pregnant(*Please note that any information in this article should not take the place of advice from your obstetrician/gynecologist or from your rheumatologist. It should equip you with some questions to discuss on your next visit. One benefit of learning about rheumatology research is that it empowers you with information like this to discuss with your doctor.)

In May this year, I highlighted our Twitter chat on patient engagement in research where patients identified three priority areas of research. One of them was the effect of medications to treat inflammatory arthritis (such as RA and PSA) on their pregnancy and unborn child. Because pregnant women are excluded from 95% of trials sponsored by the pharmaceutical industry (1), there is a lack of human data on the safety of established medications during pregnancy. Results from observational studies are inconclusive and sometimes conflicting. Women and their families want to be able to make decisions knowing potential benefits and harms, so this lack of information can be frustrating and anxiety-provoking.

I recently spoke with UAB epidemiologist, Jie “Sophie” Zhang, Ph.D. about this. It started with the question, “What do we know about this topic now?” Our discussion covered a broad range of topics and too much information to be summarized in a single post. I have organized it into several topic areas and the first of which is about the safety concerns of biologics.

First of all, it is important to note that the research we discuss below mostly comes from patients with inflammatory bowel diseases (IBD), including Crohn’s Disease and Ulcerative Colitis. A second key point is that while we are discussing biologics in general, most of the data come from anti-TNF biologics, especially the oldest and most commonly used ones including infliximab, adalimumab, etanercept, certolizumab. Finally this is not a comprehensive review (we discuss select studies).

What are the general safety concerns of biologics during pregnancy?

There are a number of concerns. Biologics are associated with increased risk of having a serious infection in the non-pregnant population. Although the extent of immune suppression in pregnant women as a result of their exposure to anti-TNF biologics and their implications are important questions to the patients and their clinicians, the infection risk is poorly understood. Additionally, because select anti-TNF biologics cross the placenta in the second and third trimesters (we will elaborate on this later), infants are exposed to these medications before they are born (2, 3). There has been one case report of the death of a healthy infant at four and a half months after receiving a live BCG (tuberculosis) vaccination, an unusual complication of the BCG vaccine (4). Because live vaccines are contraindicated—they should not be used—in patients receiving biologics and since it takes up to seven months for infliximab to become undetectable in exposed infants, it has been recommended that live vaccines for infants be avoided for six months after birth for those infants exposed to infliximab and adalimumab in utero.

Regarding other birth outcomes, a meta-analysis of over 58 studies (for a total sample size of 1,533 IBD patients), anti-TNF biologics were not associated with adverse birth outcomes including spontaneous abortion, pre-term birth, low birth weight, congenital malformation, or infections (5). Similarly, two other studies conducted with rheumatology patients reported no increased risk of adverse birth outcomes (6, 7). The opposite has also been reported: One study reported an increased risk of spontaneous abortion associated with anti-TNF biologic use at conception among patients with RA, but this finding is inconclusive because of the small sample size and other factors that might have caused the outcome instead (8). Yet another case report raised a potential safety concern of VATER association, a rare spectrum of linked birth defects (9). Inconsistencies like the ones highlighted in this paragraph show why clinical research is urgently needed to shed more light on the risks and benefits of these medications.

Let’s take a closer look at “placenta transfer” during pregnancy. First of all, what is meant by “placenta transfer?”

It’s a good idea to start by defining some terms since the topic of arthritis medications and placenta transfer during pregnancy is fairly technical. The placenta is a complex tissue that surrounds the fetus inside the mother’s uterus. Some people refer to the placenta as a membrane, but it is actually much more than a simple membrane. It moves nutrients and waste products between the mother and the fetus. This process is called “placenta transfer.” Normally, there is no mixing of blood from the mother and the fetus within the placenta. However, select molecules do cross from one side of the placenta to the other. In cases where this happens, the unborn child is exposed to the medication in utero.

To what extent are biologics transferred?

The extent to which these medications cross the placenta varies by the type of medication and by the trimester of pregnancy. In a study of eleven mothers who received infliximab, ten mothers adalimumab, and five mothers certolizumab pagol, the levels of their medications were measured in the cord/infant blood and in the mothers’ blood. In all mother-infant pairs among mothers who took infliximab and adalimumab, higher levels of medications were measured in the cord/infant blood than in maternal blood. However, the median level of certolizumab was 3.9% that of the mother, suggesting minimal transfer of certolizumab (2). As a result of this observation, certolizumab may be a better option during pregnancy among anti-TNF biologics. Moreover, stopping the use of adalimumab and infliximab four to eight  weeks prior to delivery has been considered as a strategy to reduce potential infant risks associated with in utero exposure to high levels of the two mono-clonal antibodies.

It is important to note that infliximab and adalimumab, two anti-TNF monoclonal IgG1 antibodies, are unlikely to cross the placenta in the first trimester (10). As a result, infants are not exposed to them during a critical period of fetal development. While this is good news, it does not provide definitive proof that use of anti-TNF biologics in the first trimester is not associated with increased risk of adverse birth outcomes.

What about breastfeeding once the baby is born?

The medications are not detected in the breast milk of mothers receiving infliximab (3, 11) and they are only detected in very low levels in one study in mothers receiving adalimumab (12). There is no clinical evidence that suggest any risks associated with breastfeeding while on these anti-TNF biologics. But you can always choose to bottle feed instead if you have concerns. It’s really a personal choice.

Finally, the purpose of this post is to provide you with information from recent research. Although the research presented here does not provide a simple yes or no answer to the question of safety, we hope that this information helps you have more informed discussions with your physician when you’re planning and managing before, during, and after your pregnancy. Part 2 of this series will focus on understanding the risks associated with methotrexate use during pregnancy.

We are interested in hearing the thoughts and experiences of CreakyJoints members about this topic. Your perspective as a patient is important to us and will help to speed up research in this area. As I’ve written before, rheumatology research depends on people like you and the clues that you provide. We welcome any questions you have and we will try to respond to them in our future posts. If you are interested in sharing, please send an email to me at [email protected] or Dr. Zhang at [email protected]. In the meantime, please register as a CreakyJoints member to learn more about how you can get involved in patient-led research.

References:

1.              Shields KE, Lyerly AD. Exclusion of pregnant women from industry-sponsored clinical trials. Obstet Gynecol. 2013;122(5):1077-81. doi: 10.1097/AOG.0b013e3182a9ca67. PubMed PMID: 24104789.

2.              Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-92; quiz e24. doi: 10.1016/j.cgh.2012.11.011. PubMed PMID: 23200982.

3.              Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol. 2006;4(10):1255-8. doi: 10.1016/j.cgh.2006.07.018. PubMed PMID: 17045211.

4.              Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J. Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. Journal of Crohn’s & colitis. 2010;4(5):603-5. doi: 10.1016/j.crohns.2010.05.001. PubMed PMID: 21122568.

5.              Nielsen OH, Loftus EV, Jr., Jess T. Safety of TNF-alpha inhibitors during IBD pregnancy: a systematic review. BMC Med. 2013;11:174. doi: 10.1186/1741-7015-11-174. PubMed PMID: 23902720; PubMed Central PMCID: PMC3734216.

6.              Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatology (Oxford). 2007;46(4):695-8. doi: 10.1093/rheumatology/kel400. PubMed PMID: 17158212.

7.              Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers. Scandinavian journal of rheumatology. 2012;41(3):196-201. doi: 10.3109/03009742.2011.626442. PubMed PMID: 22401133.

8.              Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70(5):823-6. Epub 2011/03/03. doi: 10.1136/ard.2010.140822

ard.2010.140822 [pii]. PubMed PMID: 21362710; PubMed Central PMCID: PMC3070273.

9.              Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol. 2006;33(5):1014-7. PubMed PMID: 16652431.

10.           Simister NE. Placental transport of immunoglobulin G. Vaccine. 2003;21(24):3365-9. PubMed PMID: 12850341.

11.           Kane S, Ford J, Cohen R, Wagner C. Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn’s disease before and after delivery. Journal of clinical gastroenterology. 2009;43(7):613-6. doi: 10.1097/MCG.0b013e31817f9367. PubMed PMID: 19142167.

12.           Ben-Horin S, Yavzori M, Katz L, Picard O, Fudim E, Chowers Y, et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol. 2010;8(5):475-6. doi: 10.1016/j.cgh.2009.11.023. PubMed PMID: 20005982.