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. 2016 Sep;11(3):221–226.

Managing Crohn’s Disease during Pregnancy

Brîndusa Ana CIMPOCA 1, Florina NEDELEA 2,3, Mirona FURTUNA 4, Gheorghe PELTECU 5,6, Anca Maria PANAITESCU 7,8
PMCID: PMC5486164  PMID: 28694857

Abstract

Crohn’s disease (CD) is a chronic infl ammatory bowel disease with onset during reproductive age. Advancement in medical therapies and treatment strategies have made pregnancy following a diagnosis of CD a viable and safe option for more women with this disease. In this review we discuss the evidence based management of Crohn’s disease during pregnancy.

Keywords:Crohn’s disease, inflammatory bowel disease, pregnancy, preconception disease control

BACKGROUND

Crohn’s disease encompasses a multisystem group of disorders with specific clinical and pathological features. The gastrointestinal tract is primary affected by focal, asymmetric, transmural and, occasionally, granulomatous inflammation. Characteristic symptoms are chronic or nocturnal diarrhea, abdominal pain, weight loss, fever, rectal bleeding and they reflect the underlying inflammatory process. Clinical signs include pallor, cachexia, abdominal masses or tenderness, perianal fissures, fistulas or abscess. The ileum and colon are the most frequently affected sites. Intestinal obstruction, inflammatory mass or abscess are usual complications (1). Although the onset is typically insidious, occasionally, CD can present in a fulminant manner at onset or with the presence of toxic megacolon. Crohn’s disease has the potential for systemic and extraintestinal complications. Associated extraintestinal features can include inflammation of the eyes, skin, or joints (1). Crohn’s disease can affect any age group, but the onset is most common during reproductive age (2). Crohn’s disease is one of the most frequent medical disorders associated with pregnancy. Both gastroenterologists and obstetricians should be ready to offer proper counseling to women affected by CD that are pursuing a pregnancy or are already pregnant. Advances in inflammatory bowel disease therapies and treatment strategies have made pregnancy following a diagnosis of Crohn’s disease a viable and safe option for more women with the disease. In this review we discuss the evidence-based management of Crohn’s disease during pregnancy.

Fertility in Crohn’s disease patients

Developing CD impacts fertility in both men and women but weather this is the effect of voluntary childlessness or of the disease is still controversial (3). In the past, many CD patients were voluntary electing childlessness secondary to concerns related to the risk of adverse pregnancy outcome, possible te ra to ge ni city of medications and heritability of the disease. Appropriate counseling should be provided that accurately addresses these issues (4). In women, active disease decreases the chances of conceiving, however, one in four will achieve a normal conception and fertilization even during an acute episode of CD. Active CD reduces fertility by several mechanisms including inflammation of the fallopian tubes and ovaries, perianal disese causing dyspareunia and previous surgical intervention. The importance of adequate disease control during conception should be emphasized to all couples pursuing a pregnancy. Adequate disease control increases the chance of both conceiving and caring out a healthy pregnancy. With active disease during conception, pregnancy will lead to deterioration of the course of CD in two-thirds of the patients and will increase the risk of miscarriage, fetal growth restriction (FGR) and preterm birth. Preconception counseling offers the possibility to encourage delay of conception until clinical remission is established and nutrition is optimized. With inactive disease at conception, the chance of a disease flare during pregnancy is low and the risks of miscarriage, FGR and preterm birth reach the rates expected in normal pregnant population. Folic acid supplementation with 5 mg should be started before conception. Most of the drugs used to control CD outside pregnancy can safely be continued throughout the pregnancy and lactation and pregnant women should be reassured that there is no higher risk for fetal malformations with these drugs. However, when a drug is not permitted during pregnancy (for example methotrexate), switching to the safer alternatives should be carried out before conception. Men with CD can experience reduced fertility or infertility when treated with sulfasalazine. This drug is known to cause reversible semen abnormalities (oligospermia, reduced motility, abnormal morphology) and infertility in up to 60% of men (5). Sperm quality is restored two months after sulfasalazine withdrawal. Switching to mesalazine also restores male fertility (6). Current medical therapies used to treat CD do not seem to have a direct impact on the quality of oocytes or sperm.

Couples are interested to find out about the heritability of CD. Crohn’s disease is a complex, multifactorial disease that results out of genetic predisposition, changes in the immune system and the presence of bacteria in the digestive tract. Recent studies have identified variations in specific genes, including ATG16L1, IL23R, IRGM, and NOD2, that influence the risk of developing CD. These genes provide instructions for making proteins that are involved in immune system function. Variations in any of these genes may disrupt the ability of intestinal cells to respond normally to bacteria. An abnormal immune response to bacteria in the intestinal walls may lead to chronic inflammation and the digestive problems characteristic of CD (7-10). The inheritance pattern of CD is not completely understood and several genetic and environmental factors are likely to be involved. Familial history of previous affected member confers a higher risk for disease as compared to the general population. Recurrence risk is around 3 to 5% for first-degree relatives. Those risks could be higher in Jewish families (11).

Effect of pregnancy on Crohn’s disease course

Crohn’s disease remains quiescent in about three-quarters of pregnant patients with inactive disease at conception. In those with active disease during conception, improvement is thought to occur in 33% to 74%. A large prospective case control study witch enrolled inflammatory bowel disease pregnant women from twelve European countries (between 2003 to 2006) reported that 74% of CD patients with active disease at conception achieved remission sometime later during pregnancy (12). The highest risk of flare-ups is in those women with active disease at the time of conception and those who develop CD for the first time in pregnancy (13).

There is controversy as to whether CD flares are more likely to occur in the postpartum period. Overall, pregnancy seems to have a beneficial effect on the disease course with CD. A small prospective study reported a reduced relapse rate of CD in the 4 years following a pregnancy when compared with the 3 years prior to pregnancy (14).

Effect of the Crohn’s disease on pregnancy

In woman with quiescent disease at the time of conception, the rates of miscarriage, stillbirth, fetal abnormality and livebirth are similar to those in the normal pregnant population. The majority (80-90%) of pregnant women with CD have full term normal pregnancies.

A meta-analysis of 23 studies that included 15,007 women with inflammatory bowel disease and over 4.6 million controls found that the disease is associated with increased odds of preterm birth, small for gestational age (SGA) birth weight, and stillbirth (15), but the results of the prospective European case-control European Crohn’s Colitis Organization (ECCO) Epi- Com study (12) reported that there are no statistically significant differences in frequency of miscarriages, preterm deliveries, caesarean sections, congenital abnormalities and birth weight when comparing CD women with healthy controls. With CD, older age was associated with congenital abnormalities and preterm delivery; smoking increased the risk of preterm delivery, the same as in the general population.

To continue the controversy, a study including newborns from 510 Crohn’s patients from 6 national registries and 3018 controls observed a significant, albeit modest decrease in birth weight, with neonates of primiparous versus multiparous Crohn’s patients weighing on average 142 g and 105 g less than those of controls after adjustment for confounding factors (16).

Pregnancy outcome is probably best dictated by disease relapse and inappropriate control. To check fetal growth extra ultrasound scans should be planned at 28, 32 and 36 weeks in patients with CD. The 22 weeks anomaly scan can reassure the mother with CD on treatment that there are no major structural defects in the fetus.

Diagnosing Crohn’s Disease during pregnancy

The diagnosis of Crohn’s disease is based on corroborating the endoscopic, radiographic and pathological findings documenting focal, asymmetric, transmural or granulomatous features. Endoscopy, colonoscopy, rectosigmoidoscopy and cholangiography are all considered safe during pregnancy according to ECCO statement, however, caution is required in relation to these procedures and there must be a strong indication for their use. The ideal moment for them to be carried out is considered the second trimester of pregnancy. Hemostasis techniques are safe, but should be performed with care (17). Serological studies analyzing antibodies against Saccharomyces cerevisiae (ASCAs), antineutrophil cytoplasmic antibodies (ANCAs), antibodies directed against CBir1 (flagellin, bacterial antigen), OmpC (outer membrane prion C of E. Coli) are evolving to provide additional support for the diagnosis of CD (18). All these antibodies are not sufficiently sensitive or specific to be recommended for use as a screening tool outside or during pregnancy (19).

Treatment of CD during preconception, pregnancy and lactation

The goal of medical treatment for Crohn’s disease is to reduce the inflammation that triggers symptoms and to improve long-term prognosis by limiting complications. In the best cases, this may lead not only to symptom relief but also to long-term remission. Therapeutic options are determined by an assessment of the disease location, severity, and extraintestinal complications. In the absence of a “gold standard” for the measurement of disease activity, severity is established on clinical parameters, systemic manifestations, and the global impact of the disease on the individual’s quality of life (17).

Most of the drugs used in the treatment of inflammatory bowel disease are not associated with increased risk of congenital anomalies or adverse effects on the fetus and are thus compatible with pregnancy (20). The 2010 European evidence-based consensus for the ECCO guidelines state that medical treatment for Crohn’s disease (except methotrexate and quinolone antibiotics) should generally continue during pregnancy, because the benefits outweigh the risks of medication (21).

Crohn’s disease patients are counseled to conceive during inactive stage of CD, in order to have the best chances for best pregnancy outcome. They should continue the treatment that offered them good control over CD outside pregnancy. If there is a flare during pregnancy, early management is required.

At present, the pharmacologic management of CD is accomplished with 5-aminosalicylic acid (Sulfasalazine, Mesalazine), corticosteroids (Prednisone, Prednisolone, Budesonide), immunomodulators (Azathioprine and 6- Mercaptopurine), antibiotics (Metronidazole, Ciprofloxacin) and tumor necrosis factor (TNF) blockers. In addition, granulocyte and monocyte adsorptive apheresis is another effective therapeutic option for treating refractory inflammatory bowel diseases (22). Treatment with anti-TNF can induce mucosal healing in the affected parts of the digestive tract and dramatically change a patient’s clinical findings of Crohn’s disease (23). There are concerns over the use of anti-TNF agents during pregnancy, although the information available to date is limited. Currently, 3 anti-TNF agents, namely infliximab, adalimumab, certolizumab pegol are FDA-approved for treatment of inflammatory bowel disease in pregnancy (24). No significant increase in the rate of adverse outcome of pregnancy have been reported in women who continued their treatment from conception to the first trimester of pregnancy. Decision making in these cases dictates that the mother’s benefits of maintaining the control of the disease through continuation of anti-TNFs exceeds the potential risks of fetal exposure (24).

Anti-TNF biological agents

Anti-TNF biological agents are either fully chimeric or humanized antibodies for ligands or soluble receptors or recombinant receptor antagonists. Their mode of action concerns inhibition of TNF-á, based on the pleiotropic function of the molecule in cellular proliferation, cell adhesion, migration, and inflammatory cytokine induction response. Their main purpose, therefore, is interference with the inflammation pathway (24).

The administration of biological agents has been associated with a number of side effects that should be known to clinicians treating these patients. Selecting the correct patients to receive biological agents as well as constant and close monitoring are essential when administering anti-TNF therapy (26,27).

In particular, although there are limited data to date concerning the use of anti-TNF agents during pregnancy, no significant increases in the adverse outcomes of pregnancy have been reported in women who continued their treatment from conception to the first trimester of pregnancy (28,29). Treatment with anti-TNF antibodies can be considered safe in the preconception period and the first part of pregnancy, because IgG antibodies do not cross the placenta in the first trimester and transplacental IgG transport mainly takes place during the late second and third trimester of pregnancy (30). Transfer of anti-TNF antibodies to the fetus during the last part of pregnancy may lead to the exposure of the neonate in the first months after birth, raising potential concerns about infection and response to vaccines (29). Infants exposed to immunosuppressive drugs during pregnancy probably should be considered to be immunocompromised, as their mothers are. It is currently recommended that live vaccines [including rotavirus, intranasal influenza vaccine and Bacillus Calmette– Guérin (BCG)] be withheld for 12 months in infants with a prenatal exposure to an anti-TNF agent (31). This concern stemmed from a case report of a 28-year-old female with refractory Crohn’s disease who received infliximab throughout her pregnancy. The baby was born healthy and received a BCG vaccine at 3 months of age, but soon after died from disseminated BCG (England, 2008) (32).

Infliximab was not detected in breast milk (33), so infliximab treatment is considered to be compatible with breastfeeding. Adalimumab is a fully humanized antibody of the IgG1 isotype. The mechanism and rate of transplacental transfer are comparable to those of infliximab. Certolizumab is a pegylated Fab' fragment of an anti-TNF monoclonal antibody without the Fc fragment. Certolizumab would therefore be expected not to be transferred across the placental barrier according to the mechanism described above. Animal studies indeed report much lower placental transfer of pegylated Fab' antibodies; data in humans are not yet available. The recent London position statement considers certolizumab pegol to be low risk prior to conception and during pregnancy. Certolizumab is compatible with breastfeeding (29).

Mode of delivery in Crohn’s disease affected patients

Vaginal delivery is safe for most patients. Caesarean section is only required for obstetrical indications. In cases of severe perinatal Crohn’s disease resulting in a deformed or scarred rectum and perineum, vaginal delivery should be avoided because of perineal inelasticity (13). Even though there is wide agreement that in CD affected pregnant women, vaginal delivery is preferred, pregnancies with Crohn’s disease end more often in cesarean section (20.9% vs. 15% in the general population in a study from United States) (34). A population- based study found that pregnancies of patients with CD who needed to be hospitalized had a higher risk of cesarean delivery compared to healthy controls (35).

Table.

Table

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TABLE. Medical treatment for Crohn’s disease and risks during pregnancy - adapted a" er Vermeire, S; 2012

CONCLUSION

Crohn’s disease is one of the most common medical conditions complicating pregnancy that obstetricians will come across within their practice. Gastroenterologists caring for women of reproductive age with CD will invariably be asked about the possibility of a pregnancy. The best outcome for affected women results from a multidisciplinary teamcare approach: an obstetrician (reproductive medicine specialist/maternal-fetal medicine specialist), a gastroenterologist and a colorectal surgeon (when indicated). Early consultation is recommended to plan appropriate pregnancy management and mode of delivery (15). The best predictor for pregnancy outcome is typically the lack of activity of the disease during conception. Most of the modern drugs used to control CD are safe in pregnancy and should be continued. Vaginal delivery is highly encouraged. Over 90% of pregnant women affected by CD have a completely uneventful pregnancy and delivery.

Summary of the strategy:

  • Conception during inactive stage of Crohn’s disease

  • 5 mg folate supplementation

  • Continue current therapy if controlled, if anti TNF – go until 2nd trimester

  • **If anti TNF treatment is continued after the 2nd trimester, infant vaccination should be postponed for up to 12 months

  • Usual prenatal screening program and Crohn’s disease biological markers

  • Usual maternal-fetal medicine first and second trimester fetal anomaly ultrasound and 28, 32 and 36 weeks fetal growth scan

  • Regular gastroenterologist check-up

  • Vaginal delivery, caesarean section – only for obstetrical indications

Conflict of interests: none declared.

Financial support: none declared.

Contributor Information

Brîndusa Ana CIMPOCA, Filantropia Clinical Hospital, Bucharest, Romania.

Florina NEDELEA, Filantropia Clinical Hospital, Bucharest, Romania; Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania.

Mirona FURTUNA, Filantropia Clinical Hospital, Bucharest, Romania.

Gheorghe PELTECU, Filantropia Clinical Hospital, Bucharest, Romania; Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania.

Anca Maria PANAITESCU, Filantropia Clinical Hospital, Bucharest, Romania; Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania.

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