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Keywords:

  • pregnancy;
  • inheritance of IBD;
  • inflammatory bowel disease

Abstract

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Women with inflammatory bowel disease (IBD) and the physicians who care for them must make difficult decisions on issues of conception, pregnancy, and breastfeeding with very limited and often contradictory information. This review provides the most current information on the inheritance of IBD, fertility, pregnancy outcomes, the management of disease during pregnancy, and the safety of medications in pregnancy and breastfeeding. We would like to emphasize that the information presented here must be individualized to the specific situation of each patient, their acceptance of risk, and their degree of disease severity.

(Inflamm Bowel Dis 2008)


INHERITANCE OF IBD

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

The risk of their offspring inheriting inflammatory bowel disease (IBD) is a major concern expressed by patients considering having a child. A positive family history is the most important risk factor to predict lifetime risk. Based on empirical lifetime risks, all first-degree relatives of Crohn's disease (CD) probands have an increased risk compared with those of ulcerative colitis (UC) probands, and relatives of Jewish patients have a greater risk than relatives of non-Jewish patients: Jewish CD versus non-Jewish CD: 7.8% versus 5.2%, and Jewish UC versus non-Jewish UC: 4.5% versus 1.6%, overall comparison P = 0028. This was seen even more so in siblings: Jewish CD versus non-Jewish CD: 16.8% versus 7.0%, and Jewish UC versus non-Jewish UC: 4.6% versus 0.9%, overall P = 0.001.1 A Danish regional cohort study observed an almost 10-fold increased risk for IBD among first-degree relatives.2 When looking specifically at offspring, the prevalence proportion ratios of CD and UC among offspring of UC patients were 2.6 and 5.1, respectively, and for CD patients were 12.8 and 4.0, respectively. Thus, the overall risk of IBD among offspring is 2–12 times higher than the general population risk, which is consistent with what has been reported in other studies.3, 4

FERTILITY

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

The majority of fertility outcomes reported among IBD patients are based on old studies and predates the increased use of thiopurines and the introduction of anti-TNFα therapies. The impact of persistently active disease on the ability and desire to conceive is certainly an important consideration when interpreting the literature. Variables such as systemic effects of disease, for example, fatigue and anemia, as well as medication effects, such as corticosteroids, on libido can impact sexual activity. Postoperative dyspareunia can similarly affect sexual activity and impact the chance of conceiving.5 Fear of inheritance of IBD in the offspring and fear of fetal exposure to IBD therapies can lead to voluntary childlessness. Educating IBD patients on the importance of disease control and working closely with high-risk obstetricians who are comfortable with following women receiving immunosuppressants will help IBD patients and their partners with decision-making when considering having children. Overall, it does not appear that UC patients have a decreased fertility rate as compared to controls.6–8 However, this statement does not apply when considering women with UC who have undergone surgery, more specifically ileal pouch anal anastomosis (IPAA), which involves significant dissection within the pelvic region. Two Scandinavian studies showed a significant decrease in fertility rates as measured by fecundability (the probability of becoming pregnant per month by unprotected intercourse) among women who have undergone an IPAA for UC.9, 10 Of interest, the same decrease was described among women who had undergone an IPAA for familial adenomatous polyposis (FAP).11 These studies were done by a phone questionnaire. Based on these earlier studies, fecundability rates were decreased as much as 80% after IPAA. There was no difference in fecundability among UC patients who had not undergone surgery as compared to controls. More recent studies confirmed a decrease in fertility rates but not to the same degree: 69% infertility in the postoperative state as compared to 46% preoperatively (P = 0.005) when evaluating a subgroup of patients who tried to conceive both pre- and postoperatively.12 Both the preoperative and postoperative infertility rates were higher in UC patients as compared to historical controls. Intraoperative blood transfusion had a negative impact on fertility. Another questionnaire study performed in Finland reported that of 54 women who had undergone IPAA surgery, 67% succeeded in becoming pregnant naturally, compared with 82% of 60 controls.13 The probability of pregnancy after 2 years of trying was 56% in the IPAA group and 91% in the control group (P < 0.001). The difference in median time to pregnancy between IPAA and control groups was 14 months, such that the probability of a women conceiving in any short time period was reduced to 47% of average. It was also found that 24% of women in the IPAA group needed infertility investigations as compared to 10% in the control group (P = 0.044). Overall, 72% of women in the IPAA group and 88% in the control group were successful in conceiving a child. This study concluded that women with IPAA suffer more from a reduction in the probability of conception rather than complete infertility, as the lifetime chance of having at least 1 live birth after IPAA was 80%. A recent systematic review reported an infertility rate of 12% before restorative proctocolectomy and 26% after surgery based on 7 studies and 945 evaluable patients.14 These findings are more promising than what was originally described by Olsen et al9, 10 and the original smaller studies. Most likely, the greatest reduction in fertility is a result of the pelvic dissection involved in creating the pouch and the adhesions and potential scarring that may result. Women may want to consider the possibility of a colectomy with an ileostomy and rectal stump with creation of the pouch after they have had their children.

The original fertility reports among a small group of CD patients suggested that the infertility rate was similar between patients and controls.15 Others suggested decreased fertility as a result of disease activity, which normalized when remission was achieved.16 One of the larger case–control studies reported a significant reduction in fertility but did not account for disease activity and surgical history.17 Surgery for CD can impact fertility such that problems were more frequently observed in women who had undergone surgery as compared to those who did not (12% versus 5% infertility rates).18 Moreover, adhesion formation can impact tubal fertility.19

DISEASE ACTIVITY

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Effect of Pregnancy on IBD

In general, women with IBD are as likely to flare during pregnancy as they are to flare when not pregnant. Nielsen et al20 reported an exacerbation rate of 34% per year during pregnancy and 32% per year when not pregnant in women with UC. Pregnant women with CD also had similar rates of disease exacerbation.21 In the Kaiser population, the majority of patients had inactive disease throughout their pregnancy with no sudden increase in disease activity in the postpartum.22 This is consistent with other published studies that found the rate of disease flare during pregnancy (26%–34%) to be similar to the rate of flare in the nonpregnant IBD population.20, 23, 24 While breastfeeding has anecdotally been associated with an increase in disease activity in the postpartum, this has not been shown to be a contributing factor independent of medication cessation done to facilitate breastfeeding.

Disease activity may even be slightly lower during pregnancy.25 One study found that the rate of relapse may decrease in the 3 years following pregnancy.26 This was further supported by a study from a 10-year follow-up of a European cohort of patients with 580 pregnancies.27 Patients with CD who were pregnant during the course of their disease did not have higher rates of stenosis (37% versus 52%, P = 0.13) or resection (0.52 versus 0.66, P = 0.37). The rates of relapse decreased in the years following pregnancy in both UC (0.34 versus 0.18 flares/year, P = 0.008) and CD patients (0.76 versus 0.12 flares/year, P = 0.004). While the etiology for this is not understood, a possible factor inducing quiescent disease may be disparity in HLA class II antigens between mother and fetus, suggesting that the maternal immune response to paternal HLA antigens may result in immunosuppression that affects maternal immune-mediated disease. This has been demonstrated in rheumatoid arthritis28 as well as in IBD.29

Effect of Disease Activity on Pregnancy

Earlier studies suggested that disease activity was a predictor of adverse outcome in pregnancy. Disease activity at conception has been associated with a higher rate of fetal loss and preterm birth20, 24; disease activity during pregnancy was associated with low birthweight (LBW) and preterm birth.30, 31 Other potential predictors of an adverse outcome include ileal CD and previous bowel resection.22, 32 In the Kaiser population, however, disease activity was not predictive of an adverse outcome in any category.22 Even when limited to the presence of moderate to severe disease activity, there was still no association with an adverse outcome. The majority of patients in this cohort with both UC and CD, however, did have inactive or mild disease throughout pregnancy. Similarly, a population-based study from Denmark also did not find an increased risk of adverse events associated with disease activity.33 They reported that women with active disease had adjusted risks of LBW, LBW at term, preterm birth, and congenital anomalies of 0.2 (0.0–2.6), 0.4 (0.0–3.7), 2.4 (0.6–9.5), and 0.8 (0.2–3.8), respectively. However, the crude risk of preterm birth was increased, with an odds ratio (OR) of 3.4 (1.1–10.6) in those with moderate–high disease activity. Overall, these 2 population-based studies did not show a significant role of disease activity in predicting adverse outcomes above that expected with the diagnosis of IBD alone.

PREGNANCY OUTCOMES

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Population-based studies have shown an increased risk of preterm birth, LBW, and small for gestational age (SGA) infants in the offspring of women with IBD.34–36 Cesarean sections are also more common in women with IBD.34 Whether there is an increase in congenital anomalies is unclear and may be related to medication use (see section on medication below).

A population-based cohort study by Dominitz et al37 used the computerized birth records of Washington State to compare pregnancy outcomes in 107 UC and 155 CD patients to 1308 controls. Women with CD had significantly higher rates of preterm delivery, LBW, and SGA infants compared to controls. Women with UC, on the other hand, had similar rates as controls, but a significantly higher rate of congenital malformations (7.9% versus 1.7%, P < 0.001). The study did not account for medication use and the results have not been replicated in other studies. The Hungarian Case Control Surveillance of congenital anomalies was queried from 1980–1996.38 The OR of congenital anomalies in UC patients versus controls was 1.3 (0.9, 1.8), adjusted for parity, age, and medication use. However, the risk of limb deficiencies, obstructive urinary congenital abnormalities, and multiple congenital abnormalities were significantly increased with OR = 6.2 (95% confidence interval [CI] = 2.9–13.1), OR = 3.3 (95% CI = 1.1–9.5), and OR = 2.6 (95% CI = 1.3–5.4), respectively. A case–control study from Italy studied 502 pregnancies in 199 women prior to a diagnosis of IBD and 121 pregnancies in 90 patients after diagnosis of IBD and compared them to 996 and 204 pregnancies, respectively, in the non-IBD control population.39 Prior to diagnosis, women with CD had higher rates of preterm delivery and LBW. After diagnosis, LBW was more common among CD patients than in UC or controls. In postdiagnosis pregnancies a higher incidence of congenital anomalies was found in IBD patients (5.5% versus 0.0%) versus controls, with no difference in rates between UC and CD. However, this is likely spurious, as a rate of 0% is not the population norm for congenital anomalies (3%–4% is the norm). Also, there was no difference in the rate of congenital anomalies between pre- and postdiagnosis IBD pregnancies, suggesting that the apparent increase in congenital anomalies in the postdiagnosis IBD patients is due to an unusual lack of anomalies in the control population.

A population representative cohort study of women with IBD in the Northern California Kaiser population compared women with IBD (n = 461) matched to controls (n = 495) by age and hospital of delivery.22 Women with IBD were significantly more likely to have a spontaneous abortion, OR = 1.65 (1.09, 2.48), an adverse pregnancy outcome (stillbirth, preterm birth, or SGA infant), OR = 1.54 (1.00, 2.38), or a complication of labor, OR = 1.78 (95% CI 1.13, 2.81). However, there was no difference in the rate of congenital malformations in IBD patients versus controls or individually among CD and UC patients. Independent predictors of an adverse outcome included a diagnosis of IBD, a history of surgery for IBD, and non-Caucasian ethnicity. Severity of disease and medical treatments were not associated with an adverse outcome in this cohort, although the majority had mild or inactive disease.

A meta-analysis by Cornish et al40 combined 12 studies totaling 3907 patients with IBD. A significant increase in preterm birth OR = 1.87 (1.52, 2.31), LBW, OR = 2.1 (1.38, 3.19), and cesarean section, OR = 1.5 (1.26, 1.79) was seen. The risk of congenital anomalies was significantly increased as well, with an OR of 2.37 (1.47, 3.82). However, the difference was seen in patients with UC, not CD, and again were primarily based on the Dominitz et al37 study reported above and an older small study by Larzilliere and Beau.41

MEDICATIONS

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

The use of medications during the conception period and pregnancy is a cause of great concern for patients and the physicians caring for them. Overall, the majority of medications used for the treatment of IBD are not associated with significant adverse effects or congenital anomalies and maintaining the health of the mother remains the priority in the management of these patients. The United States Food and Drug Administration (FDA) classification of drugs offers a guide to the use of medications during pregnancy. The FDA categories are listed in Table 1 and are noted for each drug discussed.

Table 1. Food and Drug Administration Categories for the Use of Medications in Pregnancy (Ref. 123)
FDA CategoryDefinition
AControlled studies in animals and women have shown no risk in the first trimester, and possible fetal harm is remote.
BEither animal studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester.
CNo controlled studies in humans have been performed, and animal studies have shown adverse events, or studies in humans and animals not available; give if potential benefit outweighs the risk.
DPositive evidence of fetal risk is available, but the benefits may outweigh the risk if life-threatening or serious disease.
XStudies in animals or humans show fetal abnormalities; drug contraindicated

Aminosalicylates

All aminosalicylates (sulfasalazine, mesalamine, balsalazide) are pregnancy category B except olsalazine, which is pregnancy category C. Sulfasalazine is composed of 5-aminosalicylic acid azo-bonded to sulfapyridine. Initial case reports suggested sulfasalazine teratogenicity with evidence of cardiovascular, genitourinary, and neurologic defects.42–44 However, a larger series of 181 pregnant women did not note an increase in congenital anomalies.45 A population-based study using the Hungarian Case Control Surveillance of Congenital Abnormalities database46 also did not find a significant increase in the prevalence of congenital abnormalities in the children of women treated with sulfasalazine. Given the concern over potential anti-folate effects of the drug, it is recommended that women take folic acid 2 mg daily in the prenatal period and throughout pregnancy. Breast-feeding is also considered low-risk with sulfasalazine. Unlike other sulfonamides, bilirubin displacement, and therefore kernicterus, does not occur in the infant.47 This may be due to negligible transfer via breast milk.

Case series of mesalamine use in pregnancy do not suggest an increased risk to the fetus.48–50 This has been supported by a prospective controlled trial of 165 women exposed to mesalamine compared with matched controls with no exposure (51) and a population-based cohort study from Denmark.52 Neither trial demonstrated teratogenic risk, but there was an increased risk of premature birth, LBW, and stillbirth. The latter complications may reflect disease effect because the mesalamine group had IBD and the nonexposed group was from the general population.

Antibiotics

Metronidazole is a pregnancy category B drug. Multiple studies have suggested that prenatal use of metronidazole is not associated with birth defects. These studies include 2 meta-analyses,53, 54 retrospective cohort studies,55, 56 and a prospective controlled study of 228 women exposed to metronidazole during pregnancy.57 A population-based case–control study found that overall teratogenic risk was low, but infants of women exposed to metronidazole in the second and third months of pregnancy had higher rates of cleft lip with or without cleft palate.58 This increase was slight and not believed to be clinically significant.

Quinolones (e.g., ciprofloxacin, levofloxacin, norfloxacin) are pregnancy category C drugs. Quinolones have a high affinity for bone tissue and cartilage and may cause arthropathies in children.59 The manufacturer reports damage to cartilage in weight-bearing joints after quinolone exposure in immature rats and dogs. However, a prospective controlled study of 200 women exposed to quinolones60 and a population-based cohort study of 57 women exposed to quinolones61 did not find an increased risk of congenital malformations. Overall, the risk is believed to be minimal, but given safer alternatives, the drug should be avoided in pregnancy.

Rifaximin is a pregnancy category C drug. This is a new agent, and little information exists on safety in pregnancy. Rifaximin has not been found to affect fertility or pregnancy outcome in rats62 or cause teratogenic complications in rats and rabbits in 1 study,63 although other studies have noted teratogenicity in rats and rabbits, including cleft palate and incomplete ossification.64 In general, given the limited evidence of benefit of these agents in IBD and the extended duration of use in the treatment of CD and UC, they should be avoided during pregnancy. Short courses for the treatment of pouchitis can be considered based on the safety data presented previously. An alternative antibiotic for pouchitis is amoxicillin/clavulanic acid, a pregnancy category B drug. A population-based case–control study65 and a prospective controlled study66 did not show evidence of increased teratogenic risk.

Corticosteroids

Corticosteroids are pregnancy category C drugs. A case–control study of corticosteroid use during the first trimester of pregnancy noted an increased risk of oral clefts in the newborn.67 This was confirmed by a large case–control study68 and a meta-analysis that reported a summary OR for case–control studies examining the risk of oral clefts (3.35 [95% CI, 1.97–5.69]).69 However, the overall risk of major malformations was low (1.45 [95% CI, 0.80–2.60]). Moreover, a prospective controlled study of 311 women who received glucocorticoids during the first trimester did not note an increased rate of major anomalies and no cases of oral cleft were noted.70 The study was powered to find a 2.5-fold increase in the overall rate of major anomalies. An increased risk of premature rupture of membranes and adrenal insufficiency in the newborn has been reported in the transplant setting.71 Overall, the use of corticosteroids poses a small risk to the developing infant and the mother needs to be informed of both the benefits and the risks of therapy.

There are no published data on the safety of oral budesonide in pregnancy. A case series of 4 patients with CD did not find an increased risk of adverse outcomes.72 Inhaled or intranasal budesonide is not associated with adverse fetal outcomes based on large clinical series.73, 74

Bisphosphonates

The bisphosphonates alendronate and risedronate are pregnancy category C drugs and the safety in breastfeeding is unknown. Many patients with IBD are started on these medications in conjunction with corticosteroids for prevention of bone loss. Both agents should be avoided in pregnancy because animal studies demonstrate that alendronate does cross the placenta and store in fetal bone, causing anatomic changes.75 The effects on human fetal bone development are unknown. The half-life of alendronate is more than 10 years, and it accumulates in bone. The concern in giving this agent to a woman of child-bearing potential is that the drug is slowly released from bone and may result in a low level of continuous exposure to the fetus throughout gestation. Risedronate has a reported half-life of 20 days. However, an ongoing study by the manufacturer suggests that the half-life may be significantly longer. Although the 1 study of 24 pregnancies exposed to alendronate does not report an increased risk of adverse events,76 the long-term use of bisphosphonates in women of child-bearing potential should be done with caution and under the guidance of an endocrinologist.

Immunomodulators

The immunomodulators are the most controversial agents used in the treatment of the pregnant woman with IBD.

Methotrexate

Methotrexate, a pregnancy category X drug, is clearly teratogenic and should not be used in women considering conception. Methotrexate is a folic acid antagonist, and use during the critical period of organogenesis (6–8 weeks postconception) is associated with multiple congenital anomalies collectively called methotrexate embryopathy or the fetal aminopterin-methotrexate syndrome.77 The syndrome is characterized by intrauterine growth retardation; decreased ossification of the calvarium; hypoplastic supraorbital ridges; small, low-set ears; micrognathia; limb abnormalities; and sometimes mental retardation.78 Exposure in the second and third trimesters may be associated with fetal toxicity and mortality.77 Methotrexate may persist in tissues for long periods, and it is suggested that patients wait at least 3–6 months from the discontinuation of the drug before attempting conception.

Azathioprine/6-Mercaptopurine

6-Mercaptopurine (6MP) and its prodrug azathioprine (AZA) are pregnancy category D drugs. Animal studies have demonstrated teratogenicity with increased frequencies of cleft palate, open-eye, and skeletal anomalies seen in mice exposed to AZA and cleft palate, skeletal anomalies, and urogenital anomalies seen in rats.79 Transplacental and transamniotic transmission of AZA and its metabolites from the mother to the fetus can occur.80 The oral bioavailability of AZA (47%) and 6MP (16%) is low79 and the early fetal liver lacks the enzyme inosinate pyrophosphorylase needed to convert AZA to 6MP. Both features may protect the fetus from toxic drug exposure during the crucial period of organogenesis.

The largest evidence on safety comes from transplantation studies, where rates of anomalies ranged from 0%–11.8% and no evidence of recurrent patterns of congenital anomalies emerged.79 A population-based cohort study from Denmark compared 11 women exposed to AZA or 6MP with the general population.81 The adjusted OR for congenital malformations was significantly increased at 6.7 (95% CI, 1.4–32.4). However, when a single severely ill patient with autoimmune hepatitis and multiple other medications was removed from the cohort, the OR was 3.4 (95% CI, 0.4–27.3) with confidence intervals now crossing 1 and no longer being significant.

In IBD, multiple case series have not noted an increase in congenital anomalies.82–85 One study, however, did report a higher incidence of fetal loss in women with IBD with prior treatment on 6MP compared to those who never had 6MP exposure.86 However, recently a Danish nationwide cohort study87 found that women with CD exposed to corticosteroids and AZA/6MP were more likely to have preterm birth (12.3% and 25%, respectively) compared to non-IBD controls (6.5%). Congenital anomalies were also numerically more prevalent among AZA/6MP exposed cases compared to the reference group (15.4% versus 5.7%) but the OR of 2.9 (95% CI 0.9–8.9) had confidence intervals crossing 1, which means the difference was not statistically significant. Only 26 women were exposed to AZA/6MP during conception, and the authors controlled for “disease activity” which they defined as > admissions for disease exacerbation, accounting for only the most severe patients. Finally, the largest single study to date studied women who called a teratogen information service.88 They compared 189 women exposed to AZA during pregnancy to 230 women who did not take any teratogenic medications during pregnancy. The rate of major malformations did not differ between groups with 6 neonates in each; for AZA the rate was 3.5% and for the control group rate it was 3.0% (P = 0.775; OR 1.17; CI: 0.37, 3.69). The mean birthweight and gestational age were lower in the AZA group 2995 g versus 3,252 g [P = 0.001, difference of mean: 257, 95% CI: 106.3, 408.1] and 37.8 weeks versus 39.1 weeks [P = 0.001, difference of mean: 1.3, 95% CI: 0.5, 2.0], respectively). The AZA group had more cases of prematurity (21.4% versus 5.2% [P < 0.001; OR 4.0; 95% CI: 2.0, 8.06]) and LBW (23% versus 6.0% [P < 0.001; OR 3.81; 95% CI: 2.0, 7.2]) as well, but this most likely reflects their underlying disease state, which was not controlled for.

Cyclosporine and Tacrolimus

Cyclosporine is a pregnancy category C drug. A meta-analysis of 15 studies of pregnancy outcomes after cyclosporine therapy reported a total of 410 patients with data on major malformations.89 The calculated OR of 3.83 for malformations did not achieve statistical significance (95% CI, 0.75–19.6). The rate of malformations was 4.1%, which is not different from the general population. The conclusion of the study was that cyclosporine did not appear to be a major human teratogen. In a study published in the obstetric literature,90 a retrospective review of 38 pregnancies in 29 women between 1992 and 2002 was conducted. There were 4 spontaneous abortions and 10 first-trimester terminations for worsening liver function. The mean gestational age was 36.4 weeks, and there were no intrauterine or neonatal deaths. Five minor congenital anomalies were noted. The investigators concluded that planned pregnancy at least 2 years after liver transplantation with stable allograft function and continued immunosuppression had an excellent maternal and neonatal outcome.

There are several case reports of successful cyclosporine use during pregnancy to control UC and complete the pregnancy.91–93 In the setting of severe, corticosteroid-refractory UC, cyclosporine may be a better option than colectomy given the substantial risk to the mother and fetus of surgery during this time.

Tacrolimus is also a pregnancy category C drug. The earliest experience with this medication was in 1997, with a report of 27 pregnancies with exposure to tacrolimus.94 Two infants died at weeks 23 and 24, but the mean gestational period was 36.6 weeks. There was a 36% incidence of transient perinatal hyperkalemia. One newborn had unilateral polycystic renal disease. Another study from Germany reported on 100 pregnancies in transplant recipients followed from 1992 to 1998.95 There was a 68% live birth rate, 12% spontaneous abortion rate, and 3% stillbirth rate. Fifty-nine percent of the infants were premature. Malformations occurred in 4 neonates with no consistent defects. In a later single-center experience, 49 pregnancies in 37 women over 13 years were followed up prospectively.96 Thirty-six women survived the pregnancy and 2 premature babies were seen. One infant died of Alagille syndrome; the rest survived, and 78% were of normal birth weight. No other congenital abnormalities were noted. A single case report of a patient with UC who had a successful pregnancy on maintenance tacrolimus was recently published.97 No other data in IBD are published at this time.

Thalidomide

Thalidomide, a pregnancy category X drug, has some antitumor necrosis factor effects and has been used successfully for the treatment of CD.98 However, its teratogenicity has been extensively documented and includes limb defects, central nervous system effects, and abnormalities of the respiratory, cardiovascular, gastrointestinal, and genitourinary system.77 Thalidomide is contraindicated during pregnancy and in women of childbearing age who are not using 2 reliable methods of contraception for 1 month before starting therapy, during therapy, and for 1 month after stopping therapy.99

Biologic Therapy

Infliximab

Infliximab, a pregnancy category B drug, is approved for the management of CD100 and UC.101 Infliximab is an IgG1 antibody, which does not cross the placenta in the first trimester, but very efficiently crosses the placenta in the third trimester.102 While this protects the infant from exposure during the crucial period of organogenesis, infliximab levels can cross easily in the third trimester and therefore be present in the infant for several months from birth. There is a growing body of evidence that suggests infliximab is low risk in pregnancy. There were 4 early case reports in patients with CD. In 1 case the mother received infliximab during the conception period and only the first trimester, had active disease throughout, and was also on AZA, metronidazole, and mesalamine.103 The pregnancy ended in premature birth at 24 weeks and death of the infant 3 days later of intracerebral and intrapulmonary bleeding. In the 3 other cases the pregnancy ended in a live birth; 2 infants were full-term and 1 was preterm at 36 weeks, and the infants were healthy at last follow-up.104–106

The 2 largest studies are from the TREAT Registry107 and the Infliximab Safety Database108 maintained by Centocor (Malvern, PA). The TREAT Registry is a prospective registry of patients with CD. Patients may or may not have been treated with infliximab for entry. Of the 5807 patients enrolled, 66 pregnancies were reported, 36 with prior infliximab exposure. Fetal malformations did not occur in any of the pregnancies. The rates of miscarriage (11.1% versus 7.1%; P = 0.53) and neonatal complications (8.3% versus 7.1%; P = 0.78) were not significantly different between infliximab-treated and infliximab-naïve patients, respectively.

The Infliximab Safety Database is a retrospective data collection instrument. Pregnancy outcome data are available for 96 women with direct exposure to infliximab.108 This was primarily exposure during conception and the first trimester. When patients found out they were pregnant, the treatment was often stopped. The 96 pregnancies resulted in 100 births. The expected versus observed outcomes among women exposed to infliximab were not different from those of the general population. A series of 10 women with intentional maintenance infliximab use throughout pregnancy was also reported.109 All 10 pregnancies ended in live births, with no reported congenital malformations. Another series reported 22 patients with exposure to infliximab within 3 months of conception, continued until 20 weeks of gestation, at which time the drug was stopped to minimize placental transfer.110 Several of the patients did have a flare of disease in the third trimester. There were 3 spontaneous abortions, 1 missed abortion, 1 stillbirth at 36 weeks (umbilical strangulation), 2 preterm births, 3 LBW infants, and no congenital anomalies.

Infliximab crosses the placenta preferentially in the third trimester and is detectable in the infant for several months after birth. A case report noted higher than detectable infliximab levels in an infant born to a mother receiving infliximab therapy throughout pregnancy, the last one being 4 weeks before delivery.111 The mother breastfed and continued to receive infliximab but the infant's infliximab level dropped over 6 months, suggesting placental rather than breast milk transfer. The effect of the high infliximab levels on the infant's developing immune system is not known, although at 7 months the infant had appropriate responses to vaccination. In a case series of 6 patients (4 with CD, 2 with UC) receiving infliximab during pregnancy, all 6 patients delivered a healthy infant.112 The mothers were receiving infliximab 5 mg/kg every 8 weeks and the mean time between the last infusion and delivery was 64 days (range 2–120 days). The mean infliximab level at birth for the mother, the cord blood, and the infant was 9.8 mcg/mL, 10.2 mcg/mL, and 15.5 mcg/mL, respectively. It took anywhere from 2–7 months for the infant to have undetectable infliximab levels. In every instance the levels in the infant were higher than the mother at birth, supporting the fact that IgG1 antibodies are very efficiently transported across the placenta in the third trimester, but the infant reticuloendothelial system is too immature to effectively clear the antibody rapidly.

Discontinuing infliximab early in the third trimester has been considered to decrease transport across the placenta in the third trimester and thereby decrease levels in the newborn. It can then be resumed immediately after delivery. If the mother flares during this time she can receive her appropriate dose of infliximab at the normally scheduled interval, although some argue management with corticosteroids should be considered for this short period.

Adalimumab

Adalimumab, a pregnancy category B drug, is approved for induction and maintenance of remission in CD.113 Three case reports document the successful use of adalimumab to treat CD during pregnancy, including 1 in which the patient received weekly dosing throughout pregnancy for a total of 38 doses.114–116 OTIS (Organization for Teratology Information Specialists) reports 27 women enrolled in a prospective study of adalimumab in pregnancy and an additional 47 adalimumab exposed pregnant women in a registry.117 The rate of spontaneous abortion and stillbirth was similar to the diseased comparison and the general population. The rates of congenital malformation and preterm delivery are also within the expected range.

Adalimumab, an IGg1 antibody, would be expected to cross the placenta in the third trimester as infliximab does. However, given that adalimumab levels cannot be checked commercially, this has not been able to be confirmed. Also, as the drug is dosed every other week, stopping the agent early in the third trimester is difficult and leaves a considerable time in which the mother can potentially flare. Anecdotally, we consider stopping the agent 6–8 weeks before the due date. However, again, as adalimumab levels cannot be checked commercially, the benefit or harm of this to the mother or fetus is unknown.

Certolizumab

Certolizumab pegol (FDA category B) is a PEGylated Fab′ fragment of a humanized anti-TNFα monoclonal antibody. Studies have shown its efficacy for induction and maintenance of remission in CD and it was recently approved for use in CD.118, 119 A study of pregnant rats receiving a murinized IgG1 antibody of TNFα and a PEGylated Fab′ fragment of this antibody demonstrated much lower levels of drug in the infant and in breast milk with the Fab′ fragment compared to the full antibody.120 One concern, however, may be that the Fab′ fragment may cross the placenta in low levels in the first trimester as well, which the IgG1 antibody should not do. Further human data are needed to understand the implications of this on the developing fetus and in the postpartum period.

Natalizumab

Natalizumab was recently approved for induction and maintenance of remission in CD patients failing anti-TNFα therapies. This drug is pregnancy category C. There is currently a pregnancy registry in MS patients and will likely will initiated for CD. At this point one needs to consider the individual needs of the patient in order to consider the use of the therapy during pregnancy.

Fish Oil Supplements

Many patients with IBD use fish oil supplements as an adjunct to standard medical therapy. Because this is a supplement and not a drug, it is not rated by the FDA. A randomized controlled trial of fish oil supplementation demonstrated a prolongation of pregnancy without detrimental effects on the growth of the fetus or on the course of labor.121 Fish oil supplementation may also play a role in preventing miscarriage associated with the antiphospholipid antibody syndrome.122 In women with IBD who may be at increased risk for preterm birth and miscarriage, fish oil supplementation is not harmful and may be of some benefit.

PREGNANCY AND SURGERY

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Occasionally, the pregnant IBD patient may present with severe or worsening disease during pregnancy. In such cases the decision to undergo surgery becomes easy when the patient presents with a life-threatening condition such as toxic megacolon or intestinal obstruction. In nonlife-threatening clinical scenarios, optimizing the medical management is the preferred course to avoid surgery. However, one must take into account that prolonging or avoiding surgery may place both the mother and the fetus at risk. Routine nonobstetrical surgical procedures have been considered safe in the general population, with the ideal time being during the second trimester.124

Growing evidence has found that surgeries in non-IBD patients during the third trimester have also been performed without preterm delivery.125 A retrospective analysis of pregnant females undergoing surgery for UC between 1980 and 2004 revealed a total of 5 patients who underwent subtotal colectomy with Brooke ileostomy, with successful pregnancies and delivery as well as fetal outcomes.126 Multiple small case reports have now shown that third trimester colectomies for severe colitis have been successful when surgery has been combined with C-section or with later vaginal delivery.127–129 Turnbull-Blowhole colostomy used for colonic decompression and ileal diversion in 2 cases of toxic megacolon at 16 and 18 weeks gestation reported that both patients delivered healthy babies at 35 weeks gestation, with the mothers undergoing a restorative proctocolectomy and IPAA at a later date.130 Haq et al131 suggest that patients less than 28 weeks gestation undergo a Turnbull-Blowhole colostomy, but at greater than 28 weeks to undergo a synchronous C-section and subtotal colectomy if possible.

The indications for small bowel surgery in pregnant women with CD are not different from the general population, and includes intestinal obstruction or perforation, hemorrhage, or abscess. Multiple case reports of small bowel surgery for CD during pregnancy historically had revealed high mortality to both the mother and the fetus; however, more current reports reveal better outcome.132 A case series of 6 surgeries from 11–30 weeks gestation for intraperitoneal sepsis from CD reported successful deliveries of healthy infants at or near term (1 delivered at 31 weeks) in 5 cases and 1 patient had a miscarriage.133 Temporary ileostomy is generally preferred to reduce the risk of postoperative complications that can be seen after primary anastomosis. In general, concerns for fetal loss appear to be related to the severity of maternal disease and unrelated to surgery. Thus, surgery should not be avoided nor prolonged due to the patient being pregnant.

Mode of Delivery

The pregnant IBD patient may have questions concerning the optimal mode of delivery. The importance of sphincter preservation, and the potential for developing or exacerbating perineal disease in CD, is a major concern. A survey of 179 pregnant CD patients without a history of perineal disease revealed the overall risk of developing perineal involvement after vaginal delivery, typically in patients who underwent an episiotomy, was 18%.134 This study, however, may have been limited by selection and recall bias as it has not been replicated in subsequent studies. In another study, 27 of 39 CD patients without a history of perianal disease had an episiotomy at delivery. Only 1 patient, who had a third-degree laceration and an episiotomy, ultimately developed perianal disease within 1 year of postpartum follow-up. Moreover, of the 10 patients with inactive perianal disease at the time of their episiotomy, none of these patients reported a recurrence of perineal disease over a 2-year follow-up period.135 Other studies have also shown that vaginal delivery in patients with inactive perianal disease does not appear to lead to adverse outcomes.136, 137 No substantial data exist currently to recommend a C-section to IBD patients without a history of perianal disease. Moreover, C-sections may not necessarily protect against exacerbations of perineal disease or de novo development after delivery regardless of what mode. Based on limited retrospective data, women with CD and either no history of perianal disease or inactive perianal disease during pregnancy or at time of delivery can be considered for vaginal delivery. However, it would be prudent to consider a C-section in women with active perianal disease at the time of delivery to protect the integrity of the perineum and minimize trauma to the rectal sphincter. The delivery route should be determined on a case-by-case basis and should be a joint decision between the patient, the obstetrician, and the treating gastroenterologist and colorectal surgeon when appropriate.

The other group of patients in which the mode of delivery is controversial is that of pregnant women who have undergone an IPAA. In general, anal sphincter function (daytime and nighttime stool frequency or continence) may be altered during the third trimester and immediate postpartum period, but its function typically returns to baseline in most patients, usually within 3 months after delivery.138–140 Although a few patients may have long-term disturbances in anal function, it appears unrelated to the method of delivery.138 A small study of 3 patients with a history of IPAA did not demonstrate an increased risk of injury or fissuring of the anal sphincter despite vaginal delivery.140 A survey of 232 pregnant females with a history of IPAA showed no increase in pouch complications or functional problems when comparing those who underwent vaginal delivery as compared to those who had a C-section.141 Much discussion also surrounds mode of delivery in UC patients who have not yet undergone IPAA. It remains unknown as to whether vaginal delivery could impact sphincter function in a way that can compromise the success of a future IPAA. This requires further research and discussion before C-section is uniformly recommended for all UC patients. Thus, as with perianal disease, the delivery route should be determined on a case-by-case basis and should be a joint decision between the patient, the obstetrician, and the treating gastroenterologist and colorectal surgeon when appropriate.

POSTPARTUM PERIOD

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

The postpartum period (the first 3 months after delivery) brings about several shifts in hormone balance along with physical changes. In patients with autoimmune disorders and especially in those with IBD, this time period presents a potential concern for exacerbation of their disease status. According to studies in other autoimmune disorders, postpartum flare-up is common. Several theories may explain this phenomenon including the discontinuation of medications,142 resumption of smoking,142, 143 change in hormones following delivery,143 and Clostridium difficile infection.144 Also, antiinflammatory cytokines have been found to increase in pregnancy and decrease postpartum in patients with rheumatic disease based on plasma levels of IFN-γ and IL10 markers.145 This may be due to the role of estrogens, which inhibit the production of Th1 proinflammatory cytokines, such as IL-12, TNFα, and IFNγ, whereas they stimulate the production of Th2 antiinflammatory cytokines, such as IL-10, IL-4, and TGFβ.146 In IBD it is thought that the activity prior to conception will determine activity during pregnancy and the postpartum period. Survey results showed that only 13% of patients with quiescent to mild disease at term compared to 53% of patients with active disease (P < 0.001) experienced an exacerbation in the postpartum period.147 The postpartum period does not appear to constitute a time of risk for disease flare compared to the general IBD population, unless the patient has had active disease prior to and during pregnancy, or was smoking.

BREASTFEEDING

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Breastfeeding provides an ideal form of nutrition to an infant and has many benefits to both the infant and the mother. However, when the mother must take medications for an underlying medical condition, the effect of drugs that potentially are passed through the breast milk may negate the potential benefits. Thus, many women with IBD avoid breastfeeding or are advised not to by their treating physician. While the national average of women who breastfeed is 60%, only 29% of those with CD breastfeed, fearing medication effects on the infant.142 Questions have also arisen as to whether breastfeeding itself has an effect on disease activity in the nursing mother, as has been shown in other autoimmune disorders.148, 149 There have been few reports examining the influence of breastfeeding on disease activity in IBD patients. A potential theory as to the influence of breastfeeding includes the role of prolactin, which is increased during lactation and possesses certain proinflammatory properties, including upregulation of TNFα.150 Another possible factor is the discontinuation of medications. Kane et al142 studied the effect of breastfeeding on disease activity in 122 IBD patients with asymptomatic pregnancies. Overall, 32% experienced a postpartum flare and of these, 64% had a history of breastfeeding for at least 1 month prior to the onset of their flare, and the flare occurred 4 to 12 weeks into breastfeeding. The confounder, however, was that the majority (74%) of these women had stopped medications about 4 weeks prior to delivery and breastfeeding. After adjusting for medication cessation, the overall OR for development of postpartum disease exacerbation with breastfeeding was 1.3 (CI 0.8–2.7) (P not significant). When stratified for disease type, the influence of breastfeeding on UC disease activity was not statistically significant, OR 0.9 (0.34–2.5) but CD had a significant OR for disease activity of 2.1 (1.1–8.5). In general, most differences in those who developed a flare with breastfeeding could be explained by the withdrawal of their medications. Based on these limited data, there might be a slightly increased risk of disease flare in those women breastfeeding with CD; however, this study was limited by small sample size and potential recall bias. Further studies are needed to determine if there is potential harm to the nursing mother with regard to disease activity.

It has been suggested that breastfeeding is protective against the development of IBD. A meta-analysis of breastfeeding and the development of IBD reported a protective effect for CD with an OR of 0.45 (95% CI: 0.26, 0.79) and for UC with an OR of 0.56 (95% CI: 0.38, 0.81).151 The limitations to this meta-analysis were that only 8 studies were of high methodological quality and the details of breastfeeding were not always known. For example, sole breastfeeding, duration of breastfeeding (most studies use a minimum of 4 weeks), and use of supplemental/adjuvant formula feedings were not known in majority of these studies. In contrast, a subsequent study, deemed of high methodological quality, suggested that breastfeeding, partial or exclusive, was a risk factor for CD: OR 2.1 (95% CI: 1.3, 3.4, P = 0.003) based on 222 cases. Breastfeeding had no effect, however, on the risk of UC, OR 1.07 (95% CI: 0.52, 2.22, P = 0.85), based on 60 cases.152 Potential environmental contaminants in the breast milk and inappropriate immune responses from delayed infections at weaning, as well as other factors such as genetic background, duration of breastfeeding, and use of supplemental formula versus exclusive breastfeeding, will need to be further delineated.

Safety of Medications During Breastfeeding (Table 2)

Breastfeeding poses a concern for patients taking multiple mediations for their IBD. Some medications can be passed through breast milk, while others may not be absorbed by the infant. In general, the risk of breastfeeding on medications potentially harmful to the newborn must be weighed against the benefits of breastfeeding.

Table 2. Safety of Medications During Breastfeeding
MedicationRecommendations (80)
AdalimumabNo human data: probably compatible
Azathioprine/6-mercaptopurineHuman data limited, but suggest minimal transfer to the infant
BalsalazideNo human data: potential diarrhea
CertolizumabNo human data: risk unknown
CiprofloxacinLimited human data: probably compatible
CorticosteroidsCompatible
CyclosporineLimited human data: potential toxicity
Fish oil supplementsNo human data
InfliximabNo human data: probably compatible
MesalamineLimited human data: potential diarrhea
MethotrexateContraindicated
MetronidazoleLimited human data: potential toxicity
OlsalazineLimited human data: potential diarrhea
RifaximinSafety unknown
SulfasalazineLimited human data: potential diarrhea
TacrolimusLimited human data: potential toxicity
ThalidomideNo human data: potential toxicity
Mesalamine

Mesalamine, or 5 aminosalicylic acid (5-ASA), has been shown to cross into breastmilk in small quantities. The American Academy of Pediatrics advises caution in using these medications during lactation due to a case of bloody diarrhea in a breastfed infant of a mother on this medication.153, 154 However, studies show that 5-ASA levels were either found to be undetectable or at very low levels (less than 10% of the therapeutic dose) in breastmilk (0.0006–0.006 mg/kg).155–157 The acetylated 5-ASA (the inactive metabolite) has been found in higher quantities than 5-ASA, but at still negligible levels (1.24 μmol/L).155, 157 Since this metabolite is inactive, it is unlikely to cause any therapeutic effect in the infant. The American Academy of Pediatrics also advises using caution in prescribing sulfasalazine to nursing mothers based on 1 case of bloody diarrhea.154, 158 Sulfasalazine does not appear to be associated with kernicterus, as it does not seem to displace bilirubin.159 In general, mothers on a 5-ASA agent may breastfeed, although if the infant develops significant diarrhea, stopping either the medication or breastfeeding should be considered if appropriate.

Ciprofloxacin

One case report of a 24-year-old female 17 days postpartum who received 1500 mg oral dose had breast milk collected at 4-hour intervals, showed ciprofloxacin levels of 9.1, 9.1, 9.1, and 6.0 μmol/L at 4, 8, 12, and 16 hours postdose, respectively.160 Although ciprofloxacin is excreted in human milk, its use is considered compatible with breastfeeding based on AAP guidelines.154 The manufacturer's caution the use of it based on the necessity of the drug to the mother since the potential adverse events to the infant is unknown.161

Metronidazole

The AAP and manufacturer's suggest use of caution with metronidazole due to unknown effects on nursing infants.154 In a study of 12 breastfeeding patients on 400 mg TID, mean milk metronidazole concentrations of 15.5 μg/mL and hydroxymetronidazole (the active metabolite) levels of 5.7 μg/mL were found.162 Corresponding infant mean plasma levels of metronidazole and hydroxymetronidazole were in the 1.27–2.41 and 1.1–2.4 μg/mL range, respectively.162 In all infants, no serious reactions or adverse effects occurred.162, 163 Assuming a daily intake of 500 mL of milk, the maximum infant metronidazole intake was estimated to be 3.0 mg/kg/day.163

Steroids

Corticosteroids minimally cross into breast milk,155, 164 with concentrations in breastmilk being 5%–25% of that found in maternal serum.165 Ost et al165 demonstrated that even at 80 mg of prednisolone per day, the newborn dose ingested is 0.1% of the mother's dose. It has been suggested avoiding breastfeeding during the first 4 hours after maternal ingestion to minimize exposure.165 The AAP considers steroids compatible with breastfeeding since no adverse events have been reported in infants.

AZA/6MP

The World Health Organization (WHO) recommends against breastfeeding. The controversy in the use of immunomodulators such as AZA/6MP has been due to concerns of infant bone marrow suppression, immunosuppression, hepatitis, and pancreatitis. The concentrations of AZA and its metabolite in breast milk, however, were found to be much lower than plasma concentrations based on studies in renal transplant166 and IBD patients.167 The more recent small studies in IBD suggest that the overall exposure to the infant is low. Moretti et al168 reported 4 women breastfeeding on AZA. In 2 women, multiple breast milk samples did not have detectable levels of drug by high-performance liquid chromatography, and none of the 4 infants had any complications. Two other studies measured metabolite levels in the breastfeeding infant. Gardiner et al169 reported 4 infants with undetectable metabolite levels despite mothers whose levels were in the therapeutic range. Sau et al170 collected 31 samples from 10 breastfeeding women on AZA/6MP. Only 2 samples had low levels of 6MP in breast milk (1.2 and 7.6 ng/mL in 1 patient versus a serum level of 50 ng/mL). There was no detectable 6TGN or 6MMP levels in the 10 infants, nor were there signs of hematologic or clinical immunosuppression. Overall, these 3 studies suggest that transfer of drug to the breastfeeding infant is minimal. The risks and benefits of breastfeeding must be considered carefully, however, and at this time there does not appear to be an absolute contraindication to breastfeeding.

Infliximab

Treatment with infliximab during pregnancy can result in a potential risk of immunosuppression to the newborn. A case report of a 32-year-old mother treated with infliximab throughout pregnancy for treatment-refractory CD reported undetectable infliximab levels in breast milk.111 The mother continued breastfeeding while on maintenance infliximab, and serial measurements of infant serum infliximab levels showed slow declining infliximab levels in the infant's serum. This study suggested that the serum levels at birth were explained by placental transfer and not by breastfeeding and that the half-life may be prolonged in infants.

Adalimumab and Certolizumab

There have been no known reports to date for adalimumab use during lactation. Since it is unknown whether adalimumab is excreted in human milk or absorbed systemically after ingestion, and whether potential adverse reactions can occur in the nursing infants, the use of the drug during nursing depends on the importance of the drug to the mother.161 In general, the drug is continued during breastfeeding. Adalimumab levels have not been available to measure in breast milk. Certolizumab was only recently released commercially, so data are not available.

Cyclosporine

Cyclosporine is found in breast milk based on a study of 5 mothers and infants. One infant had therapeutic levels of cyclosporine while the remainder had either low subtherapeutic or undetectable levels. No infants suffered any side effects from the medication, although nursing was stopped in the infant with the therapeutic level.171 Cyclosporine is contraindicated during breastfeeding by the AAP due to possible immune suppression and unknown effects on growth or association with carcinogenesis.154, 161

Methotrexate

Methotrexate (MTX) is excreted into breast milk in low concentrations, less than 10% of those in plasma.172 Although the effects of this low level of the drug to the infant is unknown, and the potential for long-term accumulation in the infant, it is recommended that methotrexate be avoided during breastfeeding. It is not known whether these small amounts are potentially harmful to the developing child. Due to an absence of evidence, and because there is a danger of accumulation within fetal tissues with possible immune suppression, neutropenia, and unknown effects on growth or carcinogenesis, the AAP suggests avoidance of MTX during breast feeding.154

EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

The short- and long-term implications of placental and postnatal exposure via lactation to babies born to mothers treated with immunomodulators such as 6MP/AZA or anti-TNFα therapies is relatively unknown and has become an important area of investigation. In theory, exposure is 1 element but it is also important to understand the effect of measurable serum levels of these therapies in newborns and how this potentially impacts the maturing immune system. More recent studies have shown that infliximab levels are measurable in the cord blood and out to 6 months from birth in infants born to mothers receiving infliximab throughout pregnancy including the last trimester.111, 112 Thiopurine levels have also been detected in cord blood as well as the serum of newborns.112 Unlike infliximab, which is an IgG1 subtype and can take up to 6 months to clear, given the long half-life of IgG, the clearance of thiopurines is likely more efficient in newborns but it is unknown how long the immunosuppressive effects remain even if cleared from the serum. This unknown duration of effect would apply for both thiopurines and anti-TNFα therapies. As described above, infliximab has not been measurable in breast milk and it appears that thiopurine levels are undetectable in breastfed infants and thiopurine use is no longer considered an absolute contraindication to breastfeeding in the obstetrical literature.168–170 That being said, it still remains controversial among the gastroenterology community as to whether breastfeeding on thiopurines poses an immunosuppressive risk to infants. Additionally, it remains unknown as to whether the same immune benefit to the infant can be derived from receiving breastmilk from an immunosuppressed mother.

Part of the concern stems from animal model studies that suggest that TNFα is necessary in utero and in the postnatal period for the effective development of the humoral immune system.173 In a small case series, babies exposed to infliximab in utero and via breastfeeding were able to mount an age-appropriate protective immune response to the routine vaccinations.111, 174 A more recent study showed that in utero and postnatal exposure to pegylated golimumab had no effect on T and B cell populations in blood and lymphoid tissues of macaque monkeys and did not impair the ability of the infants to mount an immune response to antigen challenge.175 Similar results applied to golimumab use during lactation.175 Although the animal studies look promising and our preliminary human data supports these findings, further human studies are indeed necessary to help understand how in utero and postnatal exposure impacts vaccination administration. The killed vaccines such as hemophilus influenza type B, tetanus, diphtheria, pertussis, and hepatitis B can be recommended to all infants irrespective of exposures during pregnancy and lactation. The authors recommended that at 7 months of age newborns exposed to anti-TNFα and quite possibly thiopurines in utero should have serological confirmation of mounting a immune response to the killed vaccines. Titers of antibodies to tetanus toxoid and hemophilus influenza type B can be tested and if undetectable the infant should receive a booster shot to confer protection.

The live vaccines, however, as is the case in all patients with IBD receiving immunosuppressive therapies, could present a problem for infants exposed in utero and during lactation. The rotavirus vaccine is the only live vaccine that is now recommended for infants below the age of 12 months. Although the preliminary data support normal immune responses, until we have more information as to the effects of anti-TNFα and thiopurine exposure in utero and during lactation on the maturing immune system, administration of the rotavirus vaccine may not be prudent. This must be balanced with the risk of rotavirus to infants, for example, in the face of specific high-risk factors such as socioeconomic status, attendance at daycare, and exposure to sibs. The next set of live vaccinations, Varicella and Measles, Mumps and Rubella (MMR) vaccine are to be administered at 12 months of age. It is highly unlikely that the infant would have any remnant effects of placentally transferred anti-TNFα therapies. Until further confirmation as to the lack of measurable thiopurine levels in the face of breastfeeding is available, it is conceivable that infants should not be exposed to thiopurines via breast milk for at least 6 weeks before receiving live vaccinations. This area requires further investigation before strict guidelines can be put into place. Both thiopurine and infliximab levels can be monitored in the newborn and young infant and physicians may want to consider monitoring drug levels to confirm clearance of these immunosuppressants from the serum before the administration of live vaccines. In addition, the mother on immunosuppressant and biologic agents should take care in handling the body fluids of the infant who recently received a live virus vaccine.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES

Advances in therapies for IBD patients have afforded more women the opportunity to conceive and successfully carry out a full-term pregnancy. As discussed in this review, there are many issues to consider when preparing a woman for pregnancy and for optimizing the gestational period. The key to both a successful conception and pregnancy is the need to maintain the disease in a quiescent state. The majority of the medications used to treat active and quiescent IBD are felt to be low risk during pregnancy and the emphasis must be placed on maintaining the health of the mother, which should then result in a healthy newborn. However, even a mother with inactive disease is at increased risk for pregnancy complications and therefore should be followed as high risk. There also remain some unanswered questions as to the effect of immunomodulatory medications on the developing fetal immune system. Further research is needed to delineate these issues. Registry studies, however, are under way to answer some of these very important questions with regard to the pregnant patient.

REFERENCES

  1. Top of page
  2. Abstract
  3. INHERITANCE OF IBD
  4. FERTILITY
  5. DISEASE ACTIVITY
  6. PREGNANCY OUTCOMES
  7. MEDICATIONS
  8. PREGNANCY AND SURGERY
  9. POSTPARTUM PERIOD
  10. BREASTFEEDING
  11. EFFECTS OF IN UTERO AND POSTNATAL EXPOSURE OF IMMUNOMODULATORS ON THE NEWBORN
  12. CONCLUSIONS
  13. REFERENCES
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