Portal de Periódicos da CAPES

A 24-Year-Old Pregnant Woman With Inflammatory Bowel Disease

2009; Elsevier BV; Volume: 7; Issue: 9 Linguagem: Inglês

10.1016/j.cgh.2009.04.022

1542-7714

Jason K. Hou, Uma Mahadevan,

Reproductive System and Pregnancy

Clinical ScenarioA 24-year-old woman, 14 weeks pregnant with her first child, is referred by her obstetrician for management of her CD. She has a 5-year history of ileocolonic CD, diagnosed by colonoscopy. She was initially treated with mesalamine, antibiotics, and prednisone. She was intolerant of azathioprine (AZA) as a result of a rash and was initiated on infliximab induction therapy followed by 5 mg/kg every 8 weeks 2 years ago. She has been in remission since then with 1–2 bowel movements per day, no pain, and no blood in her stool. She is otherwise healthy and has not required surgery for her CD. After discovering she was pregnant, she skipped her scheduled infliximab infusion 6 weeks ago out of concern for her baby and is now reporting 5 loose stools a day with abdominal pain and hematochezia.On exam, she is afebrile and non–toxic-appearing, with mild right lower quadrant abdominal tenderness. Her most recent imaging study was a computed tomographic enterography performed 2 years prior, showing narrowing and cobblestoning of the terminal ileum without proximal dilatation. Her obstetrician reports that her current pregnancy is otherwise healthy. The patient and her obstetrician are asking whether she or her child is at increased risk of complications as a result of her IBD and also for appropriate medical management.The ProblemIBD encompasses CD and UC and has a peak incidence among patients in their child-bearing years. The question of the safety of pregnancy in a patient with IBD, especially on medical therapy, can be a difficult one, with limited information on which to base a decision.Disease activity during pregnancy appears to parallel that of nonpregnant patients, with about one third of patients developing a flare during pregnancy. Two population-based studies, one in northern California by Mahadevan and one in Denmark by Norgard, did not show a statistically significant difference in pregnancy outcomes on the basis of degree of disease activity except for an increase in preterm birth in patients with moderate to high disease activity. However, in a small case control study by Reddy of patients relapsing during pregnancy and requiring hospitalization and intravenous corticosteroids, AZA/6-mercaptopurine (6-MP), cyclosporine, or colectomy, there was a significant difference in gestational age (35 vs 38.7 weeks, P = .0001) and birth weight (2001 vs 3018 g, P < .0001) compared with matched controls.Adverse pregnancy outcomes (preterm birth, low birth weight, and spontaneous abortion) and complications of labor and delivery have been noted in IBD patients in population-based studies. Dominitz et al observed a statistically significant increase in congenital malformations in patients with UC (7.9% vs 1.7%, P < .001), but other studies contradict this finding, and medication usage was not adjusted for in that study.Management Strategies and Supporting EvidenceManagement of a pregnant IBD patient should begin before conception (Figure 1). Time should be spent discussing the importance of starting and continuing appropriate medical therapy, maintaining remission, and having good communication with all treating physicians. The increased risks of conception and pregnancy outcomes need to be reviewed and the risks and benefits of continuing medical therapy weighed.With the exception of methotrexate and thalidomide, most medications commonly used for IBD can be continued during pregnancy (Table 1). Aminosalicylates are considered low risk in pregnancy and compatible with breast-feeding (rare cases of diarrhea in the infant have been reported). Patients on sulfasalazine should take at least 2 mg of folic acid daily to reduce the risk of low folate–associated neural tube defects. Antibiotics do not have a role in long-term therapy for IBD and should be avoided if possible. Quinolones in particular have been associated with arthropathy in children, although prospective studies have shown only minimal risk. Metronidazole has been associated with cleft palate in infants exposed during the first trimester and should be used if needed only in the second or third trimester. In patients with history of ileal pouch–anastomosis (IPAA) with pouchitis, short courses of antibiotics can be considered with amoxicillin/clavulanic acid because it has not been associated with significant teratogenic risk.Table 1Medications for IBD and Recommendation for Use in Pregnancy and Breast-feedingDrugFDA pregnancy categoryRecommendations for pregnancyRecommendations for breast-feedingAminosalicylates BalsalazideBLow riskNo human data: potential diarrhea MesalamineBLow riskLimited human data: potential diarrhea OlsalazineCLow riskLimited human data: potential diarrhea SulfasalazineBLow risk: give folate 2 mg dailyLimited human data: potential diarrheaAntibiotics Amoxicillin/clavulanic acidBLow riskProbably compatible Ciprofloxacin (all quinolones)CPotential toxicity to cartilage: avoidLimited human data: probably compatible MetronidazoleBLow risk: avoid in first trimesterLimited human data: potential toxicity RifaximinCAnimal teratogen: no human dataNo human dataBiologics AdalimumabBLow riskNo human data: probably compatible CertolizumabBLow riskNo human data: probably compatible InfliximabBLow riskProbably compatible NatalizumabCLimited human data: use if mother's health mandatesNo human data: risk unknownCorticosteroids (includes budesonide)CLow risk: avoid in first trimesterCompatibleImmunomodulators AZA/6-MPDAnimal teratogen: data in IBD and transplant literature suggest low riskEmerging data suggest low risk: probably compatible CyclosporineCLow riskLimited human data: potential toxicity MethotrexateXContraindicated: teratogenicContraindicated TacrolimusCUse if mother's health mandatesLimited human data: potential toxicity ThalidomideXContraindicated: teratogenicNo human data: risk unknownFDA, Food and Drug Administration. Open table in a new tab Methotrexate and thalidomide are pregnancy category X and should be discontinued at least 3–6 months before considering conception. AZA/6-MP has been associated with teratogenicity in animal studies. However, there are data from both the transplant and IBD literature suggesting no statistically significant increase in congenital anomalies. In a patient on anti–tumor necrosis factor (TNF) therapy in combination with AZA/6MP, we consider stopping the AZA/6MP to minimize risks of immunosuppression and adverse events to the fetus, given the limited benefit of combination therapy versus when a patient is maintained on AZA/6MP alone. Also, we avoid starting AZA/6MP for the first time during pregnancy, given the risk of such adverse events as pancreatitis or leukopenia, which are unpredictable and can be dangerous to the pregnancy.Adalimumab, infliximab, and certolizumab pegol are considered low risk during pregnancy. Considerable data exist for infliximab use in pregnancy in both the TREAT Registry and the Infliximab Safety Database, in which no associations between infliximab and miscarriage, neonatal complications, or fetal malformations were observed.An Organization for Teratology Information Specialists (OTIS) registry of pregnant patients on adalimumab similarly did not show association between adalimumab and adverse pregnancy or neonatal outcomes. Infliximab and adalimumab are IgG1 antibodies and do not actively cross the placenta during the first trimester but undergo efficient placental transfer during the third trimester but undergo efficient placental transfer during the second and third trimesters. Infliximab levels have been found in the cord blood at birth and in infants born to mothers receiving infliximab for up to 6 months from birth. Although no adverse effects have been noted thus far, a theoretical concern for infection exists. The last infliximab infusion before delivery should therefore be given early in the third trimester to minimize placental transfer. Timing of adalimumab is more difficult, given the shorter dosing interval and the fact that adalimumab levels cannot be commercially measured. We discontinue adalimumab 6–8 weeks before the estimated date of confinement. Limited data exist for certolizumab pegol. Unlike adalimumab and infliximab, certolizumab pegol is a Fab′ fragment, so active placental transport via Fc receptors should not occur, but low levels of diffusion might occur via alternate mechanisms in all 3 trimesters. Our current practice is to limit infliximab/adalimumab dosing in the third trimester unless the patient is having active disease, but continuing certolizumab pegol on schedule through delivery. Limited human data exist for natalizumab, but data from clinical trials and postmarketing in a small number of patients have not demonstrated an increased incidence of birth defects.Management of a flare of IBD is important because uncontrolled disease might increase the risk of adverse pregnancy or neonatal outcomes and impact the nutritional and emotional health of the mother. Diagnostic evaluation of a flare should begin with laboratory and stool studies to rule out infection and document inflammation. Hemoglobin levels vary during normal pregnancy, and C-reactive protein might be elevated in normal pregnancy as early as 4 weeks' gestation and might not be a reliable marker of inflammation after that time. Radiographic studies are occasionally required during pregnancy. In general, it is best to avoid radiographic studies unless absolutely necessary to rule out life-threatening complications such as obstruction, appendicitis, or toxic megacolon. The fetus is most susceptible to teratogenesis from radiation between the 2nd to 20th week of embryonic age. The estimated teratogenic threshold for ionizing radiation is 0.05–0.15 Gy. The estimated dose of ionizing radiation from a single pelvic CT is 0.01–0.045 Gy, and congenital malformations have not been associated with a single pelvic computed tomography. However, most physicians avoid ionizing radiation completely during pregnancy. Intravenous iodinated contrast has not been shown to be teratogenic in animal studies; however, there is a theoretical risk of neonatal hypothyroidism. Magnetic resonance imaging appears to be an attractive option to avoid radiation. Compared with exposure to ionizing radiation, magnetic resonance imaging is the modality of choice during all trimesters. Intravenous gadolinium is teratogenic in animal studies and therefore should be avoided during the first trimester.Endoscopy is rarely required during pregnancy. Refractory disease or clinically significant rectal bleeding might require endoscopic evaluation, and in most cases an unsedated flexible sigmoidoscopy will be adequate for diagnosis. The American Society for Gastrointestinal Endoscopy (ASGE) has published guidelines regarding endoscopy and the pregnant patient. Although case series have not shown adverse outcomes from endoscopy during pregnancy, it is recommended to avoid endoscopy during the first trimester if possible. Minimal or no sedation should be used for concerns of maternal or fetal hypoxia. If sedation is required, meperidine (pregnancy category B) alone is recommended, with minimal doses of midazolam (pregnancy category C) if required. If electrocautery is required, bipolar cautery is recommended. If monopolar cautery is required, the grounding pad should be placed away from the uterus. The patient should be positioned in the left lateral decubitus position to avoid compression of the vena cava or aorta, and obstetric consultation should always be obtained, with consideration of continuous fetal monitoring if performed during the third trimester.Medical management of a flare during pregnancy is similar to a nonpregnant patient. Corticosteroids might pose a small risk of oral clefts when given in the first trimester, but no associations were found for major malformations overall in a meta-analysis, and the overall benefit might warrant its use even during the first trimester. Topical steroids and budesonide have limited data but are presumed to have similar if not less risk compared with systemic steroids.Elective surgery clearly should be delayed until the postpartum period, but surgery for severe refractory disease during pregnancy should be considered. Retrospective analysis and case series suggest colectomy and small bowel surgery are safe during both the second and third trimesters. The least invasive procedure should be considered if surgery is necessary, and late in pregnancy, surgery and simultaneous delivery can be considered.Although data do not exist on this topic, elective cesarean section should be considered in a patient with active perianal disease or history of IPAA to prevent damage to the anal sphincter if a perineal tear should occur. In women without active perianal disease, data suggest no increased risk of precipitation of perianal disease after vaginal delivery.Postpartum considerations include the safety of medications during breast-feeding as well as effectiveness of neonatal vaccinations (Table 1). Use of aminosalicylates during breast-feeding has rarely been associated with diarrhea in the infant, and the American Association of Pediatrics recommends caution. In general, they are considered low risk and can be continued during breast-feeding. Prednisone is secreted in low levels in breast milk, with peak concentrations 2 hours after ingestion. No adverse effects have been observed, and the American Association of Pediatrics considers prednisone compatible with breast-feeding. Limited data exist for adalimumab, infliximab, and certolizumab pegol, but a case series reported the absence of infliximab in breast milk. They are probably compatible with breast-feeding and are usually continued. AZA/6-MP is minimally transferred in breast milk, with peak levels 4 hours after dosing. Although there is potential immune and hematologic suppression from AZA/6-MP, documented levels of AZA/6MP metabolites are low to undetectable in infants of mothers taking AZA/6-MP during breast-feeding, and we offer the mother the option of breast-feeding.Infants might receive routine vaccinations, with the exception of those exposed to anti-TNF in utero, in whom live virus vaccines (rotavirus) should be avoided for the first 6 months unless infliximab levels have been documented to be absent. Follow-up of infants exposed to infliximab in utero show an appropriate immunologic response to routine vaccinations.Areas of UncertaintyMany unanswered questions remain in the management of the pregnant patient with IBD. What is the long-term effect on the infant of anti-TNF therapy during pregnancy? Does certolizumab pegol cross the placenta and in what manner? Are natalizumab and other novel biologics safe for use in pregnancy and breast-feeding? Does vaginal delivery increase risk of incontinence in women with IPAA in the long term? Are live vaccines acceptable for infants exposed to anti-TNF agents during pregnancy?Published GuidelinesThe American Gastroenterology Association has published guidelines on the use of gastrointestinal medications during pregnancy, last revised in 2006. A thorough review of perinatal risks and medication safety of the pregnant IBD patient has been published by Dubinsky and Mahadevan. ASGE has published guidelines on endoscopy and the pregnant patient, last revised in 2005.Recommendations for This PatientThe patient was restarted on infliximab immediately, with rapid improvement of symptoms and no infusion reaction. She remained in remission throughout pregnancy on infliximab, with the last infusion given at 33 weeks' gestation. She delivered at term, with an uncomplicated vaginal delivery. The patient was given her next dose of infliximab 1 week post partum and resumed her infusion schedule every 8 weeks. The patient breast-fed, and the infant received all vaccinations on schedule except rotavirus, which was withheld. Clinical ScenarioA 24-year-old woman, 14 weeks pregnant with her first child, is referred by her obstetrician for management of her CD. She has a 5-year history of ileocolonic CD, diagnosed by colonoscopy. She was initially treated with mesalamine, antibiotics, and prednisone. She was intolerant of azathioprine (AZA) as a result of a rash and was initiated on infliximab induction therapy followed by 5 mg/kg every 8 weeks 2 years ago. She has been in remission since then with 1–2 bowel movements per day, no pain, and no blood in her stool. She is otherwise healthy and has not required surgery for her CD. After discovering she was pregnant, she skipped her scheduled infliximab infusion 6 weeks ago out of concern for her baby and is now reporting 5 loose stools a day with abdominal pain and hematochezia.On exam, she is afebrile and non–toxic-appearing, with mild right lower quadrant abdominal tenderness. Her most recent imaging study was a computed tomographic enterography performed 2 years prior, showing narrowing and cobblestoning of the terminal ileum without proximal dilatation. Her obstetrician reports that her current pregnancy is otherwise healthy. The patient and her obstetrician are asking whether she or her child is at increased risk of complications as a result of her IBD and also for appropriate medical management. A 24-year-old woman, 14 weeks pregnant with her first child, is referred by her obstetrician for management of her CD. She has a 5-year history of ileocolonic CD, diagnosed by colonoscopy. She was initially treated with mesalamine, antibiotics, and prednisone. She was intolerant of azathioprine (AZA) as a result of a rash and was initiated on infliximab induction therapy followed by 5 mg/kg every 8 weeks 2 years ago. She has been in remission since then with 1–2 bowel movements per day, no pain, and no blood in her stool. She is otherwise healthy and has not required surgery for her CD. After discovering she was pregnant, she skipped her scheduled infliximab infusion 6 weeks ago out of concern for her baby and is now reporting 5 loose stools a day with abdominal pain and hematochezia. On exam, she is afebrile and non–toxic-appearing, with mild right lower quadrant abdominal tenderness. Her most recent imaging study was a computed tomographic enterography performed 2 years prior, showing narrowing and cobblestoning of the terminal ileum without proximal dilatation. Her obstetrician reports that her current pregnancy is otherwise healthy. The patient and her obstetrician are asking whether she or her child is at increased risk of complications as a result of her IBD and also for appropriate medical management. The ProblemIBD encompasses CD and UC and has a peak incidence among patients in their child-bearing years. The question of the safety of pregnancy in a patient with IBD, especially on medical therapy, can be a difficult one, with limited information on which to base a decision.Disease activity during pregnancy appears to parallel that of nonpregnant patients, with about one third of patients developing a flare during pregnancy. Two population-based studies, one in northern California by Mahadevan and one in Denmark by Norgard, did not show a statistically significant difference in pregnancy outcomes on the basis of degree of disease activity except for an increase in preterm birth in patients with moderate to high disease activity. However, in a small case control study by Reddy of patients relapsing during pregnancy and requiring hospitalization and intravenous corticosteroids, AZA/6-mercaptopurine (6-MP), cyclosporine, or colectomy, there was a significant difference in gestational age (35 vs 38.7 weeks, P = .0001) and birth weight (2001 vs 3018 g, P < .0001) compared with matched controls.Adverse pregnancy outcomes (preterm birth, low birth weight, and spontaneous abortion) and complications of labor and delivery have been noted in IBD patients in population-based studies. Dominitz et al observed a statistically significant increase in congenital malformations in patients with UC (7.9% vs 1.7%, P < .001), but other studies contradict this finding, and medication usage was not adjusted for in that study. IBD encompasses CD and UC and has a peak incidence among patients in their child-bearing years. The question of the safety of pregnancy in a patient with IBD, especially on medical therapy, can be a difficult one, with limited information on which to base a decision. Disease activity during pregnancy appears to parallel that of nonpregnant patients, with about one third of patients developing a flare during pregnancy. Two population-based studies, one in northern California by Mahadevan and one in Denmark by Norgard, did not show a statistically significant difference in pregnancy outcomes on the basis of degree of disease activity except for an increase in preterm birth in patients with moderate to high disease activity. However, in a small case control study by Reddy of patients relapsing during pregnancy and requiring hospitalization and intravenous corticosteroids, AZA/6-mercaptopurine (6-MP), cyclosporine, or colectomy, there was a significant difference in gestational age (35 vs 38.7 weeks, P = .0001) and birth weight (2001 vs 3018 g, P < .0001) compared with matched controls. Adverse pregnancy outcomes (preterm birth, low birth weight, and spontaneous abortion) and complications of labor and delivery have been noted in IBD patients in population-based studies. Dominitz et al observed a statistically significant increase in congenital malformations in patients with UC (7.9% vs 1.7%, P < .001), but other studies contradict this finding, and medication usage was not adjusted for in that study. Management Strategies and Supporting EvidenceManagement of a pregnant IBD patient should begin before conception (Figure 1). Time should be spent discussing the importance of starting and continuing appropriate medical therapy, maintaining remission, and having good communication with all treating physicians. The increased risks of conception and pregnancy outcomes need to be reviewed and the risks and benefits of continuing medical therapy weighed.With the exception of methotrexate and thalidomide, most medications commonly used for IBD can be continued during pregnancy (Table 1). Aminosalicylates are considered low risk in pregnancy and compatible with breast-feeding (rare cases of diarrhea in the infant have been reported). Patients on sulfasalazine should take at least 2 mg of folic acid daily to reduce the risk of low folate–associated neural tube defects. Antibiotics do not have a role in long-term therapy for IBD and should be avoided if possible. Quinolones in particular have been associated with arthropathy in children, although prospective studies have shown only minimal risk. Metronidazole has been associated with cleft palate in infants exposed during the first trimester and should be used if needed only in the second or third trimester. In patients with history of ileal pouch–anastomosis (IPAA) with pouchitis, short courses of antibiotics can be considered with amoxicillin/clavulanic acid because it has not been associated with significant teratogenic risk.Table 1Medications for IBD and Recommendation for Use in Pregnancy and Breast-feedingDrugFDA pregnancy categoryRecommendations for pregnancyRecommendations for breast-feedingAminosalicylates BalsalazideBLow riskNo human data: potential diarrhea MesalamineBLow riskLimited human data: potential diarrhea OlsalazineCLow riskLimited human data: potential diarrhea SulfasalazineBLow risk: give folate 2 mg dailyLimited human data: potential diarrheaAntibiotics Amoxicillin/clavulanic acidBLow riskProbably compatible Ciprofloxacin (all quinolones)CPotential toxicity to cartilage: avoidLimited human data: probably compatible MetronidazoleBLow risk: avoid in first trimesterLimited human data: potential toxicity RifaximinCAnimal teratogen: no human dataNo human dataBiologics AdalimumabBLow riskNo human data: probably compatible CertolizumabBLow riskNo human data: probably compatible InfliximabBLow riskProbably compatible NatalizumabCLimited human data: use if mother's health mandatesNo human data: risk unknownCorticosteroids (includes budesonide)CLow risk: avoid in first trimesterCompatibleImmunomodulators AZA/6-MPDAnimal teratogen: data in IBD and transplant literature suggest low riskEmerging data suggest low risk: probably compatible CyclosporineCLow riskLimited human data: potential toxicity MethotrexateXContraindicated: teratogenicContraindicated TacrolimusCUse if mother's health mandatesLimited human data: potential toxicity ThalidomideXContraindicated: teratogenicNo human data: risk unknownFDA, Food and Drug Administration. Open table in a new tab Methotrexate and thalidomide are pregnancy category X and should be discontinued at least 3–6 months before considering conception. AZA/6-MP has been associated with teratogenicity in animal studies. However, there are data from both the transplant and IBD literature suggesting no statistically significant increase in congenital anomalies. In a patient on anti–tumor necrosis factor (TNF) therapy in combination with AZA/6MP, we consider stopping the AZA/6MP to minimize risks of immunosuppression and adverse events to the fetus, given the limited benefit of combination therapy versus when a patient is maintained on AZA/6MP alone. Also, we avoid starting AZA/6MP for the first time during pregnancy, given the risk of such adverse events as pancreatitis or leukopenia, which are unpredictable and can be dangerous to the pregnancy.Adalimumab, infliximab, and certolizumab pegol are considered low risk during pregnancy. Considerable data exist for infliximab use in pregnancy in both the TREAT Registry and the Infliximab Safety Database, in which no associations between infliximab and miscarriage, neonatal complications, or fetal malformations were observed.An Organization for Teratology Information Specialists (OTIS) registry of pregnant patients on adalimumab similarly did not show association between adalimumab and adverse pregnancy or neonatal outcomes. Infliximab and adalimumab are IgG1 antibodies and do not actively cross the placenta during the first trimester but undergo efficient placental transfer during the third trimester but undergo efficient placental transfer during the second and third trimesters. Infliximab levels have been found in the cord blood at birth and in infants born to mothers receiving infliximab for up to 6 months from birth. Although no adverse effects have been noted thus far, a theoretical concern for infection exists. The last infliximab infusion before delivery should therefore be given early in the third trimester to minimize placental transfer. Timing of adalimumab is more difficult, given the shorter dosing interval and the fact that adalimumab levels cannot be commercially measured. We discontinue adalimumab 6–8 weeks before the estimated date of confinement. Limited data exist for certolizumab pegol. Unlike adalimumab and infliximab, certolizumab pegol is a Fab′ fragment, so active placental transport via Fc receptors should not occur, but low levels of diffusion might occur via alternate mechanisms in all 3 trimesters. Our current practice is to limit infliximab/adalimumab dosing in the third trimester unless the patient is having active disease, but continuing certolizumab pegol on schedule through delivery. Limited human data exist for natalizumab, but data from clinical trials and postmarketing in a small number of patients have not demonstrated an increased incidence of birth defects.Management of a flare of IBD is important because uncontrolled disease might increase the risk of adverse pregnancy or neonatal outcomes and impact the nutritional and emotional health of the mother. Diagnostic evaluation of a flare should begin with laboratory and stool studies to rule out infection and document inflammation. Hemoglobin levels vary during normal pregnancy, and C-reactive protein might be elevated in normal pregnancy as early as 4 weeks' gestation and might not be a reliable marker of inflammation after that time. Radiographic studies are occasionally required during pregnancy. In general, it is best to avoid radiographic studies unless absolutely necessary to rule out life-threatening complications such as obstruction, appendicitis, or toxic megacolon. The fetus is most susceptible to teratogenesis from radiation between the 2nd to 20th week of embryonic age. The estimated teratogenic threshold for ionizing radiation is 0.05–0.15 Gy. The estimated dose of ionizing radiation from a single pelvic CT is 0.01–0.045 Gy, and congenital malformations have not been associated with a single pelvic computed tomography. However, most physicians avoid ionizing radiation completely during pregnancy. Intravenous iodinated contrast has not been shown to be teratogenic in animal studies; however, there is a theoretical risk of neonatal hypothyroidism. Magnetic resonance imaging appears to be an attractive option to avoid radiation. Compared with exposure to ionizing radiation, magnetic resonance imaging is the modality of choice during all trimesters. Intravenous gadolinium is teratogenic in animal studies and therefore should be avoided during the first trimester.Endoscopy is rarely required during pregnancy. Refractory disease or clinically significant rectal bleeding might require endoscopic evaluation, and in most cases an unsedated flexible sigmoidoscopy will be adequate for diagnosis. The American Society for Gastrointestinal Endoscopy (ASGE) has published guidelines regarding endoscopy and the pregnant patient. Although case series have not shown adverse outcomes from endoscopy during pregnancy, it is recommended to avoid endoscopy during the first trimester if possible. Minimal or no sedation should be used for concerns of maternal or fetal hypoxia. If sedation is required, meperidine (pregnancy category B) alone is recommended, with minimal doses of midazolam (pregnancy category C) if required. If electrocautery is required, bipolar cautery is recommended. If monopolar cautery is required, the grounding pad should be placed away from the uterus. The patient should be positioned in the left lateral decubitus position to avoid compression of the vena cava or aorta, and obstetric consultation should always be obtained, with consideration of continuous fetal monitoring if performed during the third trimester.Medical management of a flare during pregnancy is similar to a nonpregnant patient. Corticosteroids might pose a small risk of oral clefts when given in the first trimester, but no associations were found for major malformations overall in a meta-analysis, and the overall benefit might warrant its use even during the first trimester. Topical steroids and budesonide have limited data but are presumed to have similar if not less risk compared with systemic steroids.Elective surgery clearly should be delayed until the postpartum period, but surgery for severe refractory disease during pregnancy should be considered. Retrospective analysis and case series suggest colectomy and small bowel surgery are safe during both the second and third trimesters. The least invasive procedure should be considered if surgery is necessary, and late in pregnancy, surgery and simultaneous delivery can be considered.Although data do not exist on this topic, elective cesarean section should be considered in a patient with active perianal disease or history of IPAA to prevent damage to the anal sphincter if a perineal tear should occur. In women without active perianal disease, data suggest no increased risk of precipitation of perianal disease after vaginal delivery.Postpartum considerations include the safety of medications during breast-feeding as well as effectiveness of neonatal vaccinations (Table 1). Use of aminosalicylates during breast-feeding has rarely been associated with diarrhea in the infant, and the American Association of Pediatrics recommends caution. In general, they are considered low risk and can be continued during breast-feeding. Prednisone is secreted in low levels in breast milk, with peak concentrations 2 hours after ingestion. No adverse effects have been observed, and the American Association of Pediatrics considers prednisone compatible with breast-feeding. Limited data exist for adalimumab, infliximab, and certolizumab pegol, but a case series reported the absence of infliximab in breast milk. They are probably compatible with breast-feeding and are usually continued. AZA/6-MP is minimally transferred in breast milk, with peak levels 4 hours after dosing. Although there is potential immune and hematologic suppression from AZA/6-MP, documented levels of AZA/6MP metabolites are low to undetectable in infants of mothers taking AZA/6-MP during breast-feeding, and we offer the mother the option of breast-feeding.Infants might receive routine vaccinations, with the exception of those exposed to anti-TNF in utero, in whom live virus vaccines (rotavirus) should be avoided for the first 6 months unless infliximab levels have been documented to be absent. Follow-up of infants exposed to infliximab in utero show an appropriate immunologic response to routine vaccinations. Management of a pregnant IBD patient should begin before conception (Figure 1). Time should be spent discussing the importance of starting and continuing appropriate medical therapy, maintaining remission, and having good communication with all treating physicians. The increased risks of conception and pregnancy outcomes need to be reviewed and the risks and benefits of continuing medical therapy weighed. With the exception of methotrexate and thalidomide, most medications commonly used for IBD can be continued during pregnancy (Table 1). Aminosalicylates are considered low risk in pregnancy and compatible with breast-feeding (rare cases of diarrhea in the infant have been reported). Patients on sulfasalazine should take at least 2 mg of folic acid daily to reduce the risk of low folate–associated neural tube defects. Antibiotics do not have a role in long-term therapy for IBD and should be avoided if possible. Quinolones in particular have been associated with arthropathy in children, although prospective studies have shown only minimal risk. Metronidazole has been associated with cleft palate in infants exposed during the first trimester and should be used if needed only in the second or third trimester. In patients with history of ileal pouch–anastomosis (IPAA) with pouchitis, short courses of antibiotics can be considered with amoxicillin/clavulanic acid because it has not been associated with significant teratogenic risk. FDA, Food and Drug Administration. Methotrexate and thalidomide are pregnancy category X and should be discontinued at least 3–6 months before considering conception. AZA/6-MP has been associated with teratogenicity in animal studies. However, there are data from both the transplant and IBD literature suggesting no statistically significant increase in congenital anomalies. In a patient on anti–tumor necrosis factor (TNF) therapy in combination with AZA/6MP, we consider stopping the AZA/6MP to minimize risks of immunosuppression and adverse events to the fetus, given the limited benefit of combination therapy versus when a patient is maintained on AZA/6MP alone. Also, we avoid starting AZA/6MP for the first time during pregnancy, given the risk of such adverse events as pancreatitis or leukopenia, which are unpredictable and can be dangerous to the pregnancy. Adalimumab, infliximab, and certolizumab pegol are considered low risk during pregnancy. Considerable data exist for infliximab use in pregnancy in both the TREAT Registry and the Infliximab Safety Database, in which no associations between infliximab and miscarriage, neonatal complications, or fetal malformations were observed. An Organization for Teratology Information Specialists (OTIS) registry of pregnant patients on adalimumab similarly did not show association between adalimumab and adverse pregnancy or neonatal outcomes. Infliximab and adalimumab are IgG1 antibodies and do not actively cross the placenta during the first trimester but undergo efficient placental transfer during the third trimester but undergo efficient placental transfer during the second and third trimesters. Infliximab levels have been found in the cord blood at birth and in infants born to mothers receiving infliximab for up to 6 months from birth. Although no adverse effects have been noted thus far, a theoretical concern for infection exists. The last infliximab infusion before delivery should therefore be given early in the third trimester to minimize placental transfer. Timing of adalimumab is more difficult, given the shorter dosing interval and the fact that adalimumab levels cannot be commercially measured. We discontinue adalimumab 6–8 weeks before the estimated date of confinement. Limited data exist for certolizumab pegol. Unlike adalimumab and infliximab, certolizumab pegol is a Fab′ fragment, so active placental transport via Fc receptors should not occur, but low levels of diffusion might occur via alternate mechanisms in all 3 trimesters. Our current practice is to limit infliximab/adalimumab dosing in the third trimester unless the patient is having active disease, but continuing certolizumab pegol on schedule through delivery. Limited human data exist for natalizumab, but data from clinical trials and postmarketing in a small number of patients have not demonstrated an increased incidence of birth defects. Management of a flare of IBD is important because uncontrolled disease might increase the risk of adverse pregnancy or neonatal outcomes and impact the nutritional and emotional health of the mother. Diagnostic evaluation of a flare should begin with laboratory and stool studies to rule out infection and document inflammation. Hemoglobin levels vary during normal pregnancy, and C-reactive protein might be elevated in normal pregnancy as early as 4 weeks' gestation and might not be a reliable marker of inflammation after that time. Radiographic studies are occasionally required during pregnancy. In general, it is best to avoid radiographic studies unless absolutely necessary to rule out life-threatening complications such as obstruction, appendicitis, or toxic megacolon. The fetus is most susceptible to teratogenesis from radiation between the 2nd to 20th week of embryonic age. The estimated teratogenic threshold for ionizing radiation is 0.05–0.15 Gy. The estimated dose of ionizing radiation from a single pelvic CT is 0.01–0.045 Gy, and congenital malformations have not been associated with a single pelvic computed tomography. However, most physicians avoid ionizing radiation completely during pregnancy. Intravenous iodinated contrast has not been shown to be teratogenic in animal studies; however, there is a theoretical risk of neonatal hypothyroidism. Magnetic resonance imaging appears to be an attractive option to avoid radiation. Compared with exposure to ionizing radiation, magnetic resonance imaging is the modality of choice during all trimesters. Intravenous gadolinium is teratogenic in animal studies and therefore should be avoided during the first trimester. Endoscopy is rarely required during pregnancy. Refractory disease or clinically significant rectal bleeding might require endoscopic evaluation, and in most cases an unsedated flexible sigmoidoscopy will be adequate for diagnosis. The American Society for Gastrointestinal Endoscopy (ASGE) has published guidelines regarding endoscopy and the pregnant patient. Although case series have not shown adverse outcomes from endoscopy during pregnancy, it is recommended to avoid endoscopy during the first trimester if possible. Minimal or no sedation should be used for concerns of maternal or fetal hypoxia. If sedation is required, meperidine (pregnancy category B) alone is recommended, with minimal doses of midazolam (pregnancy category C) if required. If electrocautery is required, bipolar cautery is recommended. If monopolar cautery is required, the grounding pad should be placed away from the uterus. The patient should be positioned in the left lateral decubitus position to avoid compression of the vena cava or aorta, and obstetric consultation should always be obtained, with consideration of continuous fetal monitoring if performed during the third trimester. Medical management of a flare during pregnancy is similar to a nonpregnant patient. Corticosteroids might pose a small risk of oral clefts when given in the first trimester, but no associations were found for major malformations overall in a meta-analysis, and the overall benefit might warrant its use even during the first trimester. Topical steroids and budesonide have limited data but are presumed to have similar if not less risk compared with systemic steroids. Elective surgery clearly should be delayed until the postpartum period, but surgery for severe refractory disease during pregnancy should be considered. Retrospective analysis and case series suggest colectomy and small bowel surgery are safe during both the second and third trimesters. The least invasive procedure should be considered if surgery is necessary, and late in pregnancy, surgery and simultaneous delivery can be considered. Although data do not exist on this topic, elective cesarean section should be considered in a patient with active perianal disease or history of IPAA to prevent damage to the anal sphincter if a perineal tear should occur. In women without active perianal disease, data suggest no increased risk of precipitation of perianal disease after vaginal delivery. Postpartum considerations include the safety of medications during breast-feeding as well as effectiveness of neonatal vaccinations (Table 1). Use of aminosalicylates during breast-feeding has rarely been associated with diarrhea in the infant, and the American Association of Pediatrics recommends caution. In general, they are considered low risk and can be continued during breast-feeding. Prednisone is secreted in low levels in breast milk, with peak concentrations 2 hours after ingestion. No adverse effects have been observed, and the American Association of Pediatrics considers prednisone compatible with breast-feeding. Limited data exist for adalimumab, infliximab, and certolizumab pegol, but a case series reported the absence of infliximab in breast milk. They are probably compatible with breast-feeding and are usually continued. AZA/6-MP is minimally transferred in breast milk, with peak levels 4 hours after dosing. Although there is potential immune and hematologic suppression from AZA/6-MP, documented levels of AZA/6MP metabolites are low to undetectable in infants of mothers taking AZA/6-MP during breast-feeding, and we offer the mother the option of breast-feeding. Infants might receive routine vaccinations, with the exception of those exposed to anti-TNF in utero, in whom live virus vaccines (rotavirus) should be avoided for the first 6 months unless infliximab levels have been documented to be absent. Follow-up of infants exposed to infliximab in utero show an appropriate immunologic response to routine vaccinations. Areas of UncertaintyMany unanswered questions remain in the management of the pregnant patient with IBD. What is the long-term effect on the infant of anti-TNF therapy during pregnancy? Does certolizumab pegol cross the placenta and in what manner? Are natalizumab and other novel biologics safe for use in pregnancy and breast-feeding? Does vaginal delivery increase risk of incontinence in women with IPAA in the long term? Are live vaccines acceptable for infants exposed to anti-TNF agents during pregnancy? Many unanswered questions remain in the management of the pregnant patient with IBD. What is the long-term effect on the infant of anti-TNF therapy during pregnancy? Does certolizumab pegol cross the placenta and in what manner? Are natalizumab and other novel biologics safe for use in pregnancy and breast-feeding? Does vaginal delivery increase risk of incontinence in women with IPAA in the long term? Are live vaccines acceptable for infants exposed to anti-TNF agents during pregnancy? Published GuidelinesThe American Gastroenterology Association has published guidelines on the use of gastrointestinal medications during pregnancy, last revised in 2006. A thorough review of perinatal risks and medication safety of the pregnant IBD patient has been published by Dubinsky and Mahadevan. ASGE has published guidelines on endoscopy and the pregnant patient, last revised in 2005. The American Gastroenterology Association has published guidelines on the use of gastrointestinal medications during pregnancy, last revised in 2006. A thorough review of perinatal risks and medication safety of the pregnant IBD patient has been published by Dubinsky and Mahadevan. ASGE has published guidelines on endoscopy and the pregnant patient, last revised in 2005. Recommendations for This PatientThe patient was restarted on infliximab immediately, with rapid improvement of symptoms and no infusion reaction. She remained in remission throughout pregnancy on infliximab, with the last infusion given at 33 weeks' gestation. She delivered at term, with an uncomplicated vaginal delivery. The patient was given her next dose of infliximab 1 week post partum and resumed her infusion schedule every 8 weeks. The patient breast-fed, and the infant received all vaccinations on schedule except rotavirus, which was withheld. The patient was restarted on infliximab immediately, with rapid improvement of symptoms and no infusion reaction. She remained in remission throughout pregnancy on infliximab, with the last infusion given at 33 weeks' gestation. She delivered at term, with an uncomplicated vaginal delivery. The patient was given her next dose of infliximab 1 week post partum and resumed her infusion schedule every 8 weeks. The patient breast-fed, and the infant received all vaccinations on schedule except rotavirus, which was withheld.