Gastrointestinal Diseases During Pregnancy

Medical Problems During Pregnancy

Mona Akbari¹ and Jacqueline L. Wolf¹

(1)

Beth Israel Deaconess Medical Center, Department of Gastroenterology, Boston, MA, USA

Jacqueline L. Wolf

Email: jwolf1@bidmc.harvard.edu

Keywords

Gastroesophageal reflux (GERD)ConstipationIrritable bowel syndrome (IBS)Functional bowel disordersInflammatory bowel disease (IBD)Crohn’s diseaseUlcerative colitisLaxativesBiologic medicationsImmunomodulator therapy

Abbreviations

5-ASA

5-aminosalicylic acid

6-MP

6-mercaptopurine

AAP

American Academy of Pediatrics

ADA

Adalimumab

AGA

American Gastroenterology Association

anti-TNF

Antitumor necrosis factors

AZA

Azathioprine

Crohn’s disease

CZP

Certolizumab pegol

ECCO

European Crohn’s and Colitis Organization

EGD

Esophagogastroduodenoscopy

FDA

Food and Drug Administration

FODMAP

Fermentable oligo-, di-, and monosaccharrides and polyols

GERD

Gastroesophageal reflux disease

GLB

Golimumab

IBD

Inflammatory bowel disease

IBS

Irritable bowel syndrome

IFX

Infliximab

IPAA

Ileal pouch/anal anastomosis

LES

Lower esophageal sphincter

NAT

Natalizumab

PPI

Proton pump inhibitor

RPC

Restorative proctocolectomy

TCA

Tricyclic antidepressants

Ulcerative colitis

VDZ

Vedolizumab

Gastroesophageal Reflux

Case 1

P.A. is a 27-year-old healthy primigravida who is currently 24 weeks pregnant with a single fetus. She has a history of gastroesophageal reflux disease (GERD) diagnosed several years ago. At that time she took daily omeprazole for symptoms that occurred approximately 3–5 times per week, 1–2 times per day. Her BMI was 26 (ideal BMI 18.5–24.9), and weight loss was recommended. Over the course of a year, she managed to lose weight with diet and exercise. Her symptoms improved, and, ultimately, she was able to discontinue omeprazole without difficulty. She never underwent endoscopic evaluation, as her symptoms were uncomplicated and resolved with proton pump inhibitor (PPI) therapy. Her mother is overweight with hypertension and her maternal grandfather has diabetes. She has one younger sibling whose only medical issue consists of seasonal allergies. She has no family history of gastrointestinal malignancies. She is a nonsmoker and denies current alcohol consumption.

For the past 2 weeks, she has experienced symptoms of increasing regurgitation and an acid taste in her mouth that is reminiscent of her gastroesophageal reflux disease (GERD) symptoms years ago. These symptoms occur two to three times per week, typically after meals and occasionally at night. She has not taken any medications for her symptoms, as she is reluctant to take medications during her pregnancy. Her only medication at this time is a prenatal vitamin. Her prepregnancy BMI was 24. She has gained a total of 12 pounds. Because she had problems with similar symptoms when she was heavy and not pregnant, she wonders if her weight gain during this pregnancy has precipitated these symptoms. Her pregnancy thus far has been uncomplicated.

Discussion

GERD is a disease characterized by abnormal reflux of gastric contents into the esophagus. GERD symptoms are common during pregnancy. Approximately 45-80 % of women will experience GERD symptoms at some point in their pregnancies [1, 2]. In women with a diagnosis of GERD prior to pregnancy, symptoms can worsen as their pregnancy progresses. The clinical features of GERD are similar in pregnancy as in the nonpregnant general population. Symptoms include burning, acid taste, regurgitation, and provocation after meals and when lying supine. Symptoms occur more commonly in the pregnant woman than in the nonpregnant woman, and the prevalence of GERD appears to increase throughout the course of pregnancy [1–3].

The pathogenesis of GERD during pregnancy is likely multifactorial and related to a series of functional and structural changes. Possible factors that contribute to GERD symptoms during pregnancy include reduced lower esophageal sphincter (LES) pressure and impaired LES contractility in response to pharmacologic stimuli. Alterations in esophageal motility are another potential mechanism, whereas increased abdominal pressure from the enlarged gravid uterus is less likely to explain symptoms [4]. There is evidence to suggest that the functioning and responsiveness of the LES are altered, even early in pregnancy. While in the first trimester the basal LES pressure remains within normal limits, the LES is less responsive to hormonal, pharmacological, and physiological stimuli such as pentagastrin, methacholine, and protein meals [5]. Increased circulating levels of estrogen and progesterone and potentially loss of the intra-abdominal LES segment result in a decrease in basal LES pressure as pregnancy progresses [4, 6]. Esophageal motility and 24-h pH monitoring demonstrate that in the second and third trimesters, the LES pressure falls [7] and nadirs at 36 weeks [8]. The LES pressure appears to return to prepregnancy values by 4 weeks postpartum [7, 8].

The prevalence of GERD increases throughout pregnancy. Approximately 12.5–22 % of women in their first trimester report heartburn, and by the third trimester, up to 35.3–72 % of women may report heartburn [3, 9, 10]. Symptoms of acid taste in the mouth and regurgitation become more prevalent as pregnancy progresses. By the third trimester, approximately 50–80 % of women will report GERD symptoms [2, 3, 9, 11]. The severity of symptoms also progresses throughout pregnancy. GERD symptoms prior to pregnancy are a risk factor for pregnancy-related GERD [2, 10]. Other potential predictors of heartburn in pregnancy include multigravidity, high prepregnancy body mass index, and pregnancy weight gain [10]. Symptoms often abate after delivery; however, there is some limited evidence that pregnancy-related GERD may be a risk factor for developing frequent heartburn 1 year after delivery [2].

Case 1 Continued

She returns for a clinic visit and is now 30 weeks pregnant. She has tried avoiding fatty foods and eating late at night, factors that aggravated her GERD symptoms before her pregnancy. These modifications helped initially for her symptoms, but now she feels her symptoms are occurring more frequently. She has had appropriate weight gain during her pregnancy and continues to take only a prenatal vitamin daily. She denies tobacco and alcohol consumption. Her pregnancy remains uncomplicated. She has not tried any over-the-counter medications, but wonders what medications she can safely take during pregnancy.

Discussion

The risks and benefits of medical management should be weighed in pregnant women. Typically a step-up approach (Fig. 1) is adopted for the management of pregnancy-related GERD, and the first-line recommendation for all patients should include lifestyle modifications. Lifestyle modifications include eating smaller meals and avoiding late night eating. Though the data to support the avoidance of caffeine and/or spicy foods is limited, patients should avoid any foods that trigger symptoms. In a nonpregnant individual, mint can relax the LES and therefore should be avoided, even though there are no data during pregnancy if mint also triggers reflux. For patients with nighttime symptoms, elevating the head of the bed with a wedge or blocks can reduce symptoms.

Fig. 1

Management of GERD during pregnancy, step-up approach. PPI proton pump inhibitor, H ₂-receptor antagonist histamine₂-receptor antagonist

For symptoms not responding to lifestyle changes, the risks and benefits of drug therapy should be discussed (Tables 1 and 2). For the pregnant patient with mild to moderate GERD symptoms, initial therapy can begin with either an antacid or a histamine₂ (H₂)-receptor antagonist. Some expert opinion suggests that the initial medical therapy for pregnant women with mild GERD symptoms be calcium- and magnesium-based antacids [12].

Table 1

US Food and Drug Administration (FDA) categories^a

FDA category	Definition
Category A	Controlled studies show no risk to the fetus
Category B	Animal studies show no risk to the fetus; however, there are no adequate and well-controlled studies in pregnant women, or animal studies show risk but adequate and well-controlled human studies have failed to demonstrate risk
Category C	Animal studies show risk but there are no adequate and well-controlled studies in pregnant women or no adequate studies in animal or pregnant women
Category D	Fetal risk based on data from investigational, marketing experience, studies in human, but potential benefits may warrant use despite potential risks
Category X	Animal or human studies show fetal abnormalities; risks outweigh benefits

^aFDA ratings of drugs in pregnancy and lactation will be changed as of June 30, 2015

Table 2

Safety of medication use during pregnancy

Drug	FDA classification	Comments
Antacids
Calcium based	None	Low risk, preferred first line after lifestyle modification
Magnesium based	None	Low risk, preferred first line after lifestyle modification. Has tocolytic properties; avoid in the last several weeks of pregnancy
Aluminum based	None	Likely low risk in low doses, calcium- and magnesium-based antacids preferred
Histamine₂-receptor antagonist
Cimetidine	B	Low risk
Ranitidine	B	Low risk
Famotidine	B	Limited safety data
Nizatidine	B	Limited safety data
Proton pump inhibitors
Omeprazole	C	Animal study suggests fetal toxicity; epidemiologic studies in human suggest low risk
Lansoprazole	B	Likely low risk based on epidemiologic studies. Avoid during 1–4 weeks prior to conception given possible risk of birth defects
Pantoprazole	B	Likely low risk based on epidemiologic studies
Esomeprazole	B	Likely low risk based on epidemiologic studies
Sucralfate	B	Poorly absorbed, likely low risk
Metoclopramide	B	Likely low risk, avoid long-term use given neurologic side effects

Calcium-, magnesium-, and aluminum-based antacids are thought to be low risk in pregnancy [4, 13]. Low-dose (<1g/day) and high-dose (≥1 g/day) calcium supplementation during pregnancy appear to be associated with a reduced risk of hypertension and preeclampsia [14]. Oral magnesium supplementation has been shown to reduce the risk of high blood pressure compared to placebo, with conflicting results [15, 16]. Magnesium has tocolytic properties and its use is not advised during the last several weeks of pregnancy. Aluminum-containing antacids in large and chronic doses carry several potential concerns, such as constipation, malabsorption, skeletal impairment, and potential fetal neurotoxicity. For these reasons, high-dose aluminum antacids should be avoided and calcium-/magnesium-based antacids are preferred [4, 12]. Antacids containing sodium bicarbonate, which have the potential of causing metabolic alkalosis and fluid overload, should be avoided during pregnancy [4, 17].

H₂ receptor antagonists inhibit gastric secretion stimulated by histamine and can be used in management of GERD symptoms concomitant with antacids. In prospective and retrospective studies, H₂ receptor antagonist use during pregnancy was not associated with increased congenital malformations [18–20] or preterm delivery and low birth weight [19, 20]. For more severe symptoms or patients nonresponsive to therapy outlined above, a proton pump inhibitor (PPI) can be initiated. The US Food and Drug Administration (FDA) classifies all PPIs, except for omeprazole, as category B medications. Omeprazole, the first PPI approved on the market, at doses 5–56 times the human dose in animal studies resulted in embryo toxicity [21] and is therefore classified as category C.

In an earlier study, PPI use in the first trimester was associated with hypospadia [22]. However, this study was based on a small number of exposures (12 women exposed to lansoprazole, omeprazole, or esomeprazole). Moreover, there was no increased risk of hypospadia in a follow-up population-based study that included nearly 3,000 women exposed to PPI (including omeprazole) at conception or during pregnancy [23]. In a subgroup analysis restricted only to omeprazole use, the risk of hypospadia in the PPI exposed was similar to that in the unexposed group. In a meta-analysis of seven studies including data from 134,940 patients (1,530 exposed to PPIs), there was no difference in the risk of congenital malformations with first-trimester use of a PPI [24]. In many of these studies, the most common [25, 26], or often only [18, 27, 28], PPI exposure was omeprazole. In secondary analysis there was no difference in spontaneous abortions and preterm delivery. Analysis limited to omeprazole, alone, showed similar results. In two large epidemiologic studies published since this meta-analysis, exposure to PPIs in the first, second, and third trimester was not associated with congenital malformations [29, 30]. Similarly, a subgroup analysis of omeprazole use during pregnancy failed to show an increased risk of congenital malformations [29].

There is limited evidence from one epidemiologic study that PPI exposure at 1–4 weeks before conception was associated with birth heart and urinary tract defects [29]. Approximately 28 % of births exposed to PPI 1–4 weeks before conception were also exposed to other medications, such as corticosteroids, beta-blockers, and ACE inhibitors, 58 % were from mothers above the age of 30, and 23 % were from mothers reporting smoking during pregnancy. Subgroup analysis demonstrated that the risk of birth defects was significant only for lansoprazole, and not omeprazole, pantoprazole, or esomeprazole. Twenty-nine defects were reported in 541 births exposed to lansoprazole. In additional analysis looking at groups of birth defects, the odds of heart and urinary tract defects seemed to be associated with PPI exposure at 1–4 weeks before conception. The overall number of exposed cases was small with 30 cases of heart defects and 12 cases of urinary tract defects reported in 1,969 live births exposed to PPIs 1–4 weeks before conception. Further studies are needed to further explore this possible association. There are no guidelines on the use of PPI for patients contemplating pregnancy, although patients trying to become pregnant should be counseled on this possible risk [31]. If tolerated and not medically necessary, cessation of PPI therapy should be attempted in all women.

Other agents that can be considered for management of GERD symptoms include sucralfate and metoclopramide. Sucralfate, a surface agent and mucosal protectant, is poorly absorbed systemically with few side effects other than constipation and generally is regarded to be safe in pregnancy [32]. Metoclopramide, a prokinetic agent primarily used for treatment of delayed gastric emptying and nausea, may decrease GERD and has not been shown to be associated with increased adverse pregnancy outcomes [33, 34]. Metoclopramide could be considered for patients not responding to PPI therapy [31]. Its long-term use should be avoided given serious risks of neurologic complications, such as dystonia and akathisia.

Case 1 Continued

She is now 35 weeks pregnant. Her symptoms continued despite lifestyle modifications and use of calcium-based antacids and ranitidine 150 mg twice a day. She stopped these medications and it was suggested that she start a trial of pantoprazole 40 mg daily. Her symptoms have improved, although occasionally she will experience breakthrough reflux. She does admit to not taking pantoprazole daily, because she remains concerned about taking medications during her pregnancy. She denies signs or symptoms of burning or pain during swallowing, difficulty swallowing foods or food getting stuck, nausea, vomiting, and black or bloody stools. She has mild, infrequent generalized abdominal and back discomfort that developed during the course of her pregnancy. She continues to have appropriate weight gain during her pregnancy. Her labs have all been within normal limits. She wonders if she will require any further work-up now or after her pregnancy.

Discussion

The diagnosis of GERD can be made based on symptoms and more invasive testing during pregnancy is typically not necessary.

Barium radiographs, which expose the fetus to radiation, are not necessary for the diagnosis of GERD and therefore may be avoided during pregnancy. Esophageal manometry and pH studies are safe but are rarely necessary during pregnancy. For the general population, progressive symptoms or symptoms not responding to therapy can be evaluated with esophagogastroduodenoscopy (EGD). Signs and symptoms of dysphagia, odynophagia, and significant or continued gastrointestinal bleeding are considered to be indications for endoscopy during pregnancy by the American Society for Gastrointestinal Endoscopy (ASGE) [35]. Other experts have suggested that a moderate indication for EGD is recurrent nausea and emesis in patients past 16–18 weeks with a concern for peptic ulcer disease that have had inadequate response to PPI therapy [36]. Weak indications for EGD include self-limited nausea, emesis, or abdominal pain and GERD symptoms (aside from dysphagia) not responsive to empiric PPI therapy [36]. In this patient, who has no alarm features and symptoms and has been partially responsive to therapy, an EGD is not necessary. Symptoms should be monitored, daily PPI use recommended, and therapy increased with the addition of an H2 blocker at bedtime if needed.

The data on the safety and efficacy of EGD during pregnancy is sparse and limited to case series. The potential risks include maternal hypoxia, hypotension, and inferior vena cava compression during maternal positioning, as well as medication exposure to the fetus. The risks and benefits should be discussed in a multidisciplinary fashion. Maternal blood pressure and oxygen should be carefully monitored. As recommended by the American Society of Anesthesiologists and American College of Obstetrics and Gynecologists, when the fetus is previable, the fetal heart rate should be assessed before and after non-obstetric surgery, and when viable, at a minimum, fetal heart rate and contraction monitoring should be performed before and after procedure [37].

Judicious sedation is recommended. Propofol is category B by the FDA for use during pregnancy, while fentanyl and meperidine are category C and benzodiazepines are category D. The safety of propofol early in pregnancy is not known, but is considered relatively safe in pregnancy when given by a trained anesthesia provider. Meperidine and its active metabolites have been demonstrated to cross the placenta [38, 39]. Studies of teratogenicity from meperidine in animal models and humans are lacking. However, it is generally felt to be relatively safe for use during pregnancy. Fentanyl crosses the placenta as well [40], but is short acting and has faster procedural recovery time. Benzodiazepines are category D and diazepam has been associated with congenital abnormalities, including cleft lip and palate, with conflicting results [41–44]. Reports of infant floppy syndrome and neonatal withdrawal symptoms have been described in late third-trimester use of benzodiazepines [45]. If used, midazolam is the preferred benzodiazepines and should be given at its lowest effective dose.

In regard to the use of sedation during lactation, many sedatives are excreted in breast milk. Midazolam is excreted in breast milk and levels of midazolam and its metabolite appear to be undetectable after 4 h. Therefore, nursing should be withheld for at least 4 h after its exposure [35]. Fentanyl and propofol are excreted in breast milk, though at very low doses. Within 24 h of administration, 0.027 % of the propofol dose and 0.033 % of the fentanyl dose were detected in breast milk [46]. Fentanyl and propofol are considered to be compatible with breastfeeding [35]. Meperidine can be detected in breast milk up to 24 h after administration, and because of potential neurobehavioral effects on the infant, fentanyl is preferred when possible [35].

Functional Bowel Disorders

Case 2

S.T. is a 33-year-old gravida 2 para 1 woman who is currently 15 weeks pregnant. She has a history of asthma that is well controlled with rare use of albuterol inhaler as needed. During her first pregnancy, she reported constipation during her second and third trimesters. This was managed with increased fiber intake and occasional Metamucil. After her first pregnancy, her symptoms of hard stools generally resolved, though occasionally she found herself straining depending on her diet. Currently, she reports straining and hard stools, almost daily. She finds these symptoms to be more bothersome and frequent than what she experienced in her first pregnancy. She denies any vomiting, abdominal pain, or blood in her stools. She has been gaining weight appropriately. She has never had a colonoscopy. She has a paternal grandfather who had colon cancer in his seventies, but no other family members with colorectal cancer. She takes prenatal vitamins and occasionally Benadryl at night as a sleep aid. She feels that her symptoms interfere with her daily activity and would like to discuss this further.

Discussion

Functional bowel disorders such as irritable bowel syndrome (IBS) and functional constipation consist of gastrointestinal symptoms for which investigation does not reveal an organic cause. Alterations in the brain-gut axis as well as dysbiosis of the gut microbiome and its metabolic byproducts are thought to contribute to the underlying physiology of functional bowel disorders. Functional bowel symptoms can be common during pregnancy, with up to two thirds of women reporting one or more functional bowel symptoms during their first trimester of pregnancy. In a survey-based study of women in their first trimester, 46 % reported constipation, 49 % reported bloating, 44 % had irritable bowel syndrome, and 5 % reported diarrhea [47].

Constipation, often defined as hard stools, straining, incomplete evacuation, or infrequency of defecation, is a common gastrointestinal complaint during pregnancy. The prevalence of constipation during pregnancy has been reported with variable results. Approximately 45 % of women in their first trimester self-report symptoms of constipation [47, 48], and 51 % of patients self-report constipation at some point during their pregnancy [49]. Using a more narrow definition of constipation (fewer than three bowel movements per week and straining in more than 25 % of defecations), one study reported that only 5–9 % of women are affected by constipation throughout their pregnancy. The prevalence of constipation defined by the Rome criteria (Table 1), which includes symptoms of incomplete evacuation, hard stools, and use of manual maneuvers for defecation, during the first, second, and third trimester ranges from 24 to 30 %, 19 to 26 %, and 16 to 22 %, respectively [48, 49]. Similarly, in the postpartum period, the prevalence of constipation as defined by the Rome criteria is 24 % [48, 49]. Some studies suggest that the prevalence of constipation declines by the third trimester [49, 50] and in the postpartum period [50]. Sex hormones and decreased colonic transit time from elevated progesterone and reduced motilin levels may contribute to constipation. Other risk factors include decreased activity and vitamin supplementation (iron and calcium). Women with a history of treatment for constipation prior to pregnancy are more likely to report constipation during their pregnancy [49].

Despite its potentially high prevalence, bowel dysfunction and its recommended treatment are not always addressed during clinic visits, possibly reflective of underreporting or patient/provider perceptions that constipation symptoms are part of pregnancy. However, quality of life studies suggest that pregnant women reporting one or more functional bowel complaints have lower mean overall quality of life scores. Similarly, body image, health worry, activity interference, and food avoidance scores were lower for women who complained of functional bowel disorders during their pregnancy [47].

The most common symptoms of constipation during pregnancy are straining and hard stools. Occasionally women will report incomplete evacuation [49]. Anorectal obstruction and manual maneuvers to produce a stool appear to be the least commonly reported symptoms. Patients may report symptoms relating to constipation that do not conform to strict Rome criteria (Table 3). Often patients report constipation despite daily bowel movements, but further questioning will reveal symptoms such as straining, hard stools, unproductive urges, and incomplete evacuation. While the majority of pregnant women with constipation will have simple constipation without alarming underlying etiologies, history and physical examination are important in the evaluation of constipation. A number of medications, including prenatal multivitamins with iron, iron supplements, antihistamines, calcium channel blockers, and antidepressants, can be associated with constipation. A thorough review of medications, both prescription and over the counter, should be performed. Endoscopic evaluation is rarely necessary unless there are alarm signs such as gastrointestinal bleeding, uncontrolled diarrhea, new anemia not due to pregnancy, or possibly weight loss. In this patient, who has no alarm signs, endoscopic evaluation is not necessary. Limiting antihistamine use could be recommended as it can contribute to constipation.

Table 3

Rome diagnostic criteria

	Rome II	Rome III^a
IBS	At least 12 weeks (need not be consecutive) in preceding 12 months of abdominal discomfort or pain with two or more of the following: 1. Improvement with defecation 2. Onset associated with change in stool frequency 3. Onset associated with change in stool form	Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with two or more of the following: 1. Improvement with defecation 2. Onset associated with change in stool frequency 2. Onset associated with change in stool form
Functional constipation	At least 12 weeks (need not be consecutive) in preceding 12 months of the following: 1. Straining > 1/4 of defecations 2. Lumpy or hard stools > 1/4 of defecations 3. Sensation of incomplete evacuation > 1/4 of defecations 4. Sensation of anorectal obstruction or blockage > 1/4 of defecations 5. Manual maneuvers to facilitate > 1/4 of defecations 6. <3 defecations per week Loose stools are not present and there are insufficient criteria for IBS	I. Must include two or more of the following: 1. Straining in at least 25 % of defecations 2. Lumpy or hard stools in at least 25 % of defecations 3. Sensation of incomplete evacuation for at least 25 % of defecations 4. Sensation of anorectal obstruction or blockage for at least 25 % of defecations 5. Manual maneuvers to facilitate at least 25 % of defecations 6. Fewer than three defecations per week II. Loose stools are rarely present without the use of laxatives III. Insufficient criteria for IBS
Functional diarrhea	At least 12 weeks (need not be consecutive) in the preceding 12 months of: 1. Loose (mushy) or watery stools 2. Present > 3/4 of the time 3. No abdominal pain	Loose (mushy) or watery stools without pain occurring in at least 75 % of stools

IBS irritable bowel syndrome

^aCriteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

Case 2 Continued

She returns for a follow-up visit 4 weeks later and states that she has tried increasing fiber intake daily, in the form of fiber-containing cereal and wheat bran, and has been taking Metamucil, which she took intermittently during her previous pregnancy. She has stopped taking Benadryl at night for a sleep aid. She experienced bloating, which she attributes to the increased fiber intake. She asks you if there are alternative management options.

Discussion

Initial management of constipation includes increase in dietary fiber, fluids, and exercise. Dietary fibers increase stool bulk and frequency and reduce transit time. The recommended daily dietary fiber dose is 20–35 g, though these doses are often not achieved. Soluble fibers, found in oat bran, barley, nuts, and seeds, attract water forming a gel and improve bowel symptoms in chronic constipation in the general population. Fiber supplement with corn-based biscuit and wheat bran has been shown to increase the number of bowel movements and soften stool consistency in pregnant women [51]. Light exercise should also be recommended, as it can promote regular bowel movements. If symptoms persist despite the above changes, a laxative can be considered (Tables 4 and 5).

Table 4

Types of laxatives and their mechanism of action

Treatment	Examples	Mechanism of action	Side effects
Bulk-forming fiber agents	Psyllium (Metamucil) Methylcellulose (Citrucel) Polycarbophil (FiberCon) Wheat dextrin (Benefiber) Inulin	Increases luminal water binding Increases fecal mass and stool bulk	Bloating and gas
Stool softeners	Docusate	Lower surface tension of stool Facilitates passage of water into stool	Few side effects, cramping
Osmotic laxatives
Saline agents	Magnesium citrate Magnesium hydroxide	Poorly absorbed osmotic preparations Secretion of water into the intestine	Dehydration and electrolyte disturbance
Poorly absorbed sugars	Polyethylene glycol (Miralax) Lactulose	Increase osmolar tension Secretion of water into the intestine	Bloating and gas Dehydration and electrolyte disturbance
Stimulant laxatives	Bisacodyl (Dulcolax) Senna (Senokot)	Increase intestinal motor activity	Cramping and abdominal pain Dehydration and electrolyte disturbance

Table 5

Safety of medication use during pregnancy

Drug	FDA classification	Comments
Bulk-forming agents
Psyllium	None	Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise
Methylcellulose	None	Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise
Polycarbophil	None	Low risk, preferred after trial of increase in dietary fiber, fluids, and exercise
Docusate	None	Low risk for short-term use, limited efficacy in treatment of constipation
Osmotic laxatives		Low risk
Magnesium citrate	C	Avoid long-term use (risk of hypermagnesemia, hyperphosphatemia, and dehydration)
Lactulose	B	Low systemic absorption, likely low risk for short-term use
Polyethylene glycol	C	Low systemic absorption, likely low risk for short-term use
Stimulant laxatives
Bisacodyl	B	Low systemic absorption, likely low risk for short-term use
Senna	C	Low systemic absorption, likely low risk for short-term use
Cascara	C	Safety in pregnancy not well known
Aloe	None	Not recommended
Castor oil	X	Not recommended (possible induction of labor)
Mineral oil	None	Not recommended (may interfere with absorption of maternal nutrients and vitamins, possible neonatal coagulopathy and hemorrhage)
Peppermint oil	None	Likely low risk
Dicyclomine	B	Likely low risk
Hyoscyamine	C	Crosses placenta, little known on effects on fetus
TCA	C (desipramine, amitriptyline) D (nortriptyline)	Crosses placenta, possible association with adverse outcomes in neonate
Rifaximin	C	Associated teratogenicity in some but not all animal studies, no adequate studies in pregnant women

Bulk-forming fiber agents, including psyllium, methylcellulose, polycarbophil, wheat dextrin, flax seed, and guar, are not systemically absorbed and are low risk for use during pregnancy. However, their effects may take days to work, and unwanted side effects include gas, bloating, and cramping. Psyllium (e.g., Metamucil), which has a soluble/insoluble fiber ratio 70/30, increases fecal water content, but patients may complain of unwanted side effects such as gas and bloating secondary to its fermentation in the colon. Methylcellulose (e.g., Citrucel), which is 100 % soluble, is a synthetic polymer fiber that increases fecal mass, stimulates motility, and reduces colonic time. It is resistant to bacterial fermentation. Polycarbophil (e.g., FiberCon) is a hydrophilic resin that is not metabolized by intestinal bacteria. Methylcellulose, polycarbophil, and wheat dextrin (e.g., Benefiber) are less likely to cause gas and bloating.

Docusate sodium, a surfactant and stool softener, is generally well tolerated. Its efficacy and safety in pregnancy has not been established, though there have been no reports demonstrating increased risk in congenital malformations [52, 53]. Docusate is considered likely low risk [13], although there has been one report of neonatal hypomagnesemia from a mother who reported daily maternal docusate sodium use (100–200 mg or more daily) throughout pregnancy [54].

Overall, there is limited data on the use of laxatives during pregnancy. Osmotic laxatives, such as lactulose, polyethylene glycol, and magnesium-containing salts, increase the amount of fluid retained in the gut. Lactulose is a poorly absorbed sugar, classified as category B, but can cause bloating, gas, and pain in patients. Polyethylene glycol may result in less bloating and gas and is considered the first-choice osmotic laxative by the American Gastroenterology Association (AGA) during pregnancy [13]. Its systemic absorption is also low, but its safety during pregnancy has not been well established and is classified as category C. Prolonged use could theoretically lead to electrolyte disturbances. Saline laxatives, like magnesium containing agents, are likely low risk. However, in certain patients (e.g., renal dysfunction), excessive absorption of magnesium may lead to electrolyte and volume overload. Their long-term use during pregnancy is not recommended. Moreover, given its tocolytic properties, magnesium-containing agents should be avoided during the last several weeks of pregnancy.

Stimulant laxatives should be reserved for patients who do not respond to dietary measures, exercise, fiber bulking agents, or osmotic laxatives. Stimulant laxatives increase intestinal fluid secretion and stimulate colonic motility. There is limited data on the use of senna and bisacodyl during pregnancy, and both are classified as categories C and B, respectively. Senna glycosides are minimally absorbed by the intestine and excreted in bile. In rat models senna given during organogenesis was not associated with teratogenicity [55], and in case-control studies, maternal use of senna was not associated with congenital malformation [56]. There have been no animal reproductive studies reported on bisacodyl, though this medication has very little systemic absorption and is likely low risk for short-term use. It can be associated with more abdominal cramping when compared to senna. In general, when possible, the lowest dose and shortest duration of stimulant laxative ingestion needed to control symptoms are recommended during pregnancy.

Cascara, an extract from the dried, aged bark of Rhamnus purshiana, is an anthraquinone purgative with laxative properties and is available as an herbal supplement. While its use has not been well studied for during pregnancy, there is no evidence that drugs in this class pose risk to the fetus [53]. Cascara is generally well tolerated and with few side effects, though in high and chronic doses cascara has been linked to several cases of liver injury [57, 58]. Aloe, which has a laxative effect, is not recommended in pregnancy given the possible association with congenital malformations [59]. Castor oil, category X, has a potential association with induction of labor and is therefore not recommended for use during pregnancy. Mineral oil is also not recommended during pregnancy as it may interfere with absorption of important nutrients and vitamins in mothers, as well as its possible association with neonatal coagulopathy and hemorrhage [13].

Linaclotide and lubiprostone are two therapies approved for the management of chronic constipation in the general population. Linaclotide (trade name Linzess), approved by the FDA in 2012, is a guanylin peptide that acts as a selective agonist at the guanylate cyclase-C receptor of intestinal enterocytes. Linaclotide promotes small intestinal secretion of chloride and bicarbonate ions and small intestinal fluid secretion and increases intestinal transit time. In animal studies fetal toxicity occurred at doses toxic to the mother [60]. The safety of its use in pregnant women is unknown. Lubiprostone (trade name Amitiza), approved in 2008, is a prostaglandin analogue and acts locally as a chloride channel activator. At high doses, fetal toxicity was noted in animal studies, but human studies are lacking [61]. Both linaclotide and lubiprostone are classified as category C, and given their relative newness to the market, there are no societal guidelines or recommendations for use during pregnancy.

Case 3

M.L. is a 25-year-old female who recently discovered she is pregnant. She has never been pregnant. She has a history of irritable bowel syndrome (IBS) since college. Because of persistent abdominal pain, she was prescribed amitriptyline over 2 years ago. While taking the amitriptyline, she noted improvement in her symptom, but because of unpleasant side effects, she tapered off amitriptyline. Her symptoms remained manageable and she now takes peppermint oil occasionally for symptoms. For the past year, she noticed increased bloating, as well as generalized mild to moderate abdominal pain associated with belching and passing gas. She does not have any weight loss, blood in stool, worsening of abdominal pain, or changes in bowel habit. She had an unremarkable colonoscopy in her early twenties, and recent labs including work-up for celiac disease were normal. She started a probiotic with some improvement in her bloating. Dietary modifications were recommended, but she has not made any changes in her diet thus far. She is concerned about medication use and control of her symptoms during pregnancy.

Discussion

Traditional management of IBS in the nonpregnant patient focuses on improving individual symptoms, improving global symptoms, preventing unnecessary procedures, and reducing the impact of IBS on the overall quality of life. Smooth muscle relaxants (e.g., antispasmodics) and tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, and anticonvulsants are potential medical therapies used in the management of abdominal pain and discomfort.

Dicyclomine and hyoscyamine are antispasmodics used for management of IBS and are categories B and C, respectively. In clinical trials dicyclomine improves pain, tenderness, bowel habits, and overall condition [62], and in a meta-analysis of 12 different antispasmodics, including dicyclomine, patients allocated to the antispasmodic group had improvement in global symptoms of IBS or abdominal pain compared to the placebo group (39 % vs. 56 %). Adverse events occurred in 14 % of patients [63] that most commonly included dry mouth, dizziness, and blurred vision. Dicyclomine hydrochloride, an anticholinergic agent, appears to improve tenderness and overall symptoms in patients with IBS but side effects have been noted in up to 69 % of patients at doses of 160 mg/day [62].

There is limited information of dicyclomine (category B) during pregnancy use. Animal studies have not demonstrated fetal harm, and epidemiologic studies in pregnant women taking dicyclomine up to 40 mg/day during the first trimester have not shown fetal abnormalities [64]. Dicyclomine is categorized as compatible with pregnancy [53]. Hyoscyamine (class C) crosses the placenta and little is known on its effects on the fetus.

TCAs have been used to treat functional bowel symptoms and likely work by modulating pain centrally and peripherally. Controlled studies in the nonpregnant population are limited by few numbers of patients and short follow-ups. A meta-analysis showed improvement in abdominal pain scores and clinical response when pooling several TCAs for the use of IBS patients. There are no studies for their use in the pregnant population. Desipramine and amitriptyline are category C, and nortriptyline is category D. TCAs cross the placenta, and their use has been associated with preterm birth and possible complications such as jitteriness, irritability, respiratory distress, and endocrine and metabolic disturbances in the newborn [65, 66]. Few studies have looked at the teratogenic effects on a population level. While Swedish and US studies demonstrated an increased risk of congenital abnormalities in neonates exposed to TCA use during pregnancy [66, 67], another UK study did not find a significant association with their use during the first trimester [68]. The AGA recommends avoidance of TCAs during pregnancy given the limited efficacy data for IBS [17], though risk and benefit should be discussed in women requiring this medication for management of their symptoms.

Peppermint oil in animal models has been shown to reduce calcium influx resulting in the relaxation of gastrointestinal smooth muscle [69]. This mechanism of action may be responsible for its use in the treatment of IBS and abdominal pain. A meta-analysis, pooling the results of four trials comparing peppermint oil to placebo, demonstrated that the use of peppermint oil (ranging from cumulative daily doses of 450 to 600 mg) improved abdominal pain and/or global symptoms. There are few studies looking at the use of herbal supplements during pregnancy and birth outcomes. Low birth weight and preterm delivery do not seem to be increased in women taking peppermint during pregnancy [70, 71], and in a study of the use of peppermint oil for treatment of pruritus in pregnant women, no side effects were noted in patients [72].

Bloating is a common complaint reported by patients with IBS, and these patients often report associated abdominal pain. Impaired gas transit and malabsorption of short-chain carbohydrates may contribute to the symptoms of abdominal bloating and distension. Dietary modifications, such as limitation of FODMAPs (fermentable oligo-, di-, and monosaccharides and polyols), and reduction of fiber intake may improve symptoms of bloating. FODMAP short-chain carbohydrates are poorly absorbed and fermented in the intestinal lumen, causing bloating and abdominal pain. A low FODMAP diet therefore restricts a large number of foods that contain lactose, gluten, as well as many artificial sugars, and some vegetables and fruits in which there is an excess of fructose over glucose. While the exact mechanism of efficacy is not clearly understood, probiotics appear to alter immune response, reducing inflammation, and alter the gut flora composition, resulting in improved IBS symptoms as well. Bifidobacterium infantis and Bifidobacterium bifidum have been shown to improve symptoms of abdominal pain and bloating [73, 74]. VSL#3 also appears to reduce colonic transit and improve flatulence in IBS patients and bloating in patients with diarrhea-predominant IBS [75, 76]. In a randomized controlled trial of pregnant women receiving probiotics at 2–4 weeks before expected delivery, there were no congenital malformations reported in the probiotic group. A meta-analysis failed to show difference in birth weight, gestational age, and Cesarean section for maternal probiotic use during pregnancy [77].

Antibiotics may also play a role in the treatment of IBS symptoms. There are potentially important differences in enteric flora of the IBS patient compared to the general population. Lactobacilli and bifidobacilli have been found in lower amounts in stool samples of patients with IBS [78, 79]. Reduction in these beneficial bacteria, which produce short-chain fatty acids that inhibit adherence of invasive bacteria, may favor colonization of the intestine with pathogenic bacteria. Increased hydrogen release during carbohydrate fermentation is associated with bloating and gaseous symptoms, and methane production has been associated with chronic constipation [80]. Rifaximin improves global symptoms of IBS, bloating, and abdominal pain [81–83]. There is limited oral absorption of rifaximin and the exposure to the fetus is expected to be low. Rifaximin is category C and has been associated with teratogenicity in some but not all animal studies [84, 85]. There are no adequate clinical studies in pregnant women.

Inflammatory Bowel Disease

Case 4

S.M. is a 32-year-old female with a history of Crohn’s disease (CD) diagnosed 8 years ago, who presents for preconception counseling. She was diagnosed at the age of 24, while in law school, when she developed abdominal pain and bloating. A colonoscopy and cross-sectional imaging showed ileitis and biopsies were consistent with Crohn’s disease. She was started on a thiopurine, azathioprine (AZA), and a prednisone taper at diagnosis. Four years after diagnosis, she had recurrence of her symptoms and persistent ileitis, necessitating a second prednisone course as an outpatient and dose increase of her AZA. With the increased dose in AZA, she was noted to have elevations in her liver function tests. AZA was ultimately stopped and prednisone was continued. After discussion with her gastroenterologist, she was started on infliximab (IFX) 5 mg/kg. She has been in clinical and endoscopic remission since then. Prior to starting IFX and while off of AZA, she had one miscarriage at gestation week 8. At the time of her miscarriage, she was in clinical remission and managed with oral prednisone therapy.

Now she is contemplating pregnancy and has been on a stable dose of 5 mg/kg of IFX every 8 weeks for the past 2 years. She has never had any extraintestinal manifestations of CD and has not had any abdominal surgeries. She is a former smoker, but quit after she was diagnosed with CD. Currently she is asymptomatic from the perspective of her Crohn’s disease. She is on daily iron supplements and monthly vitamin B12 injections. She recently stopped her oral contraceptive therapy. She has a cousin with ulcerative colitis (UC) who had a proctocolectomy in her twenties and had a difficult time conceiving, but was ultimately successful after in vitro fertilization. She asks you whether her CD affects her ability to conceive given her family and personal history as well as the course of CD during pregnancy.

Discussion

Inflammatory bowel disease (IBD), CD and UC, often affects women during their childbearing years. Many women with IBD express concern over conception and pregnancy. A multidisciplinary approach between the obstetrician, gastroenterologist, surgeon, and nutritionist is encouraged during preconception and pregnancy (Fig. 2). Women with quiescent disease have similar fertility rates as the general population [86, 87]. While overall fertility is likely to be normal, women with IBD report voluntary childlessness and sexual dysfunction, both of which affect fertility [88]. Active disease is thought to affect fertility and previous pelvic surgery, including restorative proctocolectomy (RPC) and ileal pouch/anal anastomosis (IPAA) which appear to impair conception and reduce fertility [89, 90]. Patients appear to have more spontaneous pregnancies and shorter time to conception and are less likely to undergo in vitro fertilization pre-RPC compared to post-RPC [89].

Fig. 2

Management of IBD in patients of reproductive age

Disease activity at conception is predictive of disease activity during pregnancy. Patients in remission at conception have a milder disease course during pregnancy and are less likely to relapse postpartum, compared to those with active disease [91–93]. In a study from 12 European countries, 81 % of pregnant women with CD in remission remained in remission by the end of pregnancy, while 19 % relapsed. For those who had inactive disease at conception, the risk of relapse during pregnancy and in the postpartum period was the same as the nonpregnant patient with CD, and the cumulative probability of remaining in remission during pregnancy was the same as that in nonpregnant controls. Disease duration was a risk factor for relapse during pregnancy and postpartum period. However, in this same study, UC pregnant women demonstrated a tendency to relapse during pregnancy. Sixty-five percent of women with UC in remission remained in remission, while 35 % relapsed. There was an increased risk of relapse during the first and second trimester compared to the nonpregnant UC women [93]. In a meta-analysis, 55 % of patients with active UC at the time of pregnancy remained active during pregnancy, while only 29 % of patients with quiescent UC relapsed during pregnancy. Similarly, 46 % of patients with active CD at conception remained active during pregnancy, and 23 % of patients who were in remission prior to pregnancy relapsed during pregnancy [92]. These findings highlight the goal of achieving and maintaining remission prior to conception.

Women with IBD appear to be at an increased risk of adverse pregnancy outcomes, with an increased risk of preterm birth and low birth weight compared to women in the general population [94–97]. In a large community-based study from Northern California, IBD patients compared to pregnant women without IBD were less likely to have live birth (60 % vs. 68 %) and more likely to have adverse conception outcome, such as spontaneous abortion (23 % vs. 17 %) and adverse pregnancy outcomes, such as preterm birth, small for gestational age and stillbirth (25 % vs. 19 %). Pregnant women with IBD were also more likely to have pregnancy complications, such as abruptio placenta, premature rupture of membrane and infection, when compared to controls (25 % vs. 16 %). There was no increased risk of congenital abnormalities [98]. Therefore, in clinical practice it is recommended to first achieve and maintain quiescent disease at conception and during pregnancy. The general consensus is to wait until patients are in remission prior to conception [88].

Obstetric need should determine the mode of delivery. The European Crohn’s and Colitis Organization (ECCO) recommends that active perianal disease or rectal involvement is indication for Cesarean delivery, while IPAA and ileorectal anastomosis are relative indications [99]. Vaginal delivery carries the concern for lacerations and the risk of recurrent Crohn’s in the rectovaginal septum and fistula formation. Patients with inactive perianal disease may consider vaginal delivery [88]. The sphincter and pelvic floor integrity is key for the maintenance of fecal continence in patients with IPAA and vaginal delivery may increase the risk of pudendal nerve damage and sphincter injury.

While UC patients with IPAA may report worsening incontinence and increases in stool frequency during pregnancy, these symptoms appear to resolve in the postpartum period. A study of 29 women with UC who delivered after IPAA procedure reported the mean incontinence score increased during pregnancy and subsequently improved postpartum. Thirty-five percent of patients had worsening of daytime continence during the third trimester of pregnancy; 21 % of patients experienced transient changes in continence (reported as seepage) that improved after delivery and 14 % experienced permanent changes (reported as seepage and soilage in one patient). Stool frequency increased in 55 % of patients toward the end of the second trimester and returned to normal in most patients within a few weeks of delivery (permanent increase in stool frequency was reported by 7 % of women) [100]. Another study of 43 UC patients with IPAA reported daytime and nighttime stool frequency increased during pregnancy 5.5–6.6 stools/day and 0.9–1.4 stools/night, respectively. Stool frequency resolved at longer follow-up (greater than 3 months) postpartum. Daytime and nighttime incontinence also worsened during pregnancy, but improved postpartum [100, 101].

Nevertheless, it is not clear if patients with IPAA necessarily benefit from Cesarean delivery. In one study of 82 patients with UC and IPAA, anal manometry and anal endosonography demonstrated lower mean squeeze pressure and greater sphincter defects, respectively, in those who had vaginal delivery compared to Cesarean delivery [102]. However, stool frequency after pregnancy compared to prepregnancy was not different for women undergoing Cesarean section compared to vaginal delivery in this study and in other studies [100–102]. The presence of colostomy or ileostomy is not considered an indication for Cesarean sections, unless indicated for other reasons.

Therefore, in this patient who is in remission and has not had previous abdominal surgeries, it is unlikely that her CD will affect her fertility. Her previous miscarriage appears to have been during a time when her disease was more active and may have been unrelated to her disease. Her disease course is likely to remain inactive as she is currently in remission on her current regimen.

Case 4 Continued

She continues to express concerns regarding medication use during pregnancy. She is concerned about the potential effects of IFX on the fetus during pregnancy as well as while breastfeeding. She asks if this medication should be stopped prior to conception or during pregnancy.

Discussion

Disease activity at conception and during pregnancy appears to be an important predictor of adverse pregnancy outcomes based on multiple studies. Disease activity has been associated with preterm births, low birth weight, fetal loss, and greater risk of adverse perinatal outcomes [103–107]. In clinical practice, it is recommended that patients achieve and maintain remission prior to conception. Patients are advised to continue medical therapy for IBD with the goal of preventing both relapses during pregnancy as well as improving pregnancy and conception outcomes. Therefore, it is recommended that this patient remain on IFX at conception and during pregnancy. It is important to have a thorough discussion regarding the risks of medication (Table 6) use during pregnancy and the risks of noncompliance through a multidisciplinary approach.

Table 6

Safety of medications used for the management of IBD during pregnancy and lactation

Drug	FDA classification	Pregnancy	Lactation
5-ASA	B/C	Low risk Mesalamine can be continued in both oral and topical forms Consider switching Asacol HD (category C due to DPH coating)	Low risk
Sulfasalazine	B	Low risk and can be continued in pregnancy Supplement with folic acid 2g/day	Low risk
Corticosteroids	C or D	Likely low risk, has been associated with cleft lip with or without cleft palate and decreased infant birth weight Prednisone and prednisolone oral solution, immediate release prednisone, and methylprednisolone (category C) Prednisone oral delayed-release tablet (D)	Low risk, consider 4-h delay before breastfeeding
Budesonide	C	Limited information on use during pregnancy, likely low risk	Safety in lactation not known
AZA/6-MP	D	Low risk; recent studies suggest no increase in adverse pregnancy outcomes. Recommend continuing during pregnancy if necessary to maintain remission	Low risk, consider 4-h delay before breastfeeding
Anti-TNF agents	B	Low risk based on limited data. IFX and ADA cross the placenta, while CTP does not No live vaccinations in infants for at least the first 7 months	Low risk
Natalizumab	C	Limited data, safety not known	Safety in lactation not known
Vedolizumab	B	Limited data, safety not known	Safety in lactation not known
Methotrexate	X	Contraindicated	Contraindicated

Aminosalicylates are compounds containing 5-aminosalicylic acid (5-ASA). 5-ASAs are category B, except for olsalazine and Asacol HD, which are category C. These medications are considered to be low risk for use during pregnancy by the AGA and ECCO [17, 99]. Mesalamine crosses the placenta and has not demonstrated fetal toxicity in animal studies [108]. There is one report of increased stillbirth and preterm birth for mothers prescribed 5-ASA drugs, but there was no accounting for disease activity [109]. However, in other population-based studies as well as a meta-analysis of over 2,000 pregnant women, no significant association of adverse outcomes such as congenital abnormalities, stillbirth, spontaneous abortion, preterm delivery, and low birth weight occurred [110–112]. The reason that Asacol HD is category C is due to the coating of the tablet. Dibutyl phthalate, an ingredient in Asacol’s enteric coating, in animal studies has been associated with skeletal malformations and adverse effects on the male reproductive system. A switch from Asacol to another 5-ASA medication should be considered during pregnancy. Sulfasalazine, composed of a 5-ASA joined to sulfapyridine, is category B and is also considered low risk for use during pregnancy. Sulfapyridine crosses the placenta. A report of hemolytic anemia in infants born to a mother taking sulfasalazine has been noted [113]. However, in an epidemiologic study and in smaller case-control studies of sulfasalazine use during pregnancy, sulfasalazine was not associated with pregnancy complications or congenital abnormalities [114–116]. Sulfapyridine can inhibit folate absorption; therefore, it is recommended that women supplement with folate 2 mg/day. Sulfapyridine and low levels of mesalamine can be detected in breast milk [117, 118]. 5-ASA and sulfasalazine are considered low risk for use in breastfeeding mothers by the AGA and ECCO, though the American Academy of Pediatrics (AAP) reports an incident of bloody diarrhea in an infant exposed to sulfasalazine via breast milk [17, 99, 119, 120].

Corticosteroids cross the placenta, and short-acting steroids such as prednisone, prednisolone, and methylprednisolone reach lower concentration in the fetus than longer-acting dexamethasone. Oral clefts have been reported in newborns exposed to prednisone use during the first trimester in animal studies and in a meta-analysis [121]. Recent population-based studies have failed to demonstrate an association with prednisone use and orofacial malformations and major congenital abnormalities [122–124]. Adrenal suppression in the newborn has been reported after corticosteroid use in pregnancy [125, 126]. There is sparse information on the use of budesonide during pregnancy. Budesonide undergoes extensive first-pass metabolism in the liver and has low systemic bioavailability. In one case series, there were no adverse fetal or maternal effects related to budesonide use during pregnancy [127]. Risks and benefits to the mother and fetus should be discussed when initiating corticosteroids. Corticosteroids are felt to be overall low risk when indicated during pregnancy for management of the IBD patient [17, 99]. Corticosteroids can be excreted in breast milk, with milk/serum concentration ratio of about 0.2 at prednisolone doses ≥ 30 mg and 0.1 at lower prednisolone doses. Peak concentrations occur about 1 h after the dose is given [128]. A 4-h delay before breastfeeding can be considered [99].

Thiopurines, 6-mercaptopurine (6-MP) and AZA, are categorized as category D, based on early experience and case reports. The placenta is a relative barrier to the metabolites of 6-MP and AZA, and metabolites are detected at lower levels in the newborn than that detected in mothers. Multiple epidemiologic studies in the IBD population have not demonstrated an increased risk in small for gestational age and congenital abnormalities in newborns exposed to thiopurines at conception or during pregnancy, while studies have shown mixed results in regard to the risk of low birth weight and preterm birth [129–136]. It is recommended that thiopurines be continued during pregnancy in patients requiring this medication to sustain remission. However, it is generally recommended that thiopurines not be started for the first time in pregnancy, given their lack of efficacy for induction therapy and the small risk of pancreatitis and bone marrow suppression [137]. In regard to lactation, the levels of metabolites in breast milk appear to be very low, and concentrations of 6-MP in breast milk peak within the first 4 h of drug intake [138–140]. Although the evidence is sparse, there does not appear to be an increased risk in infectious complications in infants exposed to thiopurines via breast milk [141]. Long-term data are not available. A 4-h delay before breastfeeding can be considered to minimize an infant’s exposure to thiopurines.

Infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GLB) are antitumor necrosis factors (anti-TNFs) used for the management of IBD. IFX, ADA, and GLB are IgG1 antibodies that are transported across the placenta during the second and third trimester. IFX levels in the newborn cord blood appear to be higher than maternal levels and have been detected in infants born to mothers taking IFX up to gestational week 31 [142, 143]. In a small case series, no short-term infectious complications were seen in infants exposed to IFX in utero [142]. Based on results from a safety registry and epidemiologic studies, IFX use does not appear to be associated with neonatal complications such as low birth weight, spontaneous abortions, and congenital abnormalities [107, 144–147]. Preliminary data from the PIANO study, a prospective registry of pregnancy outcomes in IBD women, demonstrated an increased risk of infections in infants born to mothers on combination therapy of an anti-TNF and immunomodulator at 12 months of age [148]. Data on long-term effects of IFX exposure in utero are not available. ADA like IFX can be detected in the newborn cord blood [143], and based on limited safety data in pregnancy, ADA does not appear to be associated with adverse pregnancy outcomes [146]. CZP is a pegulated Fab fragment that passively diffuses across the placenta. The levels of CZP in the newborn are detected at minimal levels, though clinical data of its use during pregnancy is scarce. In one series, there were no reported congenital abnormalities or infectious complications in 12 newborns exposed to CZP in utero [149]. There are no available data on the use of GLM, which was approved for the treatment of UC by the FDA in 2013, in the pregnant IBD patient.

There are differing opinions about whether anti-TNF therapy should be held late in pregnancy [150–152]. In patients with active disease, it is generally recommended to continue anti-TNFs throughout pregnancy. Some suggest discontinuing anti-TNF therapy in the early third trimester, to minimize infant exposure [153]. However, other providers advocate continuing anti-TNF throughout pregnancy as it appears that levels are present in newborns even when anti-TNFs are stopped prior to gestation week 30 and to minimize the risk of disease relapse in mothers. In one study, 12 patients with IBD in remission on IFX who discontinued IFX at gestational weeks 18–27 did not experience relapse in pregnancy [154]. Since levels of anti-TNF are detected in infants born to mothers on these medications, live vaccines should be avoided for at least the first 7 months However, there is recent data from a prospective multicenter study that anti-TNF levels can be detected in infants up to 12 months. Therefore, delaying live vaccines up to 1 year unless anti-TNF clearance has been documented should be considered. (Reference: Julsgarrd M, Christensen LA, Gibson PR, Gearry RB, Fallingborg J, Hvas CL, Bibby BM, Uldbjerg N, Connell WR, Rosella O, Grosen A, Brown SJ, Kjeldsen J, Wildt S, Svenningsen L, Sparrow MP, Walsh A, Conner SJ, Radford-Smith G, Lawrance IC, Andrews JM, Ellard K, Bell SJ. Concentrations of adalimumab and infliximab in mothers and newborns and effects on infection. Gastroenterology. 2016; 151(1): 110-9.. In regard to lactation, there are data from small studies on the compatibility of anti-TNF therapy and lactation. The data suggest that little to no IFX is detected in breast milk and is likely compatible with breastfeeding [153, 155, 156].

Monoclonal antibodies to integrin such as natalizumab (NAT) and vedolizumab (VDZ) can be used in patients with IBD. NAT is a monoclonal antibody against the alpha-4 subunit integrin. It is approved for the treatment of Crohn’s disease and is category C. There are scant data on the use of NAT during pregnancy. In animal studies on guinea pigs treated with NAT, attributable fetal toxicity and teratogenic effects were not observed [157]; however, reduction in pregnancy rates in female guinea pigs treated with high-dose NAT was observed [158]. In a study looking at 35 women with multiple sclerosis, NAT did not show adverse pregnancy outcomes compared to women with the disease not on disease-modifying therapy [159]. VDZ is a gut-selective monoclonal antibody to alpha-4 beta-7 integrin and is approved for treatment of CD and UC. VDZ is category B. Animal studies of VDZ in rabbits and monkeys at 20 times the dose levels recommended in human did not demonstrate fetal harm. There are no studies on the use of VDZ in pregnant women. The review of VDZ clinical development program revealed that 24 VDZ-treated IBD females became pregnant during the clinical study. Two of a total of 11 live births were premature, and there was one report of congenital defect (agenesis of the corpus callosum) in a mother with a history of spontaneous abortions and ectopic pregnancy who received one dose of VDZ [160]. Methotrexate is contraindicated in pregnancy due to teratogenic effects. It is recommended that MTX be stopped in prospective mothers 3–6 months before trying to conceive and high-dose folic acid be initiated [99].

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A Special Meeting Review Edition: Highlights in Crohn’s Disease and Ulcerative Colitis: Digestive Disease Week 2012 May 19–22, 2012 * San Diego, CaliforniaSpecial Reporting on:* Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active UC: PURSUIT-SC* The Future of IBD Therapy: Individualized and Optimized Therapy and Novel Mechanisms* Infliximab Concentration and Clinical Outcome in Patients with UC* Vedolizumab Induction Therapy for UC: Results of GEMINI I, A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase III Trial* Novel Infliximab and Antibody-to-lnfliximab Assays Are Predictive of Disease Activity in Patients with CD* Accelerated Step-Care Therapy with Early Azathioprine Versus Conventional Step-Care Therapy in CD* PIANO: A 1,000-Patient Prospective Registry of Pregnancy Outcomes in Women with IBD Exposed to Immunomodulators and Biologic TherapyPLUS Meeting Abstract Summaries With Expert Commentary by: William J. Sandborn, MDChief of the Division of Gastroenterology Director of the UCSD IBD Center UC San Diego Health System La Jolla, California. Gastroenterol Hepatol. 2012;8(8 Suppl 5):1–24.

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