Irritable Bowel Syndrome in Pregnancy

Abstract

Irritable bowel syndrome (IBS) affects a significant percentage of the general population and is more common in women. A large proportion of women affected with IBS are of childbearing age; however, there is a paucity of studies and guidelines to specifically address the epidemiology, course, maternal/fetal prognosis, or management of IBS in pregnancy. This scarcity of literature on IBS and pregnancy poses significant challenges to healthcare providers in counseling and managing patients. In this comprehensive review, we summarize the current literature and knowledge gaps regarding the effects of pregnancy on IBS and vice versa, along with the efficacy and safety profiles of commonly used IBS diets and medications in pregnancy. The management of pregnant women with IBS should be multidisciplinary, with emphasis on education and judicious use of dietary modifications and pharmacologic options that are deemed relatively safe during pregnancy.

INTRODUCTION

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).

Figure 1.: Potential factors/triggers affecting irritable bowel syndrome (IBS) during pregnancy along with the areas with significant gaps of knowledge pertinent to management of IBS during preconception, pregnancy, and breastfeeding periods.

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).

Table 1.: Summary of pharmacotherapies in the management of irritable bowel syndrome with constipation (IBS-C), and their safety concerns with use in pregnancy

Table 2.: Summary of pharmacotherapies in management of irritable bowel syndrome with diarrhea (IBS-D) and their safety concerns with use in pregnancy

Table 2-A.: Summary of pharmacotherapies in management of irritable bowel syndrome with diarrhea (IBS-D) and their safety concerns with use in pregnancy

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 modifications

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.

Fiber

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.

PHARMACOTHERAPY

Management of IBS with constipation

Osmotic laxatives.

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).

Stool softeners.

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).

Secretagogues

Linaclotide.

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.

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.

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.

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.

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.

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.

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).

Tricyclic antidepressants.

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.

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.

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.

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.

Nonpharmacologic options

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).

CONCLUSIONS

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.