe in pregnancy. A 2009 metaanalysis by Gill et al. (with data from 2398 H 2 -RA exposed pregnancies and 119,892 unexposed controls) found no increased risk of fetal malformations with the use of H 2 -RAs in pregnancy [ ]. No increased risks for spontaneous abortions, preterm delivery, and small for gestational age were found either.
Despite the longstanding availability of H 2 -RAs, only ranitidine, studied at a dose of 150 mg twice daily, has been shown in a randomized, double-blind trial to be efficacious in pregnancy [ ]. However, due to the detection of low levels of N-nitrosodimethylamine (NDMA), a probable human carcinogen, in 2020, the FDA requested all manufacturers withdraw all prescription and over-the-counter ranitidine formulations from the market [ ]. Cimetidine is likely equally effective; however, due to the antiandrogenic effects seen in animals and nonpregnant humans, some authors advise against its use in pregnancy [ , ]. Although it appears to be safe, famotidine carries fewer safety data in pregnancy. Nizatidine is approved for use in pregnancy; however, studies in some animal models have reported abortions, fewer live fetuses, and low fetal weights with high dose exposure [ ]; it is a less preferred option among the H 2 -RAs [ ]. Furthermore, liquid and capsule formulations have recently been voluntary recalled by their manufacturer due to the detection of NDMA [ ].
23.1.6
Proton pump inhibitors
Proton pump inhibitors (PPIs) are typically reserved for patients with severe symptoms refractory to lifestyle modification and the older generation medications. Previous animal studies suggested concern with omeprazole; however, a growing amount of data supports the safety of PPIs during pregnancy.
In the same 2009 metaanalysis which examined H 2 -RAs, there was no statistically significant difference found in rates of major malformations, spontaneous abortions, or preterm delivery with first-trimester use of PPIs in 1530 PPI-exposed versus 133,410 nonexposed controls [ ].
A Danish cohort study examining 840,968 live births, of which 5082 were exposed to a PPI between 4 weeks before conception and the end of the first trimester, did find a minor difference in abnormalities in the newborns of exposed (3.2%) and nonexposed (2.6%) women (adjusted prevalence odds ratio, 1.23; 95% CI, 1.05–1.44) [ ]. The risk of birth defects, however, was not significantly increased in secondary analyses of exposure to individual PPIs during the first trimester.
Thus, based on the available data, PPI use in pregnancy does appear to be safe with anecdotal data favoring lansoprazole [ ]. First trimester exposure, however, should be avoided when possible due to the possible increased risk for fetal malformations. While most patients can be effectively treated with once-a-day dosing, some may need to be dosed twice daily. The various medical therapies for GERD are summarized in Table 23.1 .
Table 23.1
Medications for gastroesophageal reflux disease.
| Drug | Recommendations in pregnancy c | Recommendations in lactation | |
|---|---|---|---|
| Antacids | Calcium based | Safe | Compatible |
| Magnesium based | Avoid in late pregnancy as may arrest labor and precipitate seizures; can cause diarrhea. | Avoid magnesium trisilicate | |
| Aluminum based | Can cause constipation and possibly fetal neurotoxicity | ||
| Alginic acid | Safe | ||
| Sodium bicarbonate | Contraindicated due to risk for maternal fluid overload and metabolic alkalosis | ||
| Sucralfate | Safe | Compatible | |
| Metoclopramide | Avoid long-term, high-dose use due to risk for tardive dyskinesia | Limited human data: potential toxicity | |
| H 2 -receptor antagonists | Ranitidine | Not advised due to contamination with NMDA | Not advised |
| Cimetidine | May have antiandrogenic properties | Compatible | |
| Famotidine | Probably safe | Compatible | |
| Nizatidine | Not advised due to contamination with NMDA | Not advised | |
| Omeprazole | Reserve for refractory patients; avoid first trimester use | Not recommended | |
| Proton pump inhibitors | Lansoprazole | ||
| Pantoprazole | |||
| Rabeprazole | |||
| Esomeprazole | |||
NMDA , N nitrosodimethylamine.
23.2
Peptic ulcer disease
Older studies suggest the incidence of peptic ulcer disease (PUD) is decreased in pregnancy [ ]. The reported incidence rate of 0.005% is likely an underestimate, however, due to the underreporting of symptoms by patients and the reluctance to perform endoscopy during pregnancy by physicians. Risk factors for PUD in pregnancy include smoking, nonsteroidal antiinflammatory drug use, alcoholism, genetic predisposition, gastritis, Helicobacter pylori infection, and advanced maternal age [ ].
23.2.1
Treatment
H 2 -RAs constitute first-line therapy for PUD in pregnancy. In patients who remain symptomatic, PPIs should be used. These drug classes are covered in detail in Section 23.1 . Patients found to have H. pylori infection during their work-up should generally be treated for this after pregnancy and lactation have been completed.
The most common treatment regimen is triple therapy with a 10-day course of twice daily PPI, amoxicillin, and clarithromycin. For patients who are penicillin allergic or have resistant infection, quadruple therapy with twice daily PPI, metronidazole, bismuth, and tetracycline is used. In the rare case when treatment is warranted during pregnancy, tetracycline and bismuth should not be used. Bismuth is discussed below, while the antibiotics used to treat H. pylori are discussed in Section 23.6 and summarized in Table 23.3 .
23.2.1.1
Bismuth subsalicylate
Bismuth subsalicylate is hydrolyzed in the GI tract into organic bismuth salts which are poorly absorbed and salicylates which are readily absorbed. Although bismuth has not been reported to cause fetal abnormalities in humans, chronic administration of bismuth tartrate in animal studies has been associated with poor outcomes [ ]. Furthermore, chronic ingestion of salicylates during pregnancy may lead to fetal malformations, premature closure of the ductus arteriosus in utero, and intrauterine growth retardation [ ]. Thus, bismuth subsalicylate should not be used in pregnancy or lactation.
23.2.1.2
Pancreatitis
Acute pancreatitis in pregnancy is most commonly caused by gallstones [ ]. It generally resolves with supportive care including aggressive hydration, analgesia, and early enteral nutrition as tolerated. Unfortunately, biliary pancreatitis has an exceptionally high recurrence rate in pregnancy [ ] and early cholecystectomy should be discussed [ ]. Occasionally, patients require treatment with antimicrobials for infected pancreatic necrosis. Use of agents known to penetrate pancreatic necrosis such as metronidazole or meropenem should be considered in this setting. These antibiotics are discussed in Section 23.6 and summarized in Table 23.3 .
Chronic pancreatitis is often the result of alcohol abuse. Patients should be monitored for malabsorption. Pancreatic enzymes supplement endogenous enzyme production. They are likely safe in pregnancy; however, due to limited safety data, they should be avoided if nonessential.
23.2.1.3
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habits [ ]. Patients typically report abdominal pain, bloating, constipation, or diarrhea. Despite the prevalence of IBS among women [ ], few large studies of pregnant women with IBS have been conducted [ ]. One recent study using the United Kingdom General Practice Research database found a higher risk of miscarriage and ectopic pregnancy in women with IBS [ ]. Whether there is a causal link between IBS and these adverse outcomes or whether confounding by a comorbidity such as pelvic inflammatory disease accounts for these results is not known. Below is a discussion of the most common symptoms of IBS including recommendations for treatment in pregnancy.
23.3
Constipation
Constipation is one of the most frequently encountered GI disorders in pregnancy [ ]. It is estimated to affect up to 40% of pregnant women [ ]. Low frequency of stools (<3 per week), hard stools, and/or difficulties on evacuation of feces have been suggested to be good clinical criteria for constipation in pregnancy [ ]. The pathophysiology of constipation in pregnancy is multifactorial. Decreased colonic motility due to the effect of progesterone, poor oral intake of food and fluid due to nausea and vomiting, psychological stress, iron supplementation, thyroid disease, gestational diabetes, and mechanical pressure on the rectosigmoid colon by the gravid uterus may all contribute to its development [ ].
23.3.1
Treatment
23.3.1.1
Conservative treatment
The initial management of constipation in pregnancy includes patient education and reassurance about normal bowel function in pregnancy. In addition, patients should increase their physical activity, gain better control of pelvic floor musculature using Kegel exercises, and schedule defecation after meals to take advantage of the gastrocolic reflex. Patients should also avoid constipating foods such as those containing iron and calcium and increase their fluid and fiber intake [ ].
23.3.1.2
Stool-bulking agents
Stool-bulking agents such as methylcellulose, psyllium, and unprocessed bran are the preferred first-line therapy in pregnancy as they are not systemically absorbed and thus considered safe for the developing fetus and the neonate during lactation. Stool-bulking agents soften stool and increase stool volume by drawing water into the GI tract. A recent Cochrane review found clear evidence of the effectiveness of fiber supplements on the frequency of defecation (OR 0.18, 95% CI 0.05–0.67) and softening of stools, although notes that these agents may take several days to take full effect [ ].
23.3.1.3
Hyperosmotic agents
Hyperosmotic agents increase osmolar tension, thereby causing an increase in water secretion into the gut lumen. These include saline osmotics (magnesium and sodium salts), saccharated osmotics (lactulose, sorbitol), and polyethylene glycol (PEG). Saline osmotic laxatives such as magnesium citrate, magnesium hydroxide, and sodium phosphate work rapidly, but only provide short-term, intermittent relief and are not advisable for daily use [ ]. In addition, magnesium citrate and magnesium hydroxide can cause sodium retention in the mother and thus they are contraindicated in patients with renal and cardiac disease. Their general side effect profile includes GI upset, hypotension, and hypermagnesemia [ ].
Lactulose and sorbitol have not been associated with fetal malformations in animal models; however, human studies are lacking. Both agents can be given either orally or rectally in similar doses. Side effects of these agents include abdominal pain, flatulence, and electrolyte imbalances [ ].
PEG is the preferred treatment of the American Gastroenterological Association for chronic constipation in pregnancy [ ]. It is generally very well tolerated.
23.3.1.4
Stimulant laxatives
Stimulant laxatives directly stimulate colonic smooth muscle and/or interfere with water and sodium reabsorption. Derivatives of diphenylmethane phenolphthalein (bisacodyl), the anthraquinones (sennosides, aloe, dantron, and cascara), and castor oil are drugs in this category. Stimulant laxatives have been found to be more effective than stool-bulking agents for constipation in pregnancy (OR 0.30, 95% CI 0.14–0.61) in randomized trials; however, they also carry more side effects [ ]. In a study of 236 newborns exposed to phenolphthalein during the first trimester, no increased risk for congenital defects was found [ ].
Bisacodyl is available in oral and suppository form. Bisacodyl should not be taken within an hour of consuming calcium-containing compounds as it can cause early medication release and gastric irritation. The most common side effects are electrolyte and fluid imbalance, abdominal pain, nausea, and vomiting. Senna was not found to be associated with a higher risk for congenital abnormalities or adverse birth outcomes [ ]. It is considered acceptable for short-term use [ ]. Adverse effects include abdominal cramps, diarrhea, nausea, and vomiting. Dantron is a sennoside which has been associated with congenital malformations [ , ]. It should not be used in pregnancy.
Castor oil works quickly; however, it is contraindicated in pregnancy as it may induce uterine contractions [ ].
23.3.1.5
Emollient laxatives
Docusate sodium is widely used to treat constipation in pregnancy; however, studies on efficacy in pregnancy are lacking. It is a nonionic surfactant that allows for the penetration of intestinal fluids into the fecal mass, thereby creating softer stools.
Mineral oil use is associated with decreased maternal absorption of fat-soluble vitamins including vitamin K and increased risk for neonatal hypoprothrombinemia and hemorrhage [ ]. It is contraindicated in pregnancy.
23.3.1.6
Prokinetic agents
Lubiprostone is a chloride channel activator which increases intestinal fluid secretion. As there are no data currently on its safety in pregnant women, it is not recommended for use in pregnancy.
Linaclotide is a guanylate cyclase-C agonist which is involved in intestinal fluid secretion as well as gut afferent nerve modulation. It is thus commonly used in constipation predominant IBS. Linaclotide is minimally absorbed from the gut; however, there is insufficient data regarding its use in pregnant women [ ].
Prucalopride is a highly selective serotonin 5-HT4 receptor agonist which was recently FDA approved for the treatment of chronic constipation [ ]. Its main effect is to stimulate colonic motility. Due to insufficient data, its use is not advised during pregnancy.
23.4
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