Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits in the absence of organic causes. A significant proportion of IBS patients also suffer from bloating, distension, and sensation of incomplete evacuation (1). IBS is categorized into subtypes based on predominant bowel pattern, which include diarrhea (IBS-D), constipation (IBS-C), mixed (IBS-M), and undifferentiated forms (2).
The prevalence of IBS is estimated to be approximately 5% (3,4). Although common in both sexes, it is well established that IBS is more prevalent among women than in men (5), and this difference is more pronounced for abdominal pain and constipation (6). A large proportion of women affected with IBS are of childbearing age (7). However, there is a paucity of studies and guidelines that specifically address the epidemiology, course, maternal/fetal prognosis, or management of IBS in pregnancy. Largely, clinical trials in IBS exclude pregnant women. This is despite decades-old research highlighting increased prominence of IBS symptoms in pregnancy, with 11%–38% of pregnant women reporting increased constipation (8,9), especially in the third trimester, whereas 34% report increased stool frequency (9).
Scarcity of literature on IBS and pregnancy poses significant challenges to healthcare providers in counseling and managing patients. Through a literature search (see Supplementary Digital Content 1, https://links.lww.com/AJG/B825), we summarize the current literature and knowledge gaps in the effect of pregnancy on IBS and vice versa, along with the efficacy and safety profiles of commonly used IBS diets and medications in pregnancy. Given the above limitations and lack of gastrointestinal (GI) societal guidelines/consensus statements, it is imperative to have a dynamic discussion between the clinician and patients with IBS regarding various therapeutic options, starting during preconception evaluation and revisiting these issues throughout the pregnancy course and postpartum, where the impact of various drugs become pertinent during breastfeeding.
THE EFFECTS OF PREGNANCY ON IBS
The effects of pregnancy on IBS have not been extensively studied; however, hormonal changes during pregnancy likely affect GI function. Sex hormones, particularly estrogen, influence the peripheral and central regulatory mechanisms of the gut–brain axis implicated in the pathophysiology of IBS and contribute to visceral hypersensitivity, gut motility, mucosal permeability, and immune activation of intestinal mucosa (10–12). Rectal sensitivity varies depending on the menstrual cycle, with the threshold being significantly lower in patients with IBS during menses, highlighting that IBS symptoms may be modified by the ovarian hormonal cycle (13). In animal studies, administration of sex hormones during pregnancy produces opioid antinociception, antagonized by kappa-opiate-receptor antagonists (14). Luteal hormone, produced in the midmenstrual cycle, and human chorionic gonadotropin, prominently produced in the first trimester of pregnancy, have been shown to promote fragmentation and prolongation of the migrating motor complex cycle, which in turn can increase constipation and small intestinal bacterial overgrowth (15). The hormone relaxin, which is produced after the tenth gestational week and causes relaxation of the symphysis pubis and the cervix, also increases nitric oxide synthase and reduces ileal smooth muscle contractions, further prolonging small bowel transit time (16–18). During physiological hyperestrogenemia and hyperprogesteronemia, prolonged orocecal transit times and decreased smooth muscle function have been noted, which can also lead to constipation (19). In addition, sex steroids have been shown to impact colonic chloride ion secretion, thus affecting gut permeability, which can cause changes in gut microbiome and affect the pathogenesis of IBS (20,21). Although theoretically plausible, the literature is sparse as to whether these factors play a major role in increasing IBS symptoms during pregnancy. Finally, pregnancy can be associated with heightened stress, which in turn can augment mast cell activation; this has been shown to be associated with symptoms of functional GI disorders, including IBS (22). However, dedicated studies are needed to further enhance our understanding of the complex pathophysiology of IBS in pregnancy (Figure 1).
THE EFFECTS OF IBS ON PREGNANCY
Although data on fetal health in IBS are limited, pre-existing IBS seems to carry some risks for pregnancy. In a large retrospective study of 26,543 patients with IBS, Khashan et al. (23) showed that IBS before pregnancy was associated with spontaneous miscarriage (7%), ectopic pregnancy (0.74%), pre-eclampsia (0.43%), and stillbirth (0.22%). When compared with mothers without IBS, maternal IBS was associated with increased risk of miscarriage (odds ratio [OR] 1.21; 95% confidence interval [CI], 1.13–1.30) and ectopic pregnancy (OR 1.28; 95% CI 1.06–1.55), but not with preeclampsia (OR 1.09; 95% CI 0.85–1.39) or stillbirth (OR 1.00; 95% CI 0.69–1.44). However, this study was limited by its retrospective design and reliance on imperfect diagnostic codes for both IBS and obstetric outcomes (Tables 1 and 2).
TREATMENT OF IBS IN PREGNANCY
The treatment of pregnant women with IBS should be multidisciplinary, with an emphasis on education and dietary modifications and the judicious use of pharmacologic options that are deemed relatively safe during pregnancy. In-depth discussions between the obstetrician and gastroenterologist regarding the antenatal care of pregnant women with IBS is crucial in optimizing management plans and to ensure the safety of both the mother and fetus.
Dietary modification is a well-known tool in the management of IBS symptoms and traditionally includes avoidance of gas-producing foods such as brussels sprouts, cabbage, broccoli, wheat germ, high-carbohydrate diets, onions, and beans (24). Patients with lactose intolerance and IBS are often counseled to try a lactose-free diet (25). Despite this, there are no studies evaluating the role of dietary modification specifically for the management of IBS in pregnancy (26).
A common recommendation is a diet low in fermentable oli-, di-, and monosaccharides and polyols (FODMAPs). Studies have shown that a low FODMAPs diet may be associated with a significant overall reduction in IBS GI symptoms (27). If IBS symptoms improve after the 2- to 6-week elimination phase, then high FODMAP foods are gradually reintroduced to determine individual tolerance (28). However, such a timeline is challenging during pregnancy. In addition, the complexity of diet therapies for IBS, particularly during pregnancy when a well-rounded diet is of the utmost importance to both the mother and fetus, may make extreme dietary modifications a less favorable treatment option. Restrictive diets such as a low FODMAPs diet could result in reduced intake of fiber, calcium, zinc, folate, B and D vitamins, and natural antioxidants (29). In addition, a lactose-free diet can increase the risk of vitamin D and calcium deficiency. Restrictive diets may be associated with a lower caloric intake, which in turn can increase the risk of fetal low birth weight and potentially developmental delays later in life. Therefore, any elimination diet with potential micro- and macro-nutrient deficiencies—particularly during pregnancy when, for example, folate is critical for neural tube development—should be implemented over a short period of time (elimination phase of 2–6 weeks) under close observation of a registered dietitian, gastroenterologist, and obstetrician and abandoned after a couple of weeks of nonresponse. In addition, these diets can be associated with weight loss, which is also not ideal in pregnancy. A more cautious dietary approach would be to selectively eliminate only the most symptom-provoking foods (if these can be identified) under the supervision of a registered dietitian.
Insoluble fiber (e.g., wheat bran) increases stool bulk and reduces colonic transit time by mechanical stimulation and irritation of the gut mucosa, causing secretion and peristalsis (30,31). Soluble viscous and nonviscous fibers, which are readily fermented, increase fecal biomass, and also increase fermentation by-products such as gas and short-chain fatty acids (32,33).
In a meta-analysis, fiber was associated with modest benefits in global IBS symptoms, with a number needed to treat of 7 (34). In subgroup analysis, soluble fibers (e.g., psyllium and ispaghula husk), but not insoluble fiber, were associated with improved IBS symptoms, with the most robust effect seen in patients with IBS-C. Wheat bran contains fructans, which have a high FODMAP content, and should be avoided in patients with IBS (33,35).
Fiber supplementation is often discontinued because of the increased occurrence of gas and bloating with certain fiber products and unpalatable taste (36). However, given their favorable safety profile and the higher impact of constipation during the third trimester, soluble fiber should be considered in pregnant women with constipation.
Probiotics and prebiotics
Probiotics are live microorganisms that may confer a health benefit when consumed at sufficient quantities, whereas prebiotics are indigestible carbohydrates that serve as nutrients to probiotic bacteria, promoting their growth. Although certain probiotic strains (e.g., Bifidobacterium infantis 35624) (37) or combinations of strains seem to have beneficial effects on global IBS symptoms and abdominal pain, definite conclusions regarding efficacy cannot be drawn. The rate of adverse events was similar between probiotics (19%) and placebo (17%) (38,39).
There are studies endorsing the use of probiotics during pregnancy to regulate gut and vaginal microflora, promote mucosal immunity, reduce the risk of pre-eclampsia, and alleviate allergies and atopic diseases in infants (40–42). However, our comprehensive review did not identify any studies evaluating the role of probiotics in the management of IBS during pregnancy. In a recent meta-analysis by Jarde et al. (43), the use of probiotics and prebiotics in pregnant patients without IBS seemed safe and did not affect the risk of preterm birth or other infant or maternal adverse pregnancy outcomes.
In a randomized, double-blinded, placebo-controlled study, Shadid et al. (44) compared the effect of prebiotics on maternal and neonatal microbiota in 48 pregnant women. Supplementation with galacto-oligosaccharides and long-chain fructo-oligosaccharides had a bifidogenic effect on the maternal gut microbiota, which was not transferred to neonates. Immune parameters measured via a comprehensive examination of cord blood were unaffected.
Given the lack of clinical trials assessing the risks and benefits of prebiotics, probiotics, or symbiotics in patients with IBS during pregnancy, there is no clear guidance on their use.
Management of IBS with constipation
Osmotic laxatives such as polyethylene glycol 3350 (PEG) and milk of magnesia are commonly recommended for IBS-C (Table 1). Overall, studies have shown improvement in stool frequency and consistency, but no relief of abdominal pain or bloating (45).
PEG safety has not been extensively studied in pregnancy, so whether it can cause fetal harm remains unknown (46). However, it has minimal systemic absorption and is unlikely to be teratogenic. In an observational, prospective study evaluating the efficacy of PEG for constipation in 40 pregnant women (47), 1 spontaneous abortion (2.5%) occurred at 11 week' gestation, which was believed not to be drug related, given the rate of spontaneous abortion before 12 weeks of gestation is 4%–8%. Other adverse outcomes, including 1 preterm delivery secondary to failed cerclage and another due to severe gestational hypertension were also not considered to be related to PEG treatment. PEG was found to be an effective choice in improving spontaneous stool evacuation, pain with defecation, and abdominal pain. However, no randomized controlled trials have further explored the safety of PEG during pregnancy. One study of 225 patients demonstrated PEG safety in postpartum constipation (48).
Magnesium salts, including magnesium oxide, magnesium citrate, and magnesium sulfate, are considered gentle osmotic laxatives. Magnesium crosses the placenta, and fetal serum concentrations are similar to maternal levels. Magnesium sulfate injection has been used in the prevention and treatment of seizures during pregnancy, severe preeclampsia, or eclampsia. It has also been indicated for a reduced probability of cerebral palsy when given to mothers at risk for preterm delivery before 32 weeks of gestation (49). The American Gastroenterological Association considers the use of magnesium citrate as a laxative during pregnancy to be low risk, but long-term use should be avoided (50).
Sodium phosphate solution has been used as a colonic purge and colonoscopy preparation solution. One case of a newborn developing bone demineralization and bone growth failure because of repeated maternal use of phosphate enemas during pregnancy has been reported. As a result, its use is not recommended in pregnancy (51).
In summary, osmotic laxatives should be used with caution and for short durations because of concerns regarding electrolyte abnormalities and lack of long-term safety data specifically during pregnancy.
Stimulants: sennosides and bisacodyl.
Bisacodyl [bis (p-acetoxyphenyl)-2 pyridylmethane] is a synthetic compound that produces bowel movements by simulating peristalsis in the large bowel when it comes in contact with the colonic mucosa. It is not absorbed to any significant degree; therefore, it is less likely to cause systemic toxicity (52). Bisacodyl has not been studied in pregnant patients. However, in a study by Friedrich et al. (53), bis (p-acetoxyphenyl)-2 pyridylmethane was not excreted in human breast milk, and its use was considered safe during lactation and the postpartum period.
Sennosides (or Senna), a stimulant, plant-based, anthraquinone type laxative has been shown to be toxic during pregnancy at higher doses in animals, resulting in fetal death, cardiac and skeletal muscle necrosis, and sciatic nerve lesions (54). By contrast, in a retrospective study of 22,843 cases by Acs et al. (55), the rate of senna use did not differ significantly among pregnant women who subsequently had newborns with or without congenital abnormalities (2.2% vs 2.5%, respectively). Senna use between 10 and 30 mg was not associated with a higher risk for 23 different congenital abnormalities during the second and/or third month of pregnancy (i.e., the critical period for most major congenital abnormalities), when compared with 500 matched controls. Pregnancy duration was slightly longer (0.2 weeks) with a lower rate of preterm birth in senna users (6.6% vs 9.2%). Although this study provides some reassurance, the use of senna in pregnancy is discouraged.
Lubricants: castor oil, mineral oil, and saline hyperosmotic agents.
These agents should be avoided in pregnancy because of concerns regarding reduced maternal absorption of fat-soluble vitamins, which could subsequently lead to hemorrhage and neonatal hypoprothrombinemia (56). Castor oil can be associated with premature uterine contractions, and hyperosmotic saline products can cause fluid retention (57).
Docusate sodium has not been associated with adverse effects during pregnancy and given its mechanism of action is likely low risk in pregnancy (8, 58). A case of a newborn with hypomagnesemia secondary to chronic maternal overuse of docusate sodium has been reported (59).
Linaclotide is a minimally absorbed oligopeptide agonist of guanylate cyclase 2C, which primarily induces intestinal chloride and bicarbonate secretion (60). Linaclotide has been shown to be effective in improving abdominal pain and global IBS symptoms, in addition to increasing the number of complete spontaneous bowel movements (61). The most common adverse event associated with linaclotide is diarrhea, which resulted in a 5.7% rate of discontinuation of therapy (62).
There are no studies of linaclotide in pregnant women. However, developmental studies in animals have shown adverse fetal effects with maternal toxicity, but at doses much higher than the maximum recommended human dose (63,64). Given the absence of adequate data, the use of linaclotide should be limited to when the potential benefit justifies the potential risk to the fetus.
Plecanatide is a pH-sensitive guanylate cyclase analogue. Two large phase-3 trials (65) demonstrated overall and sustained efficacy of plecanatide in adults with IBS-C, improving complete spontaneous bowel movements and reducing abdominal pain, bloating, and discomfort. The rate of discontinuation of therapy because of diarrhea was 1.2%–1.4%.
Plecanatide is negligibly absorbed systemically and maternal use is not expected to result in fetal exposure to the drug. However, the available data on plecanatide use in pregnancy are insufficient to determine any drug-associated risks for major birth defects and miscarriage. Animal studies did not show any effect on embryogenesis or organogenesis with oral administration of the drug at levels much higher than the recommended human dosage (66).
Lubiprostone activates type 2 chloride channels in the apical membrane of intestinal epithelial cells to increase the secretion of chloride-rich intestinal fluid (67). Lubiprostone significantly improves constipation severity, stool consistency, abdominal pain, degree of straining, and abdominal bloating. The incidence of nausea, vomiting, and diarrhea was common at 2.4%–75% (68).
Lubiprostone has not been evaluated in humans during pregnancy. However, studies in guinea pigs have shown potential fetal loss. Other animal studies have also shown increased incidence of early resorption and soft-tissue malformations, but those effects were likely secondary to maternal toxicity. Animal studies have also shown significant reductions in the numbers of implantation sites and live embryos, but no effects on male and female fertility and reproductive function at oral doses up to 1,000 μg/kg per day (69).
In 1 clinical trial, a patient became pregnant while on lubiprostone (70). The patient withdrew from the study, and months later delivered a baby with bilateral clubfoot; the study concluded that this was the first and only adverse fetal event among 6 known pregnancies while taking lubiprostone. Five of the 6 pregnancies were carried to term, whereas the sixth was electively terminated. Currently, the use of lubiprostone in pregnancy is not recommended.
Tenapanor, a selective sodium hydrogen exchange 3 inhibitor, is approved for IBS-C in adults (71). It has minimal systemic absorption and acts on the apical membrane of intestinal epithelial cells, inhibiting sodium absorption and modulating tight junctions in the small intestine, although increasing transepithelial electrical resistance and reducing phosphate ion permeability and paracellular phosphate absorption in the presence of sodium hydrogen exchange 3 (72,73). Tenapanor is shown to decrease abdominal pain and increase complete spontaneous bowel movements in patients with IBS-C, with a reported diarrhea rate of 11.2% (74).
There are no clinical data on the safety of tenapanor in pregnancy. Exposure in a small number of pregnant women did not result in any drug-associated birth defects, miscarriage, or adverse maternal or fetal outcomes. In addition, there were no reported birth defects in animal models. There are no data available on the presence of tenapanor in either human or animal milk, its effect on milk production, or its effect on the breastfed infant. Given these limitations, no recommendations can be made on the use of this novel agent in the management of IBS in pregnancy (75).
Prokinetic agents (5-hydroxytryptamine (serotonin)-4 receptor agonists)
Prucalopride is a selective, high-affinity 5-hydroxytryptamine (serotonin) (5HT)-4 receptor agonist, which stimulates GI motility and improves common symptoms of chronic constipation in adults. It is currently approved for the management of chronic idiopathic constipation in the United States but not IBS-C. In an integrated analysis of 6 randomized controlled trials, prucalopride (at doses of 2 or 4 mg daily, with no statistically significant difference between the 2 doses) was shown to increase the number of spontaneous complete bowel movements, with a favorable safety and tolerability profile in management of chronic constipation. Common side effects include headache, nausea, diarrhea, and abdominal pain (76).
Experience with prucalopride during pregnancy is quite limited. However, there have been cases of spontaneous abortion during clinical studies (77). Animal studies do not indicate harmful effects to pregnancy. There have been concerns that prucalopride increases prolactin levels and miscarriages during clinical trials (78). Although data are limited, prucalopride is not recommended during pregnancy. In fact, women of childbearing age are recommended to use effective contraception during treatment with prucalopride (78,79).
Tegaserod is a 5HT-4 receptor agonist approved for the treatment of IBS-C. Adverse events have been observed in animal reproduction studies, and miscarriages have been reported in patients exposed to tegaserod. The use of tegaserod during pregnancy is not recommended (80).
Management of IBS with diarrhea
Loperamide, an opioid receptor agonist, acts directly on longitudinal and circular intestinal muscles, inhibiting peristalsis and prolonging transit time (Table 2). It reduces fecal volume, diminishes fluid and electrolytes loss, and increases viscosity (81,82). Loperamide has been shown to decrease stool frequency and improve consistency but does not significantly alleviate abdominal bloating, discomfort, pain, or global IBS symptoms (83). Common side effects include abdominal pain, bloating, nausea, vomiting, and constipation. Therefore, although loperamide may offer short-term benefit in the management of diarrhea, continuous use of loperamide is not recommended (84).
In a multicenter, prospective, controlled study of loperamide in pregnancy, no significant major fetal malformations were noted, but 3 minor malformations were reported among 95 live births in the study group (a heart murmur, a mild right pelviectasis with no symptoms, and a hypospadia [minor]). Of 89 women exposed to loperamide during the first trimester, differences between the study and control groups were not statistically significant for major/minor malformations, abortions, premature births, or mean birth weights, although 21 of 105 had babies who were 200 g smaller than babies in the control group (85). By contrast, Kallen et al. (86) showed the use of loperamide in early pregnancy may be associated with an increased risk for any congenital malformation (OR 1.43, 95% CI 1.04–1.96), including significantly increased risk of hypospadias (relative risk [RR] = 3.2, 95% CI 1.3–6.6). Loperamide may increase the maternal risk of placenta previa and likelihood of Caesarean section. Therefore, loperamide use in early pregnancy may be associated with a moderately increased risk for congenital malformations (87).
Bile acid sequestrants.
Bile acid diarrhea is typically seen in patients with active ileal Crohn's disease or ileal resection. Other etiologies such as small intestinal bacterial overgrowth, chronic pancreatitis, or celiac disease can affect bile acid absorption. A subpopulation of patients with functional diarrhea or IBS-D may have evidence of bile acid diarrhea (88).
The mainstay of therapy for bile acid diarrhea is bile acid sequestrants including cholestryramine, colestipol, and colesevelam. These medications are not absorbed systemically; however, given their binding nature, they may interfere with maternal fat and fat-soluble vitamin absorption. In addition, they may bind to other medications, including multivitamins and iron, which are routinely supplemented during pregnancy. There are no well-controlled studies of bile acid sequestrants in pregnant women. Therefore, their use requires the potential benefit of drug therapy to outweigh the risk of possible hazards to both the mother and fetus (89).
In a recently published systematic review and meta-analysis, tricyclic antidepressants (TCAs) were superior than placebo in treating IBS symptoms. The overall adverse events were significantly higher among those who received TCA compared with placebo (31.3% vs 16.5%), with the most common side effects being dry mouth and drowsiness, and a number needed to harm of 9 (84,90,91).
Adverse events have been seen for TCAs in animal reproduction studies. Amitriptyline, nortriptyline, and their metabolites cross the human placenta and can be detected in the cord blood (92). Central nervous system side effects, limb deformities, and developmental delay have been documented in case reports, although a causal relationship has not been established. TCAs may also be associated with irritability, jitteriness, and convulsion (rare) in neonates. Crying, constipation, difficulty with urination, and nausea may also occur in neonates exposed during pregnancy (93,94). Given potential concerns for adverse fetal effects, they should not be initiated during pregnancy for the treatment of IBS.
5-HT-3 receptor antagonists.
5-HT signaling pathways have been implicated in GI motility and pain perception (95). Alosetron is approved for severe refractory IBS-D in women, following reports of ischemic colitis (∼1 in 800) and complications from worsening constipation (96). Ondansetron is not approved by the US Food and Drug Administration (FDA) for chronic diarrhea or IBS-D; however, in a randomized, crossover, placebo-controlled trial, IBS symptoms severity scores decreased more in the treatment arm compared with placebo. The pain score did not change significantly in the treatment arm (96,97).
Reproduction studies in rat models have been performed at doses up to 40 mg/kg per day of alosetron (approximately 160 times higher than the recommended human dose) and showed no evidence of impaired fertility or harm to the fetus. However, there are no well-controlled studies in pregnant women. Because animal studies are not always predictive of human reproductive response, alosetron should be used during pregnancy with extreme caution, if at all (98,99). Ondansetron also readily crosses the placenta during the first trimester of pregnancy and can be detected in fetal tissue (100). Given the pregnancy-related physiologic changes, ondansetron clearance may increase as pregnancy progresses (101). Overall, the general use of ondansetron for treatment of IBS-D is not recommended.
Eluxadoline is an orally administered, minimally absorbed, mixed muopioid receptor agonist, and a delta opioid receptor antagonist in the GI tract and has been shown to be efficacious in IBS-D (102–104). The most common adverse events were constipation (2%), nausea, abdominal pain (1%), and distension, vomiting, and gastroenteritis. Given the risk of pancreatitis, eluxadoline is contraindicated in patients with previous cholecystectomy, pancreatitis, chronic alcohol use (more than 3 units per day), and any degree of hepatic impairment (104).
Animal studies do not indicate direct or indirect reproductive toxicity with eluxadoline. However, eluxadoline was not evaluated in pregnant women (105). Cholestasis can occur in pregnancy, in addition to other pancreatico-biliary conditions. Although not studied, this should increase caution in the use of drugs with side-effects linked to the presence or absence of gallbladder disease, such as cholestasis or cholelithiasis. Therefore, eluxadoline should not be used during pregnancy until further studies are performed.
Rifaximin is a minimally absorbed, GI-targeted antibiotic derived from rifamycin (106). Randomized controlled trials assessing rifaximin in nonconstipated IBS have shown adequate relief of global IBS symptoms, abdominal pain, stool consistency, and bloating (107). Retreatment is safe and effective in subjects with relapsing symptoms of IBS-D who showed initial response to rifaximin (108).
In an animal study using rats and rabbits, rifaximin doses of 50 and 100 mg/kg had no teratogenic effects and did not influence the psychophysical development of the pups (109). There are no data in pregnant women. Although poorly absorbed, rifaximin is derived from rifamycin, which has teratogenic effects. Therefore, rifaximin should be avoided during pregnancy (110).
Antispasmodics include a wide range of pharmacological therapies that can reduce spastic contractions of intestinal smooth muscles but are not approved by the FDA for the treatment of IBS. A recent systematic review found a beneficial effect for antispasmodics over placebo for improvement in abdominal pain and global symptom assessment (111).
Peppermint oil is a smooth muscle calcium channel antagonist that can cause muscle relaxation (112). It is also a kappa-opioid receptor agonist that may alter gut sensitivity (113) and has anti-inflammatory (114) and serotonergic (4-HT3) antagonistic properties (115). Although the evidence for peppermint oil is of low quality, the results are consistently favorable. In a randomized, double-blind trial of patients with IBS, small intestinal-release peppermint oil significantly reduced abdominal pain, discomfort, and IBS severity; however, neither small intestinal- nor colonic-release peppermint led to statistically significant reductions in abdominal pain response or overall symptom relief, when using FDA/European Medicines Agency recommended endpoints (116). In addition, in a network meta-analysis by Black et al. (117), peppermint oil capsules were ranked first for efficacy in improvement of global IBS symptoms with RR 0.63, 95% CI 0.48–0.83. However, side effects of peppermint oil include heartburn, constipation, nausea, and peppermint breath and taste (84,96). The use of peppermint oil in the second and third trimesters of pregnancy was not associated with low birth weight in a large epidemiologic study (118).
Other antispasmodics that have shown to be beneficial include dicyclomine, hyoscyamine, pinaverium, and trimebutine. Dicyclomine has not been shown to have any adverse events in animal reproduction studies; birth defects were not observed following maternal doses up to 40 mg daily throughout the first trimester (119). A double-blind, multicenter, randomized placebo-controlled study of nausea and vomiting during pregnancy found a similar rate of adverse events (11%) for dicyclomine (n = 273) and placebo (n = 270) (120). Hyoscyamine crosses the placenta, but animal reproduction studies have not been conducted (121). Dicyclomine and hyoscyamine should be used in pregnancy as a last resort. Per the drug monograph, the use of trimebutine is not recommended during pregnancy (122).
Selective serotonergic reuptake inhibitors.
Selective serotonergic reuptake inhibitors (SSRIs) have been prescribed as central neuromodulators in the treatment of functional brain-gut disorders. Several randomized controlled trials with SSRIs noted a reduction in IBS symptoms compared with placebo (RR = 0.68, 95% CI 0.51–0.91), although there was significant heterogeneity between studies (123). However, the literature is sparse as to the efficacy and safety of SSRIs in the management of IBS in pregnant woman. Citalopram and its metabolites have been shown to cross the human placenta, with an increased risk of teratogenic effects including cardiovascular defects; however, the available information is conflicting. Other nonteratogenic effects of SSRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia or hypertonia, hyper-reflexia, jitteriness, irritability, and tremor (124). Given the paucity of literature and potential teratogenic effect of SSRI, its routine use in pregnancy is not recommended.
Management of mixed-type IBS
Managing patients with alternating bowel habits remains a challenge for clinicians. Only a few well-conducted studies in nonpregnant patients with IBS-M have been conducted, which included peppermint and rifaximin. In a small study, Cash et al. (125) assessed a novel delivery system of peppermint oil with sustained release in the small bowel in patients with IBS-M and IBS-D that showed a significant reduction in the total IBS symptom score. A summary of evidence for peppermint and rifaximin in pregnant patients has been provided above. Managing IBS-M during pregnancy remains dependent on the predominant symptom.
The lack of successful treatment in IBS often leads to patients trying alternative medicine, such as acupuncture. Although its benefit in IBS management has been controversial (126), Pei et al. (127) demonstrated acupuncture to be more effective in decreasing IBS symptom severity scores than PEG and pinaverium bromide, with its effects lasting up to 12 weeks. Acupuncture seems to be safe during pregnancy, with few adverse events (1.9%), namely needling pain, when correctly applied (128). The addition of cognitive behavioral therapy to pharmacotherapies has also shown to further improve the global symptom score in nonpregnant patients with IBS and could be potentially considered in pregnancy (129).
Here, we provide a comprehensive overview on IBS in pregnancy to assist providers in counseling and managing their patients. A significant knowledge gap exists regarding the pathophysiology, course, and safety/efficacy of various pharmacologic and dietary options in the management of IBS during pregnancy (Figure 1). Establishing prospective database registries are required to fill the existing information gap on IBS during pregnancy.
CONFLICTS OF INTEREST
Guarantor of the article: Ali Rezaie, MD, MSc.
Specific author contributions: S.M. A.R., and M.S.W.: performed literature searches and prepared the initial draft. M.P. and A.R.: reviewed and edited the manuscript. All authors have approved the final draft submitted.
Financial support: None to report.
Potential competing interests: A.R. and M.P. report serving as consultant and speaker for and receiving research grants from Bausch Health. Cedars-Sinai Medical Center has a licensing agreement with Bausch Health and Gemelli Biotech. A.R. and M.P. have equity in Gemelli Biotech. The remaining authors have no potential competing interests.
1. von Wulffen M, Talley NJ, Hammer J, et al. Overlap of irritable bowel syndrome and functional dyspepsia in the clinical setting: Prevalence and risk factors. Dig Dis Sci 2019;64:480–6.
2. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393–407.
3. Lacy BE. Emerging treatments in neurogastroenterology: Eluxadoline—A new therapeutic option for diarrhea-predominant IBS. Neurogastroenterol Motil 2016;28:26–35.
4. Palsson OS, Whitehead W, Tornblom H, et al. Prevalence of Rome IV functional bowel disorders among adults in the United States, Canada, and the United Kingdom. Gastroenterology 2020;158:1262–73.e3.
5. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol 2014;6:71–80.
6. Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community: Systematic review and meta-analysis. Am J Gastroenterol 2012;107:991–1000.
7. Mulak A, Tache Y. Sex difference in irritable bowel syndrome: Do gonadal hormones play a role? Gastroenterol Pol 2010;17:89–97.
8. Greenhalf JO, Leonard HS. Laxatives in the treatment of constipation in pregnant and breast-feeding mothers. Practitioner 1973;210:259–63.
9. Levy N, Lemberg E, Sharf M. Bowel habit in pregnancy. Digestion 1971;4:216–22.
10. Heitkemper MM, Chang L. Do fluctuations in ovarian hormones affect gastrointestinal symptoms in women with irritable bowel syndrome? Gend Med 2009;6(Suppl 2):152–67.
11. Mulak A, Bonaz B. Irritable bowel syndrome: A model of the brain-gut interactions. Med Sci Monit 2004;10:RA55–62.
12. Mulak A, Tache Y, Larauche M. Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol 2014;20:2433–48.
13. Houghton LA, Lea R, Jackson N, et al. The menstrual cycle affects rectal sensitivity in patients with irritable bowel syndrome but not healthy volunteers. Gut 2002;50:471–4.
14. Ducker TE, Boss JW, Altug SA, et al. Luteinizing hormone and human chorionic gonadotropin fragment the migrating myoelectric complex in rat small intestine. Neurogastroenterol Motil 1996;8:95–100.
15. Dukowicz AC, Lacy BE, Levine GM. Small intestinal bacterial overgrowth: A comprehensive review. Gastroenterol Hepatol 2007;3:112–22.
16. Bani D, Baccari MC, Quattrone S, et al. Relaxin depresses small bowel motility through a nitric oxide-mediated mechanism. Studies in mice. Biol Reprod 2002;66:778–84.
17. Manning AP, Thompson WG, Heaton KW, et al. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2:653–4.
18. Hasler WL. The irritable bowel syndrome during pregnancy. Gastroenterol Clin North Am 2003;32:385–406, viii.
19. Chiloiro M, Darconza G, Piccioli E, et al. Gastric emptying and orocecal transit time in pregnancy. J Gastroenterol 2001;36:538–43.
20. Condliffe SB, Doolan CM, Harvey BJ. 17beta-oestradiol acutely regulates Cl- secretion in rat distal colonic epithelium. J Physiol 2001;530:47–54.
21. Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014;6:263ra158.
22. Weinstock LB, Pace LA, Rezaie A, et al. Mast cell activation syndrome: A primer for the gastroenterologist. Dig Dis Sci 2020. [Epub ahead of print, April 23, 2020.] doi: 10.1007/s10620-020-06264-9
23. Khashan AS, Quigley EMM, McNamee R, et al. Increased risk of miscarriage and ectopic pregnancy among women with irritable bowel syndrome. Clin Gastroenterol Hepatol 2012;10:902–9.
24. Zhu Y, Zheng X, Cong Y, et al. Bloating and distention in irritable bowel syndrome: The role of gas production and visceral sensation after lactose ingestion in a population with lactase deficiency. Am J Gastroenterol 2013;108:1516–25.
25. Yang J, Deng Y, Chu H, et al. Prevalence and presentation of lactose intolerance and effects on dairy product intake in healthy subjects and patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2013;11:262–8 e1.
26. Dionne J, Ford AC, Yuan Y, et al. A systematic review and meta-analysis evaluating the efficacy of a gluten-free diet and a low FODMAPs diet in treating symptoms of irritable bowel syndrome. Am J Gastroenterol 2018;113:1290–300.
27. Eswaran SL, Chey WD, Han-Markey T, et al. A randomized controlled trial comparing the low FODMAP diet vs. modified NICE guidelines in US adults with IBS-D. Am J Gastroenterol 2016;111:1824–32.
28. McKenzie YA, Alder A, Anderson W, et al. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet 2012;25:260–74.
29. Catassi G, Lionetti E, Gatti S, et al. The low FODMAP diet: Many question marks for a catchy acronym. Nutrients 2017;9:292.
30. Tomlin J, Read NW. Laxative properties of indigestible plastic particles. BMJ 1988;297:1175–6.
31. Lewis SJ, Heaton KW. Roughage revisited: The effect on intestinal function of inert plastic particles of different sizes and shape. Dig Dis Sci 1999;44:744–8.
32. Stephen AM, Cummings JH. Mechanism of action of dietary fibre in the human colon. Nature 1980;284:283–4.
33. Eswaran S, Muir J, Chey WD. Fiber and functional gastrointestinal disorders. Am J Gastroenterol 2013;108:718–27.
34. Moayyedi P, Quigley EM, Lacy BE, et al. The effect of fiber supplementation on irritable bowel syndrome: A systematic review and meta-analysis. Am J Gastroenterol 2014;109:1367–74.
35. Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: A clinical review. JAMA 2015;313:949–58.
36. Schiller LR. Review article: The therapy of constipation. Aliment Pharmacol Ther 2001;15:749–63.
37. Ford AC, Harris LA, Lacy BE, et al. Systematic review with meta-analysis: The efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther 2018;48:1044–60.
38. Su GL, Ko CW, Bercik P, et al. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology 2020;159:697–705.
39. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: Symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128:541–51.
40. Gerritsen J, Smidt H, Rijkers GT, et al. Intestinal microbiota in human health and disease: The impact of probiotics. Genes Nutr 2011;6:209–40.
41. Thomas DW, Greer FR, American Academy of Pediatrics Committee on Nutrition; , et al. Probiotics and prebiotics in pediatrics. Pediatrics 2010;126:1217–31.
42. Brantsaeter AL, Myhre R, Haugen M, et al. Intake of probiotic food and risk of preeclampsia in primiparous women: The Norwegian Mother and Child Cohort Study. Am J Epidemiol 2011;174:807–15.
43. Jarde A, Lewis-Mikhael AM, Moayyedi P, et al. Pregnancy outcomes in women taking probiotics or prebiotics: A systematic review and meta-analysis. BMC Pregnancy Childbirth 2018;18:14.
44. Shadid R, Haarman M, Knol J, et al. Effects of galactooligosaccharide and long-chain fructooligosaccharide supplementation during pregnancy on maternal and neonatal microbiota and immunity--a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2007;86:1426–37.
45. Chapman RW, Stanghellini V, Geraint M, et al. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol 2013;108:1508–15.
46. ASGE Standard of Practice Committee, Shergill AK, Ben-Menachem T, et al. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc 2012;76:18–24.
47. Neri I, Blasi I, Castro P, et al. Polyethylene glycol electrolyte solution (isocolan) for constipation during pregnancy: An observational open-label study. J Midwifery Womens Health 2004;49:355–8.
48. Nardulli G, Limongi F, Sue G, et al. Use of polyethylene glycol in the treatment of puerperal constipation [in German]. G E N 1995;49:224–6.
49. Shepherd E, Salam RA, Middleton P, et al. Antenatal and intrapartum interventions for preventing cerebral palsy: An overview of Cochrane systematic reviews. Cochrane Database Syst Rev 2017;8:CD012077.
50. Mahadevan U, Kane S. American gastroenterological association institute technical review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006;131:283–311.
51. Mahadevan U. Gastrointestinal medications in pregnancy. Best Pract Res Clin Gastroenterol 2007;21:849–77.
52. Lane RE. Evaluation of bisacodyl (Dulcolax) as a laxative for routine postpartum use. Obstet Gynecol 1961;17:453–4.
53. Friedrich C, Richter E, Trommeshauser D, et al. Absence of excretion of the active moiety of bisacodyl and sodium picosulfate into human breast milk: An open-label, parallel-group, multiple-dose study in healthy lactating women. Drug Metab Pharmacokinet 2011;26:458–64.
54. Barbosa-Ferreira M, Pfister JA, Gotardo AT, et al. Intoxication by Senna occidentalis seeds in pregnant goats: Prenatal and postnatal evaluation. Exp Toxicol Pathol 2011;63:263–8.
55. Acs N, Banhidy F, Puho EH, et al. Senna treatment in pregnant women and congenital abnormalities in their offspring--a population-based case-control study. Reprod Toxicol 2009;28:100–4.
56. Cullen G, O'Donoghue D. Constipation and pregnancy. Best Pract Res Clin Gastroenterol 2007;21:807–18.
57. Body C, Christie JA. Gastrointestinal diseases in pregnancy: Nausea, vomiting, hyperemesis gravidarum, gastroesophageal reflux disease, constipation, and diarrhea. Gastroenterol Clin North Am 2016;45:267–83.
58. Jick H, Holmes LB, Hunter JR, et al. First-trimester drug use and congenital disorders. JAMA 1981;246:343–6.
59. Schindler AM. Isolated neonatal hypomagnesaemia associated with maternal overuse of stool softener. Lancet 1984;2:822.
60. Bryant AP, Busby RW, Bartolini WP, et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 2010;86:760–5.
61. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: A meta-analysis. Clin Gastroenterol Hepatol 2013;11:1084–92.e3; quiz e68.
62. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107:1714–24; quiz 1725.
63. Constella (Linaclotide) [product monograph]. Allergan, Markham, ON, 2018. (https://pdf.hres.ca/dpd_pm/00047072.PDF
). Accessed October 20, 2020.
64. Thomas RH, Allmond K. Linaclotide (linzess) for irritable bowel syndrome with constipation and for chronic idiopathic constipation. P T 2013;38:154–60.
65. Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: Results of two phase 3 randomized clinical trials. Am J Gastroenterol 2018;113:735–45.
66. Sangwan YP, Solla JA. Internal anal sphincter: Advances and insights. Dis Colon Rectum 1998;41:1297–311.
67. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: A double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther 2007;25:1351–61.
68. Li F, Fu T, Tong WD, et al. Lubiprostone is effective in the treatment of chronic idiopathic constipation and irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 2016;91:456–68.
69. (Lubiprostone). Center for Drug Evaluation and Research. (https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/021908Orig1s008.pdf
). Accessed October 20, 2020.
70. Lembo AJ, Johanson JF, Parkman HP, et al. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci 2011;56:2639–45.
71. Munjal A, Dedania B, Cash B. Update on pharmacotherapy for irritable bowel syndrome. Curr Gastroenterol Rep 2019;21:25.
72. Zielinska M, Wasilewski A, Fichna J. Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome. Expert Opin Investig Drugs 2015;24:1093–9.
73. King AJ, Siegel M, He Y, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med 2018;10:eaam6474.
74. Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: A phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol 2017;112:763–74.
76. Camilleri M, Piessevaux H, Yiannakou Y, et al. Efficacy and safety of prucalopride in chronic constipation: An integrated analysis of six randomized, controlled clinical trials. Dig Dis Sci 2016;61:2357–72.
78. Prucalopride. In chronic constipation: poorly documented risks. Prescrire Int 2011;20:117–20.
80. Appel-Dingemanse S. Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity. Clin Pharmacokinet 2002;41:1021–42.
81. Baker DE. Loperamide: A pharmacological review. Rev Gastroenterol Disord 2007;7(Suppl 3):S11–8.
82. Cann PA, Read NW, Brown C, et al. Irritable bowel syndrome: Relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 1983;24:405–11.
83. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996;31:463–8.
84. Moayyedi P, Andrews CN, MacQueen G, et al. Canadian Association of Gastroenterology clinical practice guideline for the management of irritable bowel syndrome (IBS). J Can Assoc Gastroenterol 2019;2:6–29.
85. Einarson A, Mastroiacovo P, Arnon J, et al. Prospective, controlled, multicentre study of loperamide in pregnancy. Can J Gastroenterol 2000;14:185–7.
86. Kallen B, Nilsson E, Otterblad Olausson P. Maternal use of loperamide in early pregnancy and delivery outcome. Acta Paediatr 2008;97:541–5.
87. Wald A. Constipation, diarrhea, and symptomatic hemorrhoids during pregnancy. Gastroenterol Clin North Am 2003;32:309–22, vii.
88. Camilleri M. Bile acid diarrhea: Prevalence, pathogenesis, and therapy. Gut Liver 2015;9:332–9.
89. Cholestyramine Center for Drug Evaluation and Research. Cholestyramine Product Monography. (https://www.accessdata.fda.gov/drugsatfda_docs/anda/2005/077203Orig1s000.pdf
). Accessed October 20, 2020.
90. Ford AC, Lacy BE, Harris LA, et al. Effect of antidepressants and psychological therapies in irritable bowel syndrome: An updated systematic review and meta-analysis. Am J Gastroenterol 2019;114:21–39.
91. Oh SJ, Takakura W, Rezaie A. Shortcomings of trials assessing antidepressants in the management of irritable bowel syndrome: A critical review. J Clin Med 2020;9:2933.
92. Loughhead AM, Stowe ZN, Newport DJ, et al. Placental passage of tricyclic antidepressants. Biol Psychiatry 2006;59:287–90.
93. Larsen ER, Damkier P, Pedersen LH, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl 2015:1–28.
94. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: A report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:703–13.
95. Gershon MD, Tack J. The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397–414.
96. Camilleri M, Boeckxstaens G. Dietary and pharmacological treatment of abdominal pain in IBS. Gut 2017;66:966–74.
97. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut 2014;63:1617–25.
98. Gershon MD. 5-HT (serotonin) physiology and related drugs. Curr Opin Gastroenterol 2000;16:113–20.
99. Product monograph LOTRONEX (alosetron hydrochloride). (https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21107s5lbl.pdf
). Accessed October 20, 2020.
100. Siu SS, Chan MT, Lau TK. Placental transfer of ondansetron during early human pregnancy. Clin Pharmacokinet 2006;45:419–23.
101. Lemon LS, Zhang H, Hebert MF, et al. Ondansetron exposure changes in a pregnant woman. Pharmacotherapy 2016;36:e139–41.
102. Fujita W, Gomes I, Dove LS, et al. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol 2014;92:448–56.
103. Wade PR, Palmer JM, McKenney S, et al. Modulation of gastrointestinal function by MuDelta, a mixed micro opioid receptor agonist/micro opioid receptor antagonist. Br J Pharmacol 2012;167:1111–25.
104. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med 2016;374:242–53.
105. Product monograph VIBERZI eluxadoline. (https://pdf.hres.ca/dpd_pm/00047414.PDF
). Accessed October 20, 2020.
106. Jiang ZD, DuPont HL. Rifaximin: In vitro and in vivo antibacterial activity—A review. Chemotherapy 2005;51(Suppl 1):67–72.
107. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22–32.
108. Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology 2016;151:1113–21.
109. Bertoli D, Borelli G. Teratogenic action of Rifaximin in the rat and rabbit and its effect on perinatal development in the rat [in Italian]. Boll Soc Ital Biol Sper 1984;60:1079–85.
111. Ruepert L, Quartero AO, de Wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2011:CD003460.
112. Hawthorn M, Ferrante J, Luchowski E, et al. The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol Ther 1988;2:101–18.
113. Galeotti N, Di Cesare Mannelli L, Mazzanti G, et al. Menthol: A natural analgesic compound. Neurosci Lett 2002;322:145–8.
114. Juergens UR, Stober M, Vetter H. The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: A novel perspective for its therapeutic use in inflammatory diseases. Eur J Med Res 1998;3:539–45.
115. Walstab J, Wohlfarth C, Hovius R, et al. Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: Implications for treating gastrointestinal disorders. Neurogastroenterol Motil 2014;26:810–20.
116. Weerts Z, Masclee AAM, Witteman BJM, et al. Efficacy and safety of peppermint oil in a randomized, double-blind trial of patients with irritable bowel syndrome. Gastroenterology 2020;158:123–36.
117. Black CJ, Yuan Y, Selinger CP, et al. Efficacy of soluble fibre, antispasmodic drugs, and gut-brain neuromodulators in irritable bowel syndrome: A systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2020;5:117–31.
118. Moussally K, Berard A. Exposure to specific herbal products during pregnancy and the risk of low birth weight. Altern Ther Health Med 2012;18:36–43.
119. Prescription drug information: Dicyclomine hydrochloride. 2017 [cited May 26, 2020]. (https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb099db9-f635-4a64-8892-6236971dec45
120. Zhang R, Persaud N. 8-way randomized controlled trial of doxylamine, pyridoxine and dicyclomine for nausea and vomiting during pregnancy: Restoration of unpublished information. PLoS One 2017;12:e0167609.
121. SYMAX DUOTAB: hyoscyamine sulfate tablet, multilayer, extended release [prescribing information]. 2016 [cited May 26, 2020]. (https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0cab4421-d99e-4cd0-8993-e46c484dc3cb
122. Trimebutine (trimebutine maleate) [product monograph]. 2018 [cited May 26, 2020]. (https://www.aapharma.ca/downloads/en/PIL/2019/Trimebutine_EN_PM.pdf
123. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology monograph on management of irritable bowel syndrome. Am J Gastroenterol 2018;113:1–18.
124. Heikkinen T, Ekblad U, Kero P, et al. Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002;72:184–91.
125. Cash BD, Epstein MS, Shah SM. A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms Dig Dis Sci 2016;61:560–71.
126. Manheimer E, Wieland LS, Cheng K, et al. Acupuncture for irritable bowel syndrome: Systematic review and meta-analysis. Am J Gastroenterol 2012;107:835–47; quiz 848.
127. Pei L, Geng H, Guo J, et al. Effect of acupuncture in patients with irritable bowel syndrome: A randomized controlled trial. Mayo Clin Proc 2020;95:1671–83.
128. Park J, Sohn Y, White AR, et al. The safety of acupuncture during pregnancy: A systematic review. Acupunct Med 2014;32:257–66.
129. Kennedy TM, Chalder T, McCrone P, et al. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: Randomised controlled trial. Health Technol Assess 2006;10:iii–iv, ix–x, 1–67.