Reports of Retrospective Reviews of Pregnancy and Infliximab
A search of available published literature yielded few retrospective studies assessing infliximab exposure during pregnancy. These retrospective reviews, summarized below, report the pregnancy course and birth outcomes in females receiving infliximab before and during pregnancy.
Carter, 2009 (Retrospective Review of FDA Database for Congenital Abnormalities Associated With TNF-α Antagonists)
Congenital abnormalities reported in patients treated with tumor necrosis factor-α (TNF-α) antagonists were identified through a search of over 120,000 adverse events in the Food and Drug Administration (FDA) adverse event database.12017 As of December 2005, a total of 61 congenital abnormalities were reported in 41 children born to 40 females being treated with a TNF-α antagonist, including infliximab and 2 other biologic agents. Twenty-four of 41 mothers (59%) were not taking concomitant medications. Of those being treated with infliximab, 10 were not taking concomitant medications. All cases of congenital abnormalities were considered to be related to treatment with an anti-TNF- α agent.
In total, there were 34 different forms of congenital abnormalities reported, with the most commonly reported congenital abnormality being various heart defects (n=11). Other anomalies were also reported more than once, including: cystic kidney (n=3), pulmonary malformation (n=3), teratoma (n=3), tracheal stenosis (n=2), hypospadias (n=2), trisomy 21 (n=2), and hydrocele (n=2). Of the 41 children, 13 (32%) had more than one congenital abnormality. Of all cases, 24 children (59%) had 1 or more congenital abnormalities that were associated with VACTERL. VACTERL is the acronym used to describe the nonrandom association of certain birth defects, including vertebral defects, anal atresia, cardiac abnormalities, and tracheoesophageal, renal, and limb abnormalities. While only 1 child was diagnosed with VACTERL, 7 children had 2 or more VACTERL-associated defects.
There were 3 cases of spontaneous abortion and 2 cases of therapeutic termination; none of these cases occurred in women being treated with infliximab. Nineteen children were born to mothers (n=19) being treated with infliximab. Of these, 14 children had 1 reported congenital abnormality while 5 children had 2 reported congenital abnormalities.
An editorial accompanying this article disagreed with the findings of the authors, pointing out, that “Although FDA reports on TNF inhibitors did not confirm diagnoses of VACTERL, Carter, et al., suggest that, because they have some features of the VACTERL, the cases ought to be considered as VACTERL.” The editorial also points out this paper only listed adverse events without providing a comparator group.12149 In addition, pregnancy outcomes in women taking infliximab, as reported in the Infliximab Safety Database, a retrospective database that records voluntary adverse event reports associated with infliximab, were presented at ACR 2008. 12533
Berthelot, et al., 2009 (Review of 15 Cases of Pregnancy Associated With Anti-TNF-α Therapy)
Berthelot, et al., reported the outcomes of 15 pregnancies in females treated with anti-TNF-α therapies including infliximab at the time of conception or during pregnancy.11823 Data were obtained for all cases through anonymous, structured questionnaires administered by French rheumatologists in 2006. Previously reported cases were excluded from this report. Of the 15 cases reviewed, 3 females were treated with infliximab; 1 patient had treated for rheumatoid arthritis (RA), 1 patient was treated for a spondyloarthropathy (SpA), and 1 patient was treated for another immune-mediated disease. The remaining patients were treated with 1 of 2 other anti-TNF-α agents. The pregnancies and outcomes of the 3 patients treated with infliximab are summarized below.
A 31-year-old female with RA was treated with 3 mg/kg infliximab for 11 months prior to her pregnancy. This patient had no previous children and had not been exposed to either methotrexate (MTX) or nonsteroidal anti-inflammatory drugs (NSAIDs). The patient continued treatment with infliximab until 15 weeks’ gestation during her pregnancy and delivered a healthy infant via vaginal birth at 40 weeks’ gestation. No congenital abnormality, malformation, nor symptom of neonatal illnesses were noted.
A 22-year-old female with an immune-mediated disease was treated with 3 mg/kg infliximab for 12 months prior to her pregnancy. This patient had no previous children and had not been exposed to either MTX or NSAIDs. The patient continued infliximab therapy for 24 weeks during her pregnancy and, at 40 weeks’ gestation, delivered a healthy infant via vaginal birth. No congenital abnormality, malformation, nor symptom of neonatal illnesses were noted.
A 33-year-old female with a SpA was treated with 5 mg/kg infliximab for 1 month prior to her pregnancy; the patient had not been exposed to either MTX or NSAIDs. This patient had 1 previous child. The patient discontinued treatment with infliximab 4 weeks into her pregnancy and delivered a healthy infant via cesarean section at 40 weeks’ gestation. No congenital abnormality, malformation, nor symptom of neonatal illnesses were noted.
Mahadevan, et al., 2005 (Review of Patients With Crohn’s Disease)
To study the effects of infliximab on fetal outcome, Mahadevan, et al., conducted a retrospective chart review of females with Crohn’s disease (CD) treated with infliximab during pregnancy.4047 The primary outcome measure was the occurrence of congenital malformations. Secondary outcome measures included the rate of premature birth, low birth weight, small for gestational age, intrauterine growth retardation, and cesarean section. Data from the University of California San Francisco, University of Chicago, Mayo Clinic Rochester, and the Medical College of Wisconsin were compiled. Ten patients exposed to infliximab directly before or during pregnancy were identified (mean age: 31.2 years, mean duration of CD: 11.1 years). Nine patients were exposed to infliximab with or without concomitant therapy at the time of conception, 8 during the second trimester, 8 during the third trimester, and 7 in the postpartum period.
Ten live births were reported. Eight births were by cesarean section, 4 due to active perianal disease, 2 due to active CD, 1 due to preterm birth, and 1 due to prior history of cesarean section. Additional information for the pregnancy outcomes reported by Mahadevan, et al., are listed in Fig.934. There were 2 reports of neonatal illness; in 1 neonate, jaundice was reported to have resolved. Respiratory distress and a gastric ulcer were reported in the other neonate; the infant was reported healthy with no medical problems 6 months after delivery.
Figure 934 – Pregnancy Outcomes
Mahadevan U, Kane S, Sandborn WJ, et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther 2005;21(6):733-738 is used with permission of Blackwell Publishing Ltd. http://www.blackwellpublishing.com
Some figures may not display clearly when rendered as a PDF or printed.
Cush, et al., 2005 (Pregnancy Outcomes: Survey Results of US Rheumatologists)
The results of an online survey of US rheumatologists
(1023 respondents), with a 40% response rate, conducted in
Katz, et al., 2004 (Review of Pregnancy in Centocor-Maintained Safety Database)
Katz, et al., retrospectively reviewed the infliximab
safety database maintained by Centocor Ortho Biotech (Malvern, PA)
for all reports of pregnancy, including exposure both direct (maternal)
and indirect (partner) to infliximab, between
Of the 96 pregnancies with direct exposure and
outcome data, 82 received infliximab for CD, 8 for RA, 2 for juvenile
RA, 1 for ulcerative colitis, and the indication was unknown in 3
patients. Timing of conception relative to infliximab exposure was
calculated for 90 of these females. Of these, 53 were exposed to infliximab
within 3 months of conception (28 were treated both within 3 months
prior to conception and during the first trimester, and 25 were treated
within 3 months prior to conception only), and 30 began treatment
with infliximab during the first trimester. Seven received infliximab
Of the 96 pregnancies with direct exposure and outcome data, Katz, et al., reported the following: 64 live births (68 live newborns, including 4 sets of twins), 14 miscarriages, and 18 therapeutic terminations. These outcomes are similar to what had been reported in the general US pregnant population or pregnant CD patients not exposed to infliximab.
Of the 10 pregnancies with indirect exposure and outcome data, 6 received treatment for CD, 2 for RA, and 2 (20%) for SpAs. For timing of conception relative to infliximab exposure: 8 received infliximab within 3 months of their partner’s conception, and timing was unknown for 2 patients. Of the 10 pregnancies with indirect exposure and reported outcomes, Katz, et al., reported live births in 9 and miscarriage in 1.
Katz, et al., reported fetal complications in
5 infants. One infant born at 24 weeks gestation weighing
Chakravarty, et al., 2003 (Pregnancy Outcomes in Patients With Rheumatoid Arthritis)
Chakravarty, et al., published the results of a survey conducted to solicit outcomes of pregnancies occurring with individual patients receiving treatment with disease-modifying antirheumatic drugs, where known.4034 Surveys were sent to 600 practicing rheumatologists in the US Respondents were asked to list the number of pregnancies that occurred in patients taking each medication, how the patient was counseled, and the pregnancy outcome, if known (identified as "term delivery of healthy infant," "therapeutic abortion," "spontaneous abortion," "premature delivery," "congenital malformation," or "other complications"). “Congenital malformation” was not further defined. Sixty-six pregnancies were reported in patients receiving treatment for rheumatic disease, including 2 patients receiving infliximab. In total, 30 full-term healthy deliveries were reported; 1 of 2 patients receiving infliximab reported a full-term healthy delivery. The pregnancy outcome was not stated for 6 cases, including 1 patient who was receiving infliximab.
Content on this page was last reviewed on January 01, 2010.
Content on this page was last changed on March 19, 2009.
References:| 4034. | Chakravarty EF, Sanchez-Yamamoto D, Bush TM. The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol. 2003;30(2):241-246. |
| 4047. | Mahadevan U, Kane S, Sandborn WJ, et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther. 2005;21(6):733-738. |
| 4049. | Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in patients receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol. 2004;99(12):2385-2392. |
| 4061. | Srinivasan R. Infliximab treatment and pregnancy outcome in active Crohn’s disease [letter]. Am J Gastroenterol. 2001;96(7):2274-2275. |
| 10650. | Cush JJ. Biological drug use: US perspectives on indications and monitoring. Ann Rheum Dis. 2005;64(suppl 4):iv18-iv23. |
| 11823. | Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, et al. Exposition to anti-TNF drugs during pregnancy: Outcome of 15 cases and review of the literature. Joint Bone Spine. 2009;76(1):28-34. |
| 12017. | Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol. 2009;36(3):635–641. |
| 12149. | Koren G. Do Tumor Necrosis Factor Inhibitors Cause Malformations in Humans. Journal of rheumatology. 2009; 36:465–6. |
| 12533. | Y. Snoeckx’, G. Keenan2, M. Sanders1 , M. Gardiner’. Benefit Risk Management, A Division of Johnson & Johnson PRD, LLC, Horsham, PA; Centocor Ortho Biotech, Inc., Horsham, PA. Pregnancy outcomes in women taking infliximab: The infliximab safety database. Abstract, ACR 2008. |
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Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.