For many women with inflammatory bowel disease (IBD), the illness coincides with their childbearing years. IBD increases the risk of pregnancy complications and adverse pregnancy outcomes. The multidisciplinary care team should emphasize the importance of medication adherence to achieve preconception disease control and maintain corticosteroid-free remission throughout pregnancy. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease; however, any benefits of such adjustments remain theoretic and there is risk of worsening disease activity. Mode of delivery is determined by obstetric indications, except for women with active perianal disease who should consider cesarean delivery.
Key points
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Inflammatory bowel disease increases the risk of pregnancy complications and adverse pregnancy outcomes. Active disease exacerbates these risks. Universal high-risk obstetric monitoring is recommended.
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Active disease and pelvic surgery reduce female fertility. Fertility is preserved with quiescent disease. Patient misperceptions about fertility, disease risks, and medication safety contribute to voluntary childlessness.
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Most medications have a favorable safety profile for use during pregnancy and breastfeeding to induce and maintain remission. This includes the aminosalicylates, thiopurines, and biologics.
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There are potential fetal risks with intrauterine exposure to corticosteroids, certain antibiotics, methotrexate, and thiopurine-biologic combination therapy. Risk/benefit assessments should be individualized.
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Patients should be counseled about the importance of medication adherence to optimize preconception disease control and maintain remission throughout pregnancy.
Introduction
Inflammatory bowel disease (IBD) incidence peaks during the years of childbearing potential, with half of patients diagnosed before age 32. By nature of this age distribution at IBD onset, the complexities of family planning and IBD management often coincide. Although most IBD patients have successful pregnancies, women with IBD have fewer children than the general population because of voluntary childlessness. Apprehension and misperceptions about fertility, medication safety, and the potential for adverse pregnancy outcomes may explain this phenomenon. There is ample opportunity for knowledgeable providers to positively impact IBD pregnancy outcomes by optimizing disease control, mitigating medication-related risks, and enhancing patient education.
Introduction
Inflammatory bowel disease (IBD) incidence peaks during the years of childbearing potential, with half of patients diagnosed before age 32. By nature of this age distribution at IBD onset, the complexities of family planning and IBD management often coincide. Although most IBD patients have successful pregnancies, women with IBD have fewer children than the general population because of voluntary childlessness. Apprehension and misperceptions about fertility, medication safety, and the potential for adverse pregnancy outcomes may explain this phenomenon. There is ample opportunity for knowledgeable providers to positively impact IBD pregnancy outcomes by optimizing disease control, mitigating medication-related risks, and enhancing patient education.
Fertility
Women
Fear of infertility is common among patients with IBD and may adversely impact family planning decisions. In reality, women with quiescent IBD and no prior pelvic surgery have similar infertility rates (5%–14%) as the general population. Active disease does impair fertility, likely via multifactorial mechanisms, such as pelvic inflammation, poor nutrition, decreased libido, dyspareunia, and depression. A small study demonstrated decreased ovarian reserve in women with Crohn disease, especially those with active disease. Pelvic surgery significantly increases female infertility due to scarring and adhesions. A meta-analysis of ileal pouch anal anastomosis (IPAA) surgery in ulcerative colitis found a 48% postoperative infertility rate, threefold higher than the 15% rate in medically treated patients. Laparoscopic total proctocolectomy with IPAA may preserve fertility compared with open surgery. Abdominal surgeries that spare the pelvis, such as colectomy with ileorectal anastomosis, may also preserve female fertility. Women of childbearing potential should be counseled before surgery about the infertility risk of IPAA, and less invasive procedures may be considered. However, given the retrospective nature of the studies and older techniques, true rates of infertility following IPAA are not known. IPAA does not appear to impact success rates of in vitro fertilization.
Women who experience difficulty conceiving or spontaneous abortion should be assessed for occult disease activity, hypovitaminosis D, and celiac disease, all of which are associated with infertility. If women remain unable to conceive after 6 months of calculated attempts, reproductive endocrinology referral is warranted.
Men
Less is known about male fertility in IBD. Zinc deficiency in Crohn disease may impair sperm function. Certain medications have been shown to affect sperm quantity and quality. Sulfasalazine causes reversible infertility due to dose-dependent oligospermia, reduced sperm motility, and altered sperm morphology. Methotrexate may reduce sperm quality, although any such effects are reversible when the drug is discontinued. Some experts recommend that men stop methotrexate at least 3 months before attempting conception. Antitumor necrosis factor α (anti-TNF) medications may accelerate germ cell apoptosis in the seminiferous tubules, which might theoretically decrease sperm count. However, a small study of 10 men did not find a decrement in sperm concentration following infliximab infusion. It remains unknown whether medication-induced changes in sperm quality have any effect on fertility, and additional research is needed.
Complications
The interaction between IBD and pregnancy is bidirectional: IBD impacts pregnancy, and pregnancy may impact IBD. A robust comprehension of this interplay provides the framework for patient education and development of an individualized treatment strategy to mitigate risks.
Inflammatory Bowel Disease Detrimentally Impacts Pregnancy
Women with IBD, including those in remission, experience a higher rate of adverse pregnancy outcomes than the general population. A recent meta-analysis including 15,007 women with IBD found increased odds of preterm birth (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.67–2.05), small for gestational age infants (OR 1.36, 95% CI 1.16–1.60), and still birth (OR 1.57, 95% CI 1.03–2.38). The risk of congenital anomalies was also increased (OR 1.29, 95% CI 1.05–1.58), although there was evidence of publication bias. Multiple recent population-based studies failed to detect an increased risk of congenital anomalies in IBD pregnancies. IBD is associated with higher rates of pregnancy complications, such as preeclampsia, preterm premature rupture of membranes, and venous thromboembolism. Inadequate maternal weight gain has been identified as a predictor of adverse outcomes. Additional hypothesized mediators of increased risk include inflammation, anemia, hypoalbuminemia, poor nutrition, and medication exposures. Based on these findings, all IBD pregnancies should be monitored by a maternal-fetal medicine specialist. Serial ultrasonography should be considered in the third trimester to assess fetal growth.
Active disease further compounds risk
Disease activity is the strongest predictor of adverse pregnancy outcomes. Active disease at conception increases the risk of spontaneous abortion and preterm birth, whereas disease exacerbation during pregnancy increases the risk of preterm birth, still birth, and low birth weight. The risk of low birth weight doubles with an ulcerative colitis flare and triples with a Crohn flare. These observations emphasize the critical importance of maintaining remission throughout pregnancy, beginning in the preconception period.
Quiescent disease reduces risk
When patients conceive during IBD remission and maintain quiescent disease throughout pregnancy, the risks of preterm birth and low birth weight are similar to matched non-IBD controls. We recommend that women achieve and sustain remission for at least 3 to 6 months before conception to maximize the chances of a successful and healthy pregnancy.
Pregnancy May Impact Inflammatory Bowel Disease
It remains uncertain whether pregnancy itself adversely affects the course of IBD. Among women in remission at conception, the risk of subsequent disease exacerbation during pregnancy is 20% in Crohn disease and 33% in ulcerative colitis. The ongoing prospective, multicenter Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry of more than 1475 pregnant women with IBD also found a higher rate of ulcerative colitis activity relative to Crohn activity. Overlapping immune pathways, such as placental production of proinflammatory cytokines, have been hypothesized as a potential explanation for this finding. Alternatively, this may reflect less aggressive ulcerative colitis treatment, as most of these patients were on mesalamine monotherapy. A meta-analysis of 1720 patients with IBD found that disease activity during pregnancy strongly correlates with disease activity at the time of conception. Active disease affected 46% to 55% of pregnancies commenced during active disease, compared with 23% to 29% of pregnancies conceived during remission. Overall, IBD relapse rates during pregnancy are similar to rates for nonpregnant women.
Disease behavior during pregnancy and the postpartum period is likely confounded by the frequent and inappropriate discontinuation of maintenance medications, which increases the risk of flare. Providers must educate patients about the risk of disease to the pregnancy and the importance of medication adherence to optimize preconception disease control and maintain remission throughout pregnancy.
Mode of delivery
The mode of delivery in IBD pregnancies is largely determined by obstetric indications and patient preference. Cesarean delivery is more common among women with IBD compared with the general population. For example, 44% of women in the PIANO registry delivered via cesarean, often for elective reasons. Theoretic concerns that vaginal delivery might trigger perianal disease are not supported by a recent cohort study, which found no association between mode of delivery and IBD natural history. Cesarean delivery is typically recommended for women with active perianal disease, though evidence conflicts regarding the trajectory of active perianal disease following vaginal delivery. Some colorectal surgeons also recommend cesarean delivery following IPAA to protect the pouch and preserve anal sphincter integrity. However, a systemic review found no increased risk of pouch dysfunction with vaginal delivery. Finally, the mode of delivery does not appear to be a factor in the risk of childhood IBD. Rather, heritability studies estimate that a child has a 2% to 5% chance of developing IBD if a single parent has the disease and a 36% chance when both parents have IBD.
Treatment
Before initiating IBD therapy in a woman of childbearing age, the patient’s desire and timeline for pregnancy should be discussed. Preconception counseling about the low risk of most medications may improve medication adherence during pregnancy. As a general rule, active disease poses a greater risk to the fetus than IBD therapies. This principle forms the basis for IBD treatment decisions in pregnancy.
Medications
With the exception of methotrexate and thalidomide, most medications used to treat IBD are considered low risk and may be continued during pregnancy and breastfeeding ( Table 1 ). Of note, the US Food and Drug Administration recently implemented a revised medication labeling rule that removes the previously used pregnancy categories (A, B, C, D, X). We will not reference the pregnancy categories in the following discussion.
| Medication | Pregnancy Safety | Breastfeeding Safety |
|---|---|---|
| Aminosalicylates | ||
| Balsalazide | Low risk | Compatible; enters breast milk Potential risk of infantile diarrhea |
| Mesalamine | Low risk Dibutyl phthalate coating in Asacol HD may be teratogenic in animals | Compatible; enters breast milk Potential risk of infantile diarrhea |
| Olsalazine | Low risk | Compatible; enters breast milk Potential risk of infantile diarrhea |
| Sulfasalazine | Low risk; give with folic acid 2 mg daily Reversible oligospermia in men | Compatible; enters breast milk Potential risk of infantile diarrhea |
| Immunomodulators | ||
| Cyclosporine | Limited data; possible risk of pregnancy complications, preterm birth, low birthweight | Contraindicated; enters breast milk |
| Methotrexate | Contraindicated: teratogenic, abortifacient Supplement with folic acid Discontinue 3–6 mo before conception | Contraindicated; enters breast milk |
| Thiopurines (azathioprine, 6-mercaptopurine) | Low risk in monotherapy Delayed infant infections in combination therapy | Compatible; clinically insignificant concentration enters breast milk Wait 4 h after ingestion if able |
| Tofacitinib | Limited human data | Unknown; no human data |
| Biologics | ||
| Adalimumab | Low risk in monotherapy | Compatible; clinically insignificant concentration enters breast milk |
| Certolizumab pegol | Low risk Does not actively cross placenta | Compatible; clinically insignificant concentration enters breast milk |
| Golimumab | Low risk in monotherapy | Compatible; undetectable |
| Infliximab | Low risk in monotherapy | Compatible; clinically insignificant concentration enters breast milk |
| Natalizumab | Low risk in monotherapy | Compatible; undetectable |
| Ustekinumab | Limited human data | Likely compatible; limited human data |
| Vedolizumab | Low risk in monotherapy; limited data | Likely compatible; no human data |
| Corticosteroids | ||
| Budesonide | Low risk | Compatible; clinically insignificant concentration enters breast milk |
| Prednisone | Moderate risk; possible orofacial cleft (first trimester exposure), adrenal insufficiency, gestational diabetes, premature rupture of membranes, preterm birth, infant infections | Compatible; clinically insignificant concentration enters breast milk |
| Antibiotics | ||
| Amoxicillin with clavulanic acid | Low risk; preferred antibiotic during pregnancy | Compatible; enters breast milk |
| Ciprofloxacin | Low risk; affinity for cartilage | Compatible; enters breast milk |
| Metronidazole | Low risk; avoid in first trimester due to possible risk of orofacial clefts | Contraindicated; enters breast milk |
Corticosteroids
Corticosteroid safety is discussed later in this article in the context of IBD exacerbations.
Aminosalicylates
The 5-aminosalicylates (balsalazide, mesalamine, olsalazine, and sulfasalazine) are considered safe in pregnancy. The coating of delayed release mesalamine in Asacol HD (Actavis) contains dibutyl phthalate (DBP), which has been associated with congenital anomalies in animals at doses more than 190 times the therapeutic human dose. All agents aside from Asacol HD do not have DBP in their coating, and multiple human studies have failed to identify mesalamine teratogenicity. Women taking sulfasalazine should receive supplemental folic acid 2 mg daily to prevent folate deficiency. Aminosalicylates enter breast milk but are considered compatible with use during breastfeeding. There is a rare association with diarrhea in the infant, which resolves on breastfeeding cessation. Mesalamine enemas and suppositories may be continued without any known pregnancy risk.
Immunomodulators
Methotrexate
Methotrexate is an abortifacient, teratogenic inhibitor of DNA synthesis and is contraindicated during conception and pregnancy. Women should not attempt conception within 3 to 6 months of methotrexate use due to the drug’s long half-life. Although there are limited data pertaining to the lower doses commonly used to modulate the immunogenicity of biologic medications, it is recommended that methotrexate be given only to those women of childbearing potential who practice 1 to 2 methods of contraception and take supplemental folic acid. Methotrexate is also contraindicated in breastfeeding. Although it is excreted in breast milk at levels below 10% of maternal plasma concentration, the long half-life allows accumulation in neonatal tissue.
Thiopurines
Like methotrexate, the thiopurines (azathioprine and 6-mercaptopurine) inhibit DNA synthesis. High doses are teratogenic in animals. The metabolite 6-thioguanine crosses the human placenta and has been associated with newborn anemia. However, most studies of thiopurine safety during pregnancy are confounded by unmeasured disease activity. Nearly 25% of women in a recent study discontinued thiopurines early in pregnancy, highlighting the uncertainty surrounding thiopurine management during pregnancy.
Recent large studies of thiopurine-exposed pregnancies failed to detect an elevated risk of congenital anomalies. A population-based study that attempted to account for disease activity found that thiopurine exposure increased the risk of preterm delivery irrespective of disease activity. Conversely, a multicenter study comparing the disease activity and outcomes of pregnant women treated with thiopurines, anti–tumor necrosis factor (TNF) drugs, or neither medication class found no difference in pregnancy complications among the groups. In multivariate analysis, thiopurine treatment was actually associated with favorable global pregnancy outcome. Two meta-analyses found that thiopurine use was associated with preterm delivery (relative risk [RR] 1.67; 95% CI 1.2–2.4), but disease activity was not directly assessed in any of the included studies. The risk of congenital anomalies was increased compared with healthy women (RR 1.45; 95% CI 1.07–1.96), but there was no difference compared with unexposed IBD controls.
Among more than 335 thiopurine-exposed pregnancies in the PIANO registry, there is no heightened risk of congenital anomalies or pregnancy complications. After adjusting for disease activity, thiopurine-exposed infants have equivalent or better achievement of developmental milestones compared with unexposed infants. However, infections at 9 to 12 months of age were more common among the 107 infants exposed to thiopurine plus anti-TNF combination therapy (RR 1.50; 95% CI 1.08–2.09).
It is reasonable to continue thiopurine monotherapy during pregnancy to maintain remission, as the risks of active disease likely outweigh the risks associated with thiopurine use. Due to the potential for delayed infant infections, a woman in durable remission using a thiopurine in combination with a biologic may consider stopping the thiopurine before conception. Thiopurines generally should not be initiated during pregnancy due to their slow onset of action and the risks of bone marrow suppression and pancreatitis.
Clinically insignificant thiopurine concentrations in breast milk peak within 4 hours of maternal ingestion. Lactating mothers might consider breastfeeding avoidance during this interval.
Biologics
Anti–tumor necrosis factor agents
Of the 4 anti-TNF medications approved for IBD, infliximab and adalimumab provide most pregnancy safety information. Although mainly limited to case series, available data on the anti-TNF class suggest low risk for use during pregnancy. However, the long-term implications of intrauterine exposure remain unknown, especially with respect to immune system development and function.
Series with more than 100 IBD pregnancies each exposed to infliximab, adalimumab, and certolizumab pegol found no adverse effect on pregnancy outcomes. Golimumab is predicted to have a similar safety profile. More than 500 women in the PIANO registry have been exposed to anti-TNF medications during pregnancy: more than 260 infliximab, more than 150 adalimumab, more than 65 certolizumab pegol, and 29 multiple agents. There is no increased risk of congenital anomalies compared with the unexposed IBD cohort. A systematic review including more than 1500 anti-TNF exposed pregnancies found no pattern of adverse pregnancy outcomes or congenital anomalies. A recent meta-analysis showed a similar rate of unfavorable pregnancy outcomes between women taking anti-TNF therapy and unexposed controls (OR 1.00; 95% CI 0.72–1.41), including preterm delivery (OR 1.00; 95% CI 0.62–1.62), low birth weight (OR 1.05; 95% CI 0.62–1.78), and congenital anomalies (OR 1.10; 95% CI 0.58–2.09).
Combination therapy with an anti-TNF and thiopurine may be associated with a higher risk of preterm birth (OR 2.4; 95% CI 1.3–4.3) and any pregnancy complication (OR 1.7; 95% CI 1.0–2.2), in addition to the risk of delayed infant infections described previously.
There is clinically insignificant anti-TNF excretion into breast milk, with milk concentrations less than 1% of maternal plasma concentrations. Furthermore, antibodies ingested orally are unlikely to be bioavailable. In the PIANO registry, breastfed infants exposed to anti-TNF monoclonal antibodies have similar rates of growth and milestone achievement compared with unexposed breastfed infants, with no increased risk of infection.
Transplacental drug transfer
Monoclonal immunoglobulin G1 (IgG1) medications (infliximab, adalimumab, golimumab) are actively transported across the placenta along with other maternal antibodies, beginning in the second trimester. Fetal IgG1 concentrations increase logarithmically, with 80% of transfer occurring in the third trimester. Cord blood infliximab and adalimumab concentrations at birth exceed maternal levels by up to fourfold, and these agents remain detectable in infants for up to 12 months. This raises concern about potential adverse effects on neonatal immune system development. In the PIANO registry, third trimester anti-TNF exposure did not detrimentally affect infant growth rate, immune development, number of infections, or achievement of developmental milestones. A small study of 25 anti-TNF exposed children reported appropriate serologic response to vaccination and normal cellular immunity.
Until the implications of intrauterine anti-TNF exposure are better understood, it is reasonable for women in sustained remission to consider third trimester dosing adjustments to reduce neonatal exposure ( Table 2 ). Therapeutic drug monitoring with trough serum concentrations in the late second or early third trimester may also help guide dosing before delivery. However, any decision to alter medication dosing schedule should be individualized and balanced against the risks, which include triggering active disease or maternal immunization with diminished future drug effectiveness.
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