Fig. 1
Management of GERD during pregnancy, step-up approach. PPI proton pump inhibitor, H 2 -receptor antagonist histamine2-receptor antagonist
For symptoms not responding to lifestyle changes, the risks and benefits of drug therapy should be discussed (Tables 1 and 2). For the pregnant patient with mild to moderate GERD symptoms, initial therapy can begin with either an antacid or a histamine2 (H2)-receptor antagonist. Some expert opinion suggests that the initial medical therapy for pregnant women with mild GERD symptoms be calcium- and magnesium-based antacids [12].
Table 1
US Food and Drug Administration (FDA) categoriesa
FDA category | Definition |
|---|---|
Category A | Controlled studies show no risk to the fetus |
Category B | Animal studies show no risk to the fetus; however, there are no adequate and well-controlled studies in pregnant women, or animal studies show risk but adequate and well-controlled human studies have failed to demonstrate risk |
Category C | Animal studies show risk but there are no adequate and well-controlled studies in pregnant women or no adequate studies in animal or pregnant women |
Category D | Fetal risk based on data from investigational, marketing experience, studies in human, but potential benefits may warrant use despite potential risks |
Category X | Animal or human studies show fetal abnormalities; risks outweigh benefits |
Table 2
Safety of medication use during pregnancy
Drug | FDA classification | Comments |
|---|---|---|
Antacids | ||
Calcium based | None | Low risk, preferred first line after lifestyle modification |
Magnesium based | None | Low risk, preferred first line after lifestyle modification. Has tocolytic properties; avoid in the last several weeks of pregnancy |
Aluminum based | None | Likely low risk in low doses, calcium- and magnesium-based antacids preferred |
Histamine2-receptor antagonist | ||
Cimetidine | B | Low risk |
Ranitidine | B | Low risk |
Famotidine | B | Limited safety data |
Nizatidine | B | Limited safety data |
Proton pump inhibitors | ||
Omeprazole | C | Animal study suggests fetal toxicity; epidemiologic studies in human suggest low risk |
Lansoprazole | B | Likely low risk based on epidemiologic studies. Avoid during 1–4 weeks prior to conception given possible risk of birth defects |
Pantoprazole | B | Likely low risk based on epidemiologic studies |
Esomeprazole | B | Likely low risk based on epidemiologic studies |
Sucralfate | B | Poorly absorbed, likely low risk |
Metoclopramide | B | Likely low risk, avoid long-term use given neurologic side effects |
Calcium-, magnesium-, and aluminum-based antacids are thought to be low risk in pregnancy [4, 13]. Low-dose (<1g/day) and high-dose (≥1 g/day) calcium supplementation during pregnancy appear to be associated with a reduced risk of hypertension and preeclampsia [14]. Oral magnesium supplementation has been shown to reduce the risk of high blood pressure compared to placebo, with conflicting results [15, 16]. Magnesium has tocolytic properties and its use is not advised during the last several weeks of pregnancy. Aluminum-containing antacids in large and chronic doses carry several potential concerns, such as constipation, malabsorption, skeletal impairment, and potential fetal neurotoxicity. For these reasons, high-dose aluminum antacids should be avoided and calcium-/magnesium-based antacids are preferred [4, 12]. Antacids containing sodium bicarbonate, which have the potential of causing metabolic alkalosis and fluid overload, should be avoided during pregnancy [4, 17].
H2 receptor antagonists inhibit gastric secretion stimulated by histamine and can be used in management of GERD symptoms concomitant with antacids. In prospective and retrospective studies, H2 receptor antagonist use during pregnancy was not associated with increased congenital malformations [18–20] or preterm delivery and low birth weight [19, 20]. For more severe symptoms or patients nonresponsive to therapy outlined above, a proton pump inhibitor (PPI) can be initiated. The US Food and Drug Administration (FDA) classifies all PPIs, except for omeprazole, as category B medications. Omeprazole, the first PPI approved on the market, at doses 5–56 times the human dose in animal studies resulted in embryo toxicity [21] and is therefore classified as category C.
In an earlier study, PPI use in the first trimester was associated with hypospadia [22]. However, this study was based on a small number of exposures (12 women exposed to lansoprazole, omeprazole, or esomeprazole). Moreover, there was no increased risk of hypospadia in a follow-up population-based study that included nearly 3,000 women exposed to PPI (including omeprazole) at conception or during pregnancy [23]. In a subgroup analysis restricted only to omeprazole use, the risk of hypospadia in the PPI exposed was similar to that in the unexposed group. In a meta-analysis of seven studies including data from 134,940 patients (1,530 exposed to PPIs), there was no difference in the risk of congenital malformations with first-trimester use of a PPI [24]. In many of these studies, the most common [25, 26], or often only [18, 27, 28], PPI exposure was omeprazole. In secondary analysis there was no difference in spontaneous abortions and preterm delivery. Analysis limited to omeprazole, alone, showed similar results. In two large epidemiologic studies published since this meta-analysis, exposure to PPIs in the first, second, and third trimester was not associated with congenital malformations [29, 30]. Similarly, a subgroup analysis of omeprazole use during pregnancy failed to show an increased risk of congenital malformations [29].
There is limited evidence from one epidemiologic study that PPI exposure at 1–4 weeks before conception was associated with birth heart and urinary tract defects [29]. Approximately 28 % of births exposed to PPI 1–4 weeks before conception were also exposed to other medications, such as corticosteroids, beta-blockers, and ACE inhibitors, 58 % were from mothers above the age of 30, and 23 % were from mothers reporting smoking during pregnancy. Subgroup analysis demonstrated that the risk of birth defects was significant only for lansoprazole, and not omeprazole, pantoprazole, or esomeprazole. Twenty-nine defects were reported in 541 births exposed to lansoprazole. In additional analysis looking at groups of birth defects, the odds of heart and urinary tract defects seemed to be associated with PPI exposure at 1–4 weeks before conception. The overall number of exposed cases was small with 30 cases of heart defects and 12 cases of urinary tract defects reported in 1,969 live births exposed to PPIs 1–4 weeks before conception. Further studies are needed to further explore this possible association. There are no guidelines on the use of PPI for patients contemplating pregnancy, although patients trying to become pregnant should be counseled on this possible risk [31]. If tolerated and not medically necessary, cessation of PPI therapy should be attempted in all women.
Other agents that can be considered for management of GERD symptoms include sucralfate and metoclopramide. Sucralfate, a surface agent and mucosal protectant, is poorly absorbed systemically with few side effects other than constipation and generally is regarded to be safe in pregnancy [32]. Metoclopramide, a prokinetic agent primarily used for treatment of delayed gastric emptying and nausea, may decrease GERD and has not been shown to be associated with increased adverse pregnancy outcomes [33, 34]. Metoclopramide could be considered for patients not responding to PPI therapy [31]. Its long-term use should be avoided given serious risks of neurologic complications, such as dystonia and akathisia.
Case 1 Continued
She is now 35 weeks pregnant. Her symptoms continued despite lifestyle modifications and use of calcium-based antacids and ranitidine 150 mg twice a day. She stopped these medications and it was suggested that she start a trial of pantoprazole 40 mg daily. Her symptoms have improved, although occasionally she will experience breakthrough reflux. She does admit to not taking pantoprazole daily, because she remains concerned about taking medications during her pregnancy. She denies signs or symptoms of burning or pain during swallowing, difficulty swallowing foods or food getting stuck, nausea, vomiting, and black or bloody stools. She has mild, infrequent generalized abdominal and back discomfort that developed during the course of her pregnancy. She continues to have appropriate weight gain during her pregnancy. Her labs have all been within normal limits. She wonders if she will require any further work-up now or after her pregnancy.
Discussion
The diagnosis of GERD can be made based on symptoms and more invasive testing during pregnancy is typically not necessary.
Barium radiographs, which expose the fetus to radiation, are not necessary for the diagnosis of GERD and therefore may be avoided during pregnancy. Esophageal manometry and pH studies are safe but are rarely necessary during pregnancy. For the general population, progressive symptoms or symptoms not responding to therapy can be evaluated with esophagogastroduodenoscopy (EGD). Signs and symptoms of dysphagia, odynophagia, and significant or continued gastrointestinal bleeding are considered to be indications for endoscopy during pregnancy by the American Society for Gastrointestinal Endoscopy (ASGE) [35]. Other experts have suggested that a moderate indication for EGD is recurrent nausea and emesis in patients past 16–18 weeks with a concern for peptic ulcer disease that have had inadequate response to PPI therapy [36]. Weak indications for EGD include self-limited nausea, emesis, or abdominal pain and GERD symptoms (aside from dysphagia) not responsive to empiric PPI therapy [36]. In this patient, who has no alarm features and symptoms and has been partially responsive to therapy, an EGD is not necessary. Symptoms should be monitored, daily PPI use recommended, and therapy increased with the addition of an H2 blocker at bedtime if needed.
The data on the safety and efficacy of EGD during pregnancy is sparse and limited to case series. The potential risks include maternal hypoxia, hypotension, and inferior vena cava compression during maternal positioning, as well as medication exposure to the fetus. The risks and benefits should be discussed in a multidisciplinary fashion. Maternal blood pressure and oxygen should be carefully monitored. As recommended by the American Society of Anesthesiologists and American College of Obstetrics and Gynecologists, when the fetus is previable, the fetal heart rate should be assessed before and after non-obstetric surgery, and when viable, at a minimum, fetal heart rate and contraction monitoring should be performed before and after procedure [37].
Judicious sedation is recommended. Propofol is category B by the FDA for use during pregnancy, while fentanyl and meperidine are category C and benzodiazepines are category D. The safety of propofol early in pregnancy is not known, but is considered relatively safe in pregnancy when given by a trained anesthesia provider. Meperidine and its active metabolites have been demonstrated to cross the placenta [38, 39]. Studies of teratogenicity from meperidine in animal models and humans are lacking. However, it is generally felt to be relatively safe for use during pregnancy. Fentanyl crosses the placenta as well [40], but is short acting and has faster procedural recovery time. Benzodiazepines are category D and diazepam has been associated with congenital abnormalities, including cleft lip and palate, with conflicting results [41–44]. Reports of infant floppy syndrome and neonatal withdrawal symptoms have been described in late third-trimester use of benzodiazepines [45]. If used, midazolam is the preferred benzodiazepines and should be given at its lowest effective dose.
In regard to the use of sedation during lactation, many sedatives are excreted in breast milk. Midazolam is excreted in breast milk and levels of midazolam and its metabolite appear to be undetectable after 4 h. Therefore, nursing should be withheld for at least 4 h after its exposure [35]. Fentanyl and propofol are excreted in breast milk, though at very low doses. Within 24 h of administration, 0.027 % of the propofol dose and 0.033 % of the fentanyl dose were detected in breast milk [46]. Fentanyl and propofol are considered to be compatible with breastfeeding [35]. Meperidine can be detected in breast milk up to 24 h after administration, and because of potential neurobehavioral effects on the infant, fentanyl is preferred when possible [35].
Functional Bowel Disorders
Case 2
S.T. is a 33-year-old gravida 2 para 1 woman who is currently 15 weeks pregnant. She has a history of asthma that is well controlled with rare use of albuterol inhaler as needed. During her first pregnancy, she reported constipation during her second and third trimesters. This was managed with increased fiber intake and occasional Metamucil. After her first pregnancy, her symptoms of hard stools generally resolved, though occasionally she found herself straining depending on her diet. Currently, she reports straining and hard stools, almost daily. She finds these symptoms to be more bothersome and frequent than what she experienced in her first pregnancy. She denies any vomiting, abdominal pain, or blood in her stools. She has been gaining weight appropriately. She has never had a colonoscopy. She has a paternal grandfather who had colon cancer in his seventies, but no other family members with colorectal cancer. She takes prenatal vitamins and occasionally Benadryl at night as a sleep aid. She feels that her symptoms interfere with her daily activity and would like to discuss this further.
Discussion
Functional bowel disorders such as irritable bowel syndrome (IBS) and functional constipation consist of gastrointestinal symptoms for which investigation does not reveal an organic cause. Alterations in the brain-gut axis as well as dysbiosis of the gut microbiome and its metabolic byproducts are thought to contribute to the underlying physiology of functional bowel disorders. Functional bowel symptoms can be common during pregnancy, with up to two thirds of women reporting one or more functional bowel symptoms during their first trimester of pregnancy. In a survey-based study of women in their first trimester, 46 % reported constipation, 49 % reported bloating, 44 % had irritable bowel syndrome, and 5 % reported diarrhea [47].
Constipation, often defined as hard stools, straining, incomplete evacuation, or infrequency of defecation, is a common gastrointestinal complaint during pregnancy. The prevalence of constipation during pregnancy has been reported with variable results. Approximately 45 % of women in their first trimester self-report symptoms of constipation [47, 48], and 51 % of patients self-report constipation at some point during their pregnancy [49]. Using a more narrow definition of constipation (fewer than three bowel movements per week and straining in more than 25 % of defecations), one study reported that only 5–9 % of women are affected by constipation throughout their pregnancy. The prevalence of constipation defined by the Rome criteria (Table 1), which includes symptoms of incomplete evacuation, hard stools, and use of manual maneuvers for defecation, during the first, second, and third trimester ranges from 24 to 30 %, 19 to 26 %, and 16 to 22 %, respectively [48, 49]. Similarly, in the postpartum period, the prevalence of constipation as defined by the Rome criteria is 24 % [48, 49]. Some studies suggest that the prevalence of constipation declines by the third trimester [49, 50] and in the postpartum period [50]. Sex hormones and decreased colonic transit time from elevated progesterone and reduced motilin levels may contribute to constipation. Other risk factors include decreased activity and vitamin supplementation (iron and calcium). Women with a history of treatment for constipation prior to pregnancy are more likely to report constipation during their pregnancy [49].
Despite its potentially high prevalence, bowel dysfunction and its recommended treatment are not always addressed during clinic visits, possibly reflective of underreporting or patient/provider perceptions that constipation symptoms are part of pregnancy. However, quality of life studies suggest that pregnant women reporting one or more functional bowel complaints have lower mean overall quality of life scores. Similarly, body image, health worry, activity interference, and food avoidance scores were lower for women who complained of functional bowel disorders during their pregnancy [47].
The most common symptoms of constipation during pregnancy are straining and hard stools. Occasionally women will report incomplete evacuation [49]. Anorectal obstruction and manual maneuvers to produce a stool appear to be the least commonly reported symptoms. Patients may report symptoms relating to constipation that do not conform to strict Rome criteria (Table 3). Often patients report constipation despite daily bowel movements, but further questioning will reveal symptoms such as straining, hard stools, unproductive urges, and incomplete evacuation. While the majority of pregnant women with constipation will have simple constipation without alarming underlying etiologies, history and physical examination are important in the evaluation of constipation. A number of medications, including prenatal multivitamins with iron, iron supplements, antihistamines, calcium channel blockers, and antidepressants, can be associated with constipation. A thorough review of medications, both prescription and over the counter, should be performed. Endoscopic evaluation is rarely necessary unless there are alarm signs such as gastrointestinal bleeding, uncontrolled diarrhea, new anemia not due to pregnancy, or possibly weight loss. In this patient, who has no alarm signs, endoscopic evaluation is not necessary. Limiting antihistamine use could be recommended as it can contribute to constipation.
Table 3
Rome diagnostic criteria
Rome II | Rome IIIa | |
|---|---|---|
IBS | At least 12 weeks (need not be consecutive) in preceding 12 months of abdominal discomfort or pain with two or more of the following: 1. Improvement with defecation 2. Onset associated with change in stool frequency 3. Onset associated with change in stool form | Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with two or more of the following: 1. Improvement with defecation 2. Onset associated with change in stool frequency 2. Onset associated with change in stool form |
Functional constipation | At least 12 weeks (need not be consecutive) in preceding 12 months of the following: 1. Straining > 1/4 of defecations 2. Lumpy or hard stools > 1/4 of defecations 3. Sensation of incomplete evacuation > 1/4 of defecations 4. Sensation of anorectal obstruction or blockage > 1/4 of defecations 5. Manual maneuvers to facilitate > 1/4 of defecations 6. <3 defecations per week Loose stools are not present and there are insufficient criteria for IBS | I. Must include two or more of the following: 1. Straining in at least 25 % of defecations 2. Lumpy or hard stools in at least 25 % of defecations 3. Sensation of incomplete evacuation for at least 25 % of defecations 4. Sensation of anorectal obstruction or blockage for at least 25 % of defecations 5. Manual maneuvers to facilitate at least 25 % of defecations 6. Fewer than three defecations per week II. Loose stools are rarely present without the use of laxatives III. Insufficient criteria for IBS |
Functional diarrhea | At least 12 weeks (need not be consecutive) in the preceding 12 months of: 1. Loose (mushy) or watery stools 2. Present > 3/4 of the time 3. No abdominal pain | Loose (mushy) or watery stools without pain occurring in at least 75 % of stools |
Case 2 Continued
She returns for a follow-up visit 4 weeks later and states that she has tried increasing fiber intake daily, in the form of fiber-containing cereal and wheat bran, and has been taking Metamucil, which she took intermittently during her previous pregnancy. She has stopped taking Benadryl at night for a sleep aid. She experienced bloating, which she attributes to the increased fiber intake. She asks you if there are alternative management options.
Discussion
Initial management of constipation includes increase in dietary fiber, fluids, and exercise. Dietary fibers increase stool bulk and frequency and reduce transit time. The recommended daily dietary fiber dose is 20–35 g, though these doses are often not achieved. Soluble fibers, found in oat bran, barley, nuts, and seeds, attract water forming a gel and improve bowel symptoms in chronic constipation in the general population. Fiber supplement with corn-based biscuit and wheat bran has been shown to increase the number of bowel movements and soften stool consistency in pregnant women [51]. Light exercise should also be recommended, as it can promote regular bowel movements. If symptoms persist despite the above changes, a laxative can be considered (Tables 4 and 5).
Table 4
Types of laxatives and their mechanism of action
Treatment | Examples | Mechanism of action | Side effects |
|---|---|---|---|
Bulk-forming fiber agents | Psyllium (Metamucil) Methylcellulose (Citrucel) Polycarbophil (FiberCon) Wheat dextrin (Benefiber) Inulin | Increases luminal water binding Increases fecal mass and stool bulk | Bloating and gas |
Stool softeners | Docusate | Lower surface tension of stool Facilitates passage of water into stool | Few side effects, cramping |
Osmotic laxatives | |||
Saline agents | Magnesium citrate Magnesium hydroxide | Poorly absorbed osmotic preparations Secretion of water into the intestine | Dehydration and electrolyte disturbance |
Poorly absorbed sugars | Polyethylene glycol (Miralax) Lactulose | Increase osmolar tension Secretion of water into the intestine | Bloating and gas Dehydration and electrolyte disturbance |
Stimulant laxatives | Bisacodyl (Dulcolax) Senna (Senokot) | Increase intestinal motor activity | Cramping and abdominal pain Dehydration and electrolyte disturbance |
Table 5
Safety of medication use during pregnancy
Drug | FDA classification | Comments |
|---|---|---|
Bulk-forming agents | ||
Psyllium | None | Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise |
Methylcellulose | None | Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise |
Polycarbophil | None | Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise |
Docusate | None | Low risk for short-term use, limited efficacy in treatment of constipation |
Osmotic laxatives | Low risk | |
Magnesium citrate | C | Avoid long-term use (risk of hypermagnesemia, hyperphosphatemia, and dehydration) |
Lactulose | B | Low systemic absorption, likely low risk for short-term use |
Polyethylene glycol | C | Low systemic absorption, likely low risk for short-term use |
Stimulant laxatives | ||
Bisacodyl | B | Low systemic absorption, likely low risk for short-term use |
Senna | C | Low systemic absorption, likely low risk for short-term use |
Cascara | C | Safety in pregnancy not well known |
Aloe | None | Not recommended |
Castor oil | X | Not recommended (possible induction of labor) |
Mineral oil | None | Not recommended (may interfere with absorption of maternal nutrients and vitamins, possible neonatal coagulopathy and hemorrhage) |
Peppermint oil | None | Likely low risk |
Dicyclomine | B | Likely low risk |
Hyoscyamine | C | Crosses placenta, little known on effects on fetus |
TCA | C (desipramine, amitriptyline) D (nortriptyline) | Crosses placenta, possible association with adverse outcomes in neonate |
Rifaximin | C | Associated teratogenicity in some but not all animal studies, no adequate studies in pregnant women |
Bulk-forming fiber agents, including psyllium, methylcellulose, polycarbophil, wheat dextrin, flax seed, and guar, are not systemically absorbed and are low risk for use during pregnancy. However, their effects may take days to work, and unwanted side effects include gas, bloating, and cramping. Psyllium (e.g., Metamucil), which has a soluble/insoluble fiber ratio 70/30, increases fecal water content, but patients may complain of unwanted side effects such as gas and bloating secondary to its fermentation in the colon. Methylcellulose (e.g., Citrucel), which is 100 % soluble, is a synthetic polymer fiber that increases fecal mass, stimulates motility, and reduces colonic time. It is resistant to bacterial fermentation. Polycarbophil (e.g., FiberCon) is a hydrophilic resin that is not metabolized by intestinal bacteria. Methylcellulose, polycarbophil, and wheat dextrin (e.g., Benefiber) are less likely to cause gas and bloating.
Docusate sodium, a surfactant and stool softener, is generally well tolerated. Its efficacy and safety in pregnancy has not been established, though there have been no reports demonstrating increased risk in congenital malformations [52, 53]. Docusate is considered likely low risk [13], although there has been one report of neonatal hypomagnesemia from a mother who reported daily maternal docusate sodium use (100–200 mg or more daily) throughout pregnancy [54].
Overall, there is limited data on the use of laxatives during pregnancy. Osmotic laxatives, such as lactulose, polyethylene glycol, and magnesium-containing salts, increase the amount of fluid retained in the gut. Lactulose is a poorly absorbed sugar, classified as category B, but can cause bloating, gas, and pain in patients. Polyethylene glycol may result in less bloating and gas and is considered the first-choice osmotic laxative by the American Gastroenterology Association (AGA) during pregnancy [13]. Its systemic absorption is also low, but its safety during pregnancy has not been well established and is classified as category C. Prolonged use could theoretically lead to electrolyte disturbances. Saline laxatives, like magnesium containing agents, are likely low risk. However, in certain patients (e.g., renal dysfunction), excessive absorption of magnesium may lead to electrolyte and volume overload. Their long-term use during pregnancy is not recommended. Moreover, given its tocolytic properties, magnesium-containing agents should be avoided during the last several weeks of pregnancy.
Stimulant laxatives should be reserved for patients who do not respond to dietary measures, exercise, fiber bulking agents, or osmotic laxatives. Stimulant laxatives increase intestinal fluid secretion and stimulate colonic motility. There is limited data on the use of senna and bisacodyl during pregnancy, and both are classified as categories C and B, respectively. Senna glycosides are minimally absorbed by the intestine and excreted in bile. In rat models senna given during organogenesis was not associated with teratogenicity [55], and in case-control studies, maternal use of senna was not associated with congenital malformation [56]. There have been no animal reproductive studies reported on bisacodyl, though this medication has very little systemic absorption and is likely low risk for short-term use. It can be associated with more abdominal cramping when compared to senna. In general, when possible, the lowest dose and shortest duration of stimulant laxative ingestion needed to control symptoms are recommended during pregnancy.
Cascara, an extract from the dried, aged bark of Rhamnus purshiana, is an anthraquinone purgative with laxative properties and is available as an herbal supplement. While its use has not been well studied for during pregnancy, there is no evidence that drugs in this class pose risk to the fetus [53]. Cascara is generally well tolerated and with few side effects, though in high and chronic doses cascara has been linked to several cases of liver injury [57, 58]. Aloe, which has a laxative effect, is not recommended in pregnancy given the possible association with congenital malformations [59]. Castor oil, category X, has a potential association with induction of labor and is therefore not recommended for use during pregnancy. Mineral oil is also not recommended during pregnancy as it may interfere with absorption of important nutrients and vitamins in mothers, as well as its possible association with neonatal coagulopathy and hemorrhage [13].
Linaclotide and lubiprostone are two therapies approved for the management of chronic constipation in the general population. Linaclotide (trade name Linzess), approved by the FDA in 2012, is a guanylin peptide that acts as a selective agonist at the guanylate cyclase-C receptor of intestinal enterocytes. Linaclotide promotes small intestinal secretion of chloride and bicarbonate ions and small intestinal fluid secretion and increases intestinal transit time. In animal studies fetal toxicity occurred at doses toxic to the mother [60]. The safety of its use in pregnant women is unknown. Lubiprostone (trade name Amitiza), approved in 2008, is a prostaglandin analogue and acts locally as a chloride channel activator. At high doses, fetal toxicity was noted in animal studies, but human studies are lacking [61]. Both linaclotide and lubiprostone are classified as category C, and given their relative newness to the market, there are no societal guidelines or recommendations for use during pregnancy.
Case 3
M.L. is a 25-year-old female who recently discovered she is pregnant. She has never been pregnant. She has a history of irritable bowel syndrome (IBS) since college. Because of persistent abdominal pain, she was prescribed amitriptyline over 2 years ago. While taking the amitriptyline, she noted improvement in her symptom, but because of unpleasant side effects, she tapered off amitriptyline. Her symptoms remained manageable and she now takes peppermint oil occasionally for symptoms. For the past year, she noticed increased bloating, as well as generalized mild to moderate abdominal pain associated with belching and passing gas. She does not have any weight loss, blood in stool, worsening of abdominal pain, or changes in bowel habit. She had an unremarkable colonoscopy in her early twenties, and recent labs including work-up for celiac disease were normal. She started a probiotic with some improvement in her bloating. Dietary modifications were recommended, but she has not made any changes in her diet thus far. She is concerned about medication use and control of her symptoms during pregnancy.
Discussion
Traditional management of IBS in the nonpregnant patient focuses on improving individual symptoms, improving global symptoms, preventing unnecessary procedures, and reducing the impact of IBS on the overall quality of life. Smooth muscle relaxants (e.g., antispasmodics) and tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, and anticonvulsants are potential medical therapies used in the management of abdominal pain and discomfort.
Dicyclomine and hyoscyamine are antispasmodics used for management of IBS and are categories B and C, respectively. In clinical trials dicyclomine improves pain, tenderness, bowel habits, and overall condition [62], and in a meta-analysis of 12 different antispasmodics, including dicyclomine, patients allocated to the antispasmodic group had improvement in global symptoms of IBS or abdominal pain compared to the placebo group (39 % vs. 56 %). Adverse events occurred in 14 % of patients [63] that most commonly included dry mouth, dizziness, and blurred vision. Dicyclomine hydrochloride, an anticholinergic agent, appears to improve tenderness and overall symptoms in patients with IBS but side effects have been noted in up to 69 % of patients at doses of 160 mg/day [62].
There is limited information of dicyclomine (category B) during pregnancy use. Animal studies have not demonstrated fetal harm, and epidemiologic studies in pregnant women taking dicyclomine up to 40 mg/day during the first trimester have not shown fetal abnormalities [64]. Dicyclomine is categorized as compatible with pregnancy [53]. Hyoscyamine (class C) crosses the placenta and little is known on its effects on the fetus.
TCAs have been used to treat functional bowel symptoms and likely work by modulating pain centrally and peripherally. Controlled studies in the nonpregnant population are limited by few numbers of patients and short follow-ups. A meta-analysis showed improvement in abdominal pain scores and clinical response when pooling several TCAs for the use of IBS patients. There are no studies for their use in the pregnant population. Desipramine and amitriptyline are category C, and nortriptyline is category D. TCAs cross the placenta, and their use has been associated with preterm birth and possible complications such as jitteriness, irritability, respiratory distress, and endocrine and metabolic disturbances in the newborn [65, 66]. Few studies have looked at the teratogenic effects on a population level. While Swedish and US studies demonstrated an increased risk of congenital abnormalities in neonates exposed to TCA use during pregnancy [66, 67], another UK study did not find a significant association with their use during the first trimester [68]. The AGA recommends avoidance of TCAs during pregnancy given the limited efficacy data for IBS [17], though risk and benefit should be discussed in women requiring this medication for management of their symptoms.
Peppermint oil in animal models has been shown to reduce calcium influx resulting in the relaxation of gastrointestinal smooth muscle [69]. This mechanism of action may be responsible for its use in the treatment of IBS and abdominal pain. A meta-analysis, pooling the results of four trials comparing peppermint oil to placebo, demonstrated that the use of peppermint oil (ranging from cumulative daily doses of 450 to 600 mg) improved abdominal pain and/or global symptoms. There are few studies looking at the use of herbal supplements during pregnancy and birth outcomes. Low birth weight and preterm delivery do not seem to be increased in women taking peppermint during pregnancy [70, 71], and in a study of the use of peppermint oil for treatment of pruritus in pregnant women, no side effects were noted in patients [72].
Bloating is a common complaint reported by patients with IBS, and these patients often report associated abdominal pain. Impaired gas transit and malabsorption of short-chain carbohydrates may contribute to the symptoms of abdominal bloating and distension. Dietary modifications, such as limitation of FODMAPs (fermentable oligo-, di-, and monosaccharides and polyols), and reduction of fiber intake may improve symptoms of bloating. FODMAP short-chain carbohydrates are poorly absorbed and fermented in the intestinal lumen, causing bloating and abdominal pain. A low FODMAP diet therefore restricts a large number of foods that contain lactose, gluten, as well as many artificial sugars, and some vegetables and fruits in which there is an excess of fructose over glucose. While the exact mechanism of efficacy is not clearly understood, probiotics appear to alter immune response, reducing inflammation, and alter the gut flora composition, resulting in improved IBS symptoms as well. Bifidobacterium infantis and Bifidobacterium bifidum have been shown to improve symptoms of abdominal pain and bloating [73, 74]. VSL#3 also appears to reduce colonic transit and improve flatulence in IBS patients and bloating in patients with diarrhea-predominant IBS [75, 76]. In a randomized controlled trial of pregnant women receiving probiotics at 2–4 weeks before expected delivery, there were no congenital malformations reported in the probiotic group. A meta-analysis failed to show difference in birth weight, gestational age, and Cesarean section for maternal probiotic use during pregnancy [77].
Antibiotics may also play a role in the treatment of IBS symptoms. There are potentially important differences in enteric flora of the IBS patient compared to the general population. Lactobacilli and bifidobacilli have been found in lower amounts in stool samples of patients with IBS [78, 79]. Reduction in these beneficial bacteria, which produce short-chain fatty acids that inhibit adherence of invasive bacteria, may favor colonization of the intestine with pathogenic bacteria. Increased hydrogen release during carbohydrate fermentation is associated with bloating and gaseous symptoms, and methane production has been associated with chronic constipation [80]. Rifaximin improves global symptoms of IBS, bloating, and abdominal pain [81–83]. There is limited oral absorption of rifaximin and the exposure to the fetus is expected to be low. Rifaximin is category C and has been associated with teratogenicity in some but not all animal studies [84, 85]. There are no adequate clinical studies in pregnant women.
Inflammatory Bowel Disease
Case 4
S.M. is a 32-year-old female with a history of Crohn’s disease (CD) diagnosed 8 years ago, who presents for preconception counseling. She was diagnosed at the age of 24, while in law school, when she developed abdominal pain and bloating. A colonoscopy and cross-sectional imaging showed ileitis and biopsies were consistent with Crohn’s disease. She was started on a thiopurine, azathioprine (AZA), and a prednisone taper at diagnosis. Four years after diagnosis, she had recurrence of her symptoms and persistent ileitis, necessitating a second prednisone course as an outpatient and dose increase of her AZA. With the increased dose in AZA, she was noted to have elevations in her liver function tests. AZA was ultimately stopped and prednisone was continued. After discussion with her gastroenterologist, she was started on infliximab (IFX) 5 mg/kg. She has been in clinical and endoscopic remission since then. Prior to starting IFX and while off of AZA, she had one miscarriage at gestation week 8. At the time of her miscarriage, she was in clinical remission and managed with oral prednisone therapy.
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