Proper care should begin well before pregnancy with preconception counseling and stabilization of disease. Preconception counseling allows clinicians to address specific patient concerns, optimize control of disease activity and minimize chance of relapse during pregnancy, avoid inappropriate medication cessation, and discontinue medications that may adversely affect pregnancy [2]. Women with IBD have a higher rate of voluntary childlessness, possibly due to misinformation regarding fertility, medications, and their effects on the fetus, and concerns regarding passing the disease on to their children [3].

Women with IBD have the same rate of fertility as age-matched controls [4]. However, women with active disease or with prior surgery in the pelvis have impaired fertility. Infertility is increased with active disease due to inflammation involving the fallopian tubes or ovaries, dyspareunia related to perianal disease, decreased libido, and depression [5–7]. Women with Crohn’s disease may also have decreased ovarian reserve [8]. Among women with inactive disease, surgery in the pelvis, particularly an ileal pouch anal anastomosis (IPAA) , increases infertility threefold [9]. Pelvic scarring and surgical adhesions may lead to tubal infertility [10]. This reduction in fertility is also seen in patients who undergo IPAA for familial adenomatous polyposis syndrome, a noninflammatory condition. Procedures that do not invade the pelvis and result in fewer abdominal and pelvic adhesions, such as ileo-rectal anastomosis (IRA) and laparoscopic surgery, do not appear to impair fertility [11]. These less invasive procedures may be preferable in female children, adolescents, and women who require surgery but wish to preserve fertility.

Before attempting conception, women should be up to date on health care maintenance, vaccinations (hepatitis A and B, pneumococcal, influenza, tetanus/diphtheria/pertussis, and Human Papilloma Virus), and age-appropriate cancer screening [12]. Routine laboratory testing including complete blood count, vitamin B12, folic acid , and iron levels, should be performed. Patients who are having difficulty conceiving or have had previous miscarriages should be screened for vitamin D deficiency and celiac disease, which have been associated with infertility [13, 14].

IBD should be well controlled at the time of conception, and women should be in a durable remission for at least 6 months before attempting conception. The presence of disease activity is associated with reduced ability to conceive, greater chance of disease activity during pregnancy, and increased risk of adverse pregnancy outcomes, including spontaneous abortion, preterm birth, and low birth weight. A large Swedish cohort study of births among 2500 women with IBD reported an increased risk of preterm birth for both UC (aOR 1.78; 95 % CI 1.49–2.13) and Crohn’s disease (aOR 1.65; 95 % CI 1.3–2.06), and the risk was greater with increasing disease activity [15]. The risk of low birth weight was also increased in both UC and Crohn’s disease. For women with disease flare, the risk of low birth weight was doubled in UC and tripled in Crohn’s disease. Small for gestational age (SGA) infants, low Apgar score, and stillbirth were also more common in women with IBD, and risk was greater with increased disease activity.

Given this data, women and their physicians should have a treatment plan in place before, during, and after pregnancy in order to improve compliance and outcomes [2]. The greatest risk of flare occurs when women discontinue medications [16]. Preconception counseling and education regarding the low risk of most medications used to treat IBD and the high risk of significant flare during pregnancy is important in improving compliance and relieving anxiety during pregnancy. Preconception counseling should also include a discussion of appropriate and effective contraceptive use. Women with IBD use contraception at a lower rate than the general population, and a quarter of women with IBD at risk for unintended pregnancy do not use contraception [17].

Pregnant women with IBD have the same risk of flare as nonpregnant IBD patients, but disease activity at time of conception affects the risk of flare during pregnancy [18]. Among women with active UC at the time of conception, 45 % will have worsening flare during pregnancy, 24 % will have stable active disease, and 25 % will improve [19]. Among women with active Crohn’s disease at the time of conception, one third will have worsening flare, one third will have stable active disease, and one third will achieve remission. Risk of flare is not increased in the postpartum period, except if medication is discontinued [16]. The Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry is an ongoing multicenter national prospective study of pregnancy and neonatal outcomes in women with IBD and their offspring in the United States. The registry records mother’s medication exposure, IBD history and disease activity, and pregnancy and postpartum complications. The PIANO registry and the European Crohn-Colitis Organization (ECCO) Study Group of Epidemiology Committee (EpiCom) study found a significantly higher rate of disease activity among women with UC compared with Crohn’s disease [20, 21]. This difference may be related to secretion by the placenta of pro-inflammatory cytokines associated with UC or under treatment of UC patients during pregnancy [22].

Pregnant women with IBD are at increased risk of complications , including miscarriage, preterm birth, SGA infants, and complications of labor and delivery compared to age match controls [23]. A 2007 cohort study in Northern California found increased rates of spontaneous abortion and pregnancy complications, including eclampsia/preeclampsia, placental abruption, fetal distress, placenta previa, and prolonged/premature rupture of membranes compared to healthy age-matched controls regardless of disease activity, though the majority of patients had mild to inactive disease [24]. In contrast, a prospective study by ECCO found no significant difference in frequency of preterm birth, cesarean section, birth weight, or abortions among women with IBD compared to age-matched controls [25]. However, 87 % of IBD patients in this study were in remission at conception and 86 % maintained quiescent disease throughout pregnancy. Additionally, inadequate weight gain during pregnancy is associated with adverse pregnancy outcomes including preterm birth, SGA infants and fetal growth restriction, and disease activity correlates with reduced weight gain [26]. Therefore, pregnant women with IBD should be followed by maternal fetal medicine specialists or obstetricians experienced with complicated pregnancies.

If a woman develops a disease flare during pregnancy, the evaluation and management are similar to nonpregnant patients except for a few important considerations unique to pregnancy. Laboratory testing may be difficult to interpret, as low albumin and hemoglobin, and elevated erythrocyte sedimentation rate and alkaline phosphatase are common in pregnancy. Women with IBD in the peripartum period are at increased risk of clostridium difficile infection, and stool studies should be obtained to rule out infection in patients with diarrhea [27]. If imaging is required, magnetic resonance imaging is preferable to computerized tomography scan to avoid radiation exposure to the fetus. Gadolinium should be avoided in the first trimester due to potential teratogenicity [28]. Endoscopic evaluation can be performed safely with an unsedated flexible sigmoidoscopy. If a full colonoscopy is required, it should be performed with anesthesia and fetal monitoring when appropriate. The indications for surgery in a pregnant patient are the same as in the nonpregnant patient and include severe bleeding, medically refractory disease, perforation, or obstruction. Non-emergent but necessary operations should ideally be performed during the second trimester [29].

Large population-based studies have shown that women with IBD have a 1.5–2 times the rate of cesarean delivery. In the PIANO registry, 44 % of women had a cesarean section, mainly for elective reasons [30]. The greater frequency of cesarean delivery is likely due to the concern of patients and providers for complications such as anal sphincter damage, worsening perianal disease, or pouch dysfunction in patients with IPAA [31, 32]. However, large studies have shown that vaginal delivery with inactive perianal disease does not lead to worsening disease [33]. Two recent studies found no increased risk in symptomatic perianal flares in women with perianal Crohn’s disease who delivered vaginally or by cesarean section [34, 35]. Mode of delivery also did not influence the natural history of IBD. However, patients with active perianal disease at the time of delivery should have a cesarean section to avoid trauma that may exacerbate the disease. Some surgeons recommend cesarean section for women with an IPAA in order to avoid anal sphincter damage and preserve continence. However, vaginal delivery does not appear to significantly alter pouch function [36]. An ileostomy should not be oversewn during a cesarean section. Most women can be safely considered for a vaginal delivery. However, cesarean section should not be unnecessarily delayed if labor is prolonged, as uncontrolled tears and forceps delivery can affect pelvic floor function and substantially impact future bowel habits [37]. In general, decision regarding mode of delivery should be based on obstetric indications, and made on an individual basis with discussion of the risks and benefits.

Women who have a medication plan before conception are more likely to adhere to recommended therapies [16]. Discontinuation of medications can lead to active disease flare, which is a greater risk to the pregnancy than any potential adverse medication effects. In general, most medications used to treat IBD, with the exception of methotrexate, are considered low risk and can be continued during pregnancy and breastfeeding. In 2015, the Federal Drug Administration (FDA) implemented a new rule that removed the previously used pregnancy risk categories A, B, C, D, and X from human prescription drug labeling. New labeling will require a summary of the risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation [38]. Here we will briefly discuss pregnancy specific concerns with common IBD medications (Table 57.2).

Methotrexate (MTX) is an abortifacient and is contraindicated during conception and pregnancy. When taken during organogenesis, it can cause congenital anomalies [39]. Pregnancy should be avoided if either the woman or her partner is receiving MTX. Because it is a folate antagonist, MTX should always be taken with folic acid supplementation. MTX should be discontinued for a minimum of 3 months for males and for at least 3–6 months for females prior to conception. MTX is excreted in breast milk and can accumulate in neonatal tissue and interfere with cellular metabolism. It is contraindicated in breastfeeding [40].

Ciprofloxacin and metronidazole are the two antibiotics used most commonly in management of IBD. A prospective study of women exposed to fluoroquinolones during pregnancy showed a low risk of clinically significant major musculoskeletal abnormalities or birth defects [41]. However, it has a high affinity for cartilage and has been associated with arthropathy in animals and human case reports. Ciprofloxacin is excreted in breast milk, but the American Academy of Pediatrics considers it compatible with breastfeeding.

A case–control study of 17,300 women exposed to metronidazole showed that exposure during the first trimester was associated with a small increased incidence of cleft lip and palate [42]. Animal studies have also shown teratogenicity. Therefore, metronidazole should be avoided in the first trimester. It is excreted in breast milk and is not recommended in breastfeeding due to potential toxicity.

Amoxicillin-clavulanic acid is the preferred antibiotic during pregnancy. A population-based case–control study of exposure to amoxicillin-clavulanic acid during pregnancy did not find an increased risk of congenital malformations, and it is compatible with breastfeeding [43].

Prednisone and budesonide may be used in pregnancy when needed to treat disease flares. One study reported a small increased risk of orofacial clefts in infants exposed to corticosteroids in the month before conception and in the first trimester (OR 3.35; 95 % CI: 1.97–5.69) [44]. However, this finding has not been replicated in all studies and the overall risk of major malformations is low (OR 1.45; 95 % CI: 0.80–2.60). In the PIANO registry, after controlling for disease activity and concurrent immunosuppressive medications, maternal corticosteroid use was associated with a significant increase in low birth weight and gestational diabetes and a nonsignificant increase in preterm birth and infant infections within the first 4 months of life [45]. A small case series showed no increase in rates of adverse pregnancy outcomes or congenital anomalies with budesonide [46]. Thus, steroids should be used minimally in the first trimester and at the lowest effective dose for as short a duration as possible during pregnancy. However, controlling disease activity and treating a flare are essential, and steroids cannot always be avoided. Prednisolone is the metabolite of prednisone and is minimally excreted in breast milk. Both prednisone and budesonide are compatible with breastfeeding [47].

Aminosalicylates (5-ASAs) are commonly used in treatment of IBD and come in multiple formulations. Sulfasalazine, the original formulation that combines sulfapyridine and salicylate, should be given with at least 2 mg of folic acid during pregnancy due to anti-folate effects. Asacol HD^® contains dibutylphthalate, a chemical that has been associated with congenital abnormalities in animal studies [48]. These animal studies used doses greater than 190 times what is used in IBD patients and showed skeletal malformations and adverse effects on the male reproductive system. Human studies with Asacol HD^® have not demonstrated an increased risk of birth defects. Sulfasalazine and 5-ASAs are compatible with lactation. Two case reports described reversible diarrhea with aminosalicylate use during breastfeeding [49, 50]. While patients should be aware of this rare complication, they may breastfeed unless the infant gets diarrhea.

Thiopurine immunomodulators, 6-mercaptopurine (6-MP) , and the prodrug azathioprine (AZA) show evidence of teratogenicity in animal studies. However, no replicable pattern of birth defects has been seen in humans. In vivo studies have shown that 6-MP does not cross the placenta, but one of its metabolites, 6-thioguanine, has been detected in the blood of infants born to mothers on AZA or 6-MP [51]. Studies of pregnancy outcomes among women exposed to 6-MP or AZA have had inconsistent results. One study of women exposed to AZA early in pregnancy showed a trend toward increased congenital anomalies (OR 1.41; 95 % CI: 0.98–2.04) and an increased risk of ventricular and atrial septal defects (OR 3.18; 95 % CI: 1.45–6.04) [52]. The exposed women also had increased rates of preterm delivery, low birth weight, and SGA infants; however, these findings are likely due to greater disease severity in the women on AZA. On the other hand, several more recent studies have shown no increased risk of birth defects among infants born to women on 6-MP/AZA. In the PIANO registry, nearly 300 infants born to mothers on AZA have not had an increased rate of congenital malformations [20]. A retrospective multicenter study also did not show an association between thiopurine exposure and perinatal complications [53]. A meta-analysis suggested a relationship between thiopurine exposure and preterm birth, but increased congenital anomalies were not seen [54]. Finally, another small study showed that children of mothers on AZA/6MP had no differences in health status or rates of infections compared to age-matched controls [55]. AZA/6-MP should not be started for the first time during pregnancy because of the time required for response and the small risks of pancreatitis or bone marrow suppression. Finally, AZA/6-MP are excreted at low levels in breast milk, and the greatest levels are seen within four hours of drug ingestion [56]. Both are considered compatible with breastfeeding, but mothers may be advised to wait 4 h after taking the medication before breastfeeding. If this is not possible with a newborn infant, mothers may still breastfeed, as breast milk transfer is very low.