Crohn's Disease Forum » Pregnancy, Trying to Conceive & Breast Feeding with IBD » Measuring What Counts—Safety of IBD Medications in Pregnancy

03-19-2011, 04:03 PM   #1
David in Seattle
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Measuring What Counts—Safety of IBD Medications in Pregnancy

Measuring What Counts—Safety of IBD Medications in Pregnancy
Barrett G. Levesque; Sunanda V. Kane
Nat Rev Gastroenterol Hepatol. 2011;8(3) © 2011


Uncertainty about the risks of medications for IBD during pregnancy is a challenge for clinicians and patients. A recent prospective cohort study suggests that women under medical care for their disease have few adverse events.


Women with IBD who plan to become pregnant seek medical care to help them reach their goals of healthy pregnancies and healthy children. Active Crohn's disease and ulcerative colitis during conception and pregnancy have been associated with an increased risk of adverse perinatal outcomes, such as preterm delivery and low birth weight.[1,2] Thiopurines have been associated with increased rates of steroid-free remission and maintenance of remission in both ulcerative colitis and Crohn's disease compared with placebo.[3,4] These agents are available as an addition or alternative to other medical options available to treat patients with IBD, including 5-aminosalicylic acid preparations, biologic therapies, steroids and ciclosporin. A recent paper by the CESAME study group describes the pregnancy outcomes of a cohort of 204 women with IBD in France.[5] The study examined pregnancy outcomes in three different groups of patients: women taking thiopurines with or without other medications; women taking other medications for IBD; and women taking no medications for IBD.

The benefits of thiopurines in efficacy of induction or maintenance of remission must be balanced against their risks to mother and neonate. Clinicians are faced with different clinical scenarios. First, and probably most commonly, if a woman is planning pregnancy or becomes pregnant and is in steroid-free remission, do the potential risks of thiopurines to a fetus outweigh a thiopurine's contribution to a healthy pregnancy? Second, if a woman has active disease, do the benefits of thiopurines in treating that disease outweigh their risks? Data from prospective randomized trials of thiopurines in pregnant women stratified by disease activity—which would provide an independent estimate of the efficacy and risks of thiopurines in these situations—are, justifiably, lacking. Therefore, data from cohort and case–control studies are used to estimate the utility of thiopurines in different states of disease activity and to aid clinical decision making.

The CESAME study group provides valuable insight into these different clinical scenarios.[5] The study examined pregnancy outcomes in women with IBD under the care of gastroenterologists. Approximately 40% of the patients were treated with thiopurines as part of their medical regimen, 39% received other drugs for their IBD and 21% of patients were not receiving any medication. Differences in live births, prematurity, birth weight and congenital abnormalities between the three groups were assessed.

As the authors acknowledge, information about disease activity, which is a key variable in the equation of the choice of therapy and outcomes of mother and child, was not recorded; further commentary regarding its impact on the different outcomes of the groups is merited. It is reasonable to hypothesize that patients may be receiving a thiopurine owing to more severe disease, and that this disease severity may also affect pregnancy outcomes. In fact, what was not measured may count as much as what was accounted for in the cohort. Disease activity has been related to birth outcomes and is a factor in therapy choice, and thus a confounder, by definition, of the differences found between the groups. Therefore, the lack of a difference in pregnancy and fetal outcomes in the three groups of patients with IBD does not necessarily mean that thiopurines are not independently associated with adverse outcomes. However, one would suspect that women with more severe disease activity would be in one of the groups taking medications, and would, therefore, bias the study towards showing an adverse effect due to thiopurines if there was one. It can be hypothesized that disease activity and severity were reduced in the group of women taking no medications, given that they were under medical care; if a patient has severe disease and is under medical care, it is likely that she will receive therapy for her Crohn's disease. Therefore, untreated patients in this cohort probably yield information about the outcomes of mild or quiescent IBD. These outcomes were not significantly different from treated disease; however, primary data about disease activity to confirm this assumption is lacking.

The cohort study, as a snapshot of clinical outcomes in a 'real-world' setting of patients receiving a range of medical therapies, provides several reassurances to clinicians considering thiopurines and other medications to treat women with IBD. First, all groups had rates of live births in the range of the general population. Second, the overall rate of congenital malformations in children whose mothers were receiving medication (3.5%) was not significantly greater than for the general population in France (3.2%).[6] The caveat that the study is limited by its sample size and powered to detect only a relatively large (fivefold) increase in malformations between the treatment groups is acknowledged. Third, although there were higher rates of prematurity and low birth weight among all patients, which are concerning, the severity and impact of these differences on neonatal outcomes is unclear (because this information is unavailable). Although many studies have reported higher rates of preterm deliveries in women with IBD, the majority occurred after 35 weeks gestation.[7,8] The reason for these premature births is unclear, and hypotheses include increased levels of circulating prostaglandins during a flare or increased gut permeability altering nutritional and immunologic factors that affect pregnancy.[9,10] Overall, pregnancy outcomes in this cohort of women under medical care were similar to the general population and not what would be expected from a cohort of women whose IBD was active and severe.

The outcomes of pregnant patients in the CESAME cohort provide an additional measure of reassurance that the benefits of medications in IBD probably outweigh their risks. Compared with historically significant rates of adverse pregnancy outcomes in active severe disease,[2,3] the study shows relatively lower risks of adverse events than would be expected with active disease. Outcomes of low birth weight and prematurity are limited by lack of data on severity and impact on neo natal outcomes. Larger studies are needed to detect smaller incremental increase in risks; results from the ongoing Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry in the USA will be interesting.[11] However, in the meantime, a useful clinical rule of thumb is that the treatment strategy that is most likely to lead to remission of a mother's Crohn's disease is the one that is most likely to help her have a healthy child.


Practice Points

* Active Crohn's disease or ulcerative colitis during conception and pregnancy is the primary risk factor for adverse perinatal outcomes
* Outcomes of low birth weight and prematurity are limited by lack of data on severity and impact on neonatal outcomes
* On the basis of existing data, thiopurines for women with IBD should not be discouraged
* The treatment strategy that is most likely to lead to remission of a mother's Crohn's disease is the one that is most likely to help her have a healthy child
03-19-2011, 04:03 PM   #2
David in Seattle
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1. Baiocco, P. J. & Korelitz, B. I. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J. Clin. Gastroenterol. 6, 211–216 (1984).
2. Bush, M. C., Patel, s., Lapinski, R. H. & Stone, J. L. Perinatal outcomes in inflammatory bowel disease. J. Matern. Fetal Neonatal Med. 15, 237–241 (2004).
3. Hawthorne, A. B. et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 305, 20–22 (1992).
4. Candy, s. et al. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 37, 674–678 (1995).
5. Coelho, J. et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME study. Gut 60, 198–203 (2011).
6. De vigan, C. et al. Prevalence and prenatal diagnosis of congenital malformations in the Parisian population: twenty years of surveillance by the Paris Registry of congenital malformations [French]. J. Gynecol. Obstet. Biol. Reprod. (Paris) 34, 8–16 (2005).
7. Dominitz, J. A., Young, J. C. & Boyko, E. J. Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study. Am. J. Gastroenterol. 97, 641–648 (2002).
8. nguyen, G. C., Boudreau, H., Harris, M. L. & Maxwell, C. V. Outcomes of obstetric hospitalizations among women with inflammatory bowel disease in the United states. Clin. Gastroenterol. Hepatol. 7, 329–334 (2009).
9. Gould, S. R., Brash, A. R., Conolly, M. E. & Lennard-Jones, J. E. Studies of prostaglandins and sulphasalazine in ulcerative colitis. Prostaglandins Med. 6, 165–182 (1981).
10. Reddy, D., Murphy, S. J., Kane, S. V., Present, D. H. & Kornbluth, A. A. Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes. Am. J. Gastroenterol. 103, 1203–1209 (2008).
11. Mahadevan, U. et al. A multi-center national prospective study of pregnancy and neonatal outcomes in women with inflammatory bowel disease exposed to immunomodulators and biologic therapy [abstract]. Gastroenterology 136 (suppl. 1), A-88 (2009).
03-20-2011, 01:39 AM   #3
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Thank you, David. I wish I would have had this information when I was pregnant with my daughter. I used my Pentasa throughout the pregnancy. I had one flare-up that required a small round of Prednisone. My baby girl arrived just three days before her due date, beautiful and healthy.
Diagnosed with Crohn's Disease in 2005

Pentasa 2x500mg (4 times a day)
Zofran (as needed for nausea)
Ginger Capsules (for Nausea)
Zoloft 150 mg
Ranitidine 150 mg (2 times a day)
Entocort 3 mg (3 capsules by mouth for 8 weeks, then tapering to 2 capsules for three months)
03-20-2011, 05:05 PM   #4
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Yup, great article I can file away for the future!
February 2010 - diagnosed with Crohn's disease.
January 2011 - Inflammation downgraded from moderate-severe to mild with no symptoms!
January 2014 - adopted a mostly Paleo diet
May 2015 - still in remission!

Currently Taking
Humira - 40mg/week
Imuran - 125 mg/day
Calcium magnesium citrate
Fermented cod liver oil/butter blend
Culturelle probiotics
Vitamin D
Vitamin C
03-20-2011, 05:34 PM   #5
David in Seattle
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Yes, I think it sounds very encouraging for any IBD sufferers who are or may become pregnant. Glad you found it interesting!

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