Infliximab has limited ability to cross the placenta and animal studies using analogous monoclonal antibody constructs have revealed no evidence of fetotoxicity or teratogenicity. However, maternal and fetal outcomes in humans related to exposure to anti-TNF-a therapies during pregnancy are unstudied. Here, Katz et al (Am J Gastroenterol 99:2385, 2004) examine outcomes in women with RA or Crohns disease with direct or indirect exposure (i.e. male partner with exposure) to infliximab during pregnancy.
Methods:
Subjects were all pregnant women with direct or indirect exposures to infliximab voluntarily reported and entered into the manufacturers clinical trial safety and post-marketing pharmacovigilance database from October 1999 through October 2001. Women receiving infliximab for RA or Crohns disease in Europe and North America were included, with follow-up on pregnancy outcomes obtained by telephone or postal contact through early 2003. Pregnancy outcomes of infliximab-exposed women were compared to outcomes of historical controls compiled by the U.S. National Center for Health Statistics and historical controls of women with Crohns disease (without exposure to infliximab).
Results:
Of 146 pregnancies with exposure to infliximab reported to the manufacturer, 106 had available information on pregnancy outcomes (96 with direct exposure to infliximab, 10 with indirect exposure). 48% of reports were from patients enrolled in clinical trials. Mean maternal age was 33 years.
| Direct exposure (n=96) |
Indirect exposure (n=10) |
|
| Receiving infliximab for Crohns | 82(85%) | 6(60%) |
| Receiving infliximab for RA | 8(8%) | 2(20%) |
| Infliximab within 3 months of conception | 53 (55%) 28/53 within 3 months of conception and during 1st trimester | 8 (80%) 3/8 within 3 months of conception and during 1st trimester |
| Infliximab during first trimester only | 30(31%) | — |
| Concomitant medications | 72 (75%) methotrexate: n=8 | 8 (80%) methotrexate: n = 2 |
| Pregnancies resulting in live births | 64 (67%) | 9 (90%) |
| Miscarriages | 14 (15%) – < 10 wks: n = 8 – < 20 wks: n = 2 – < 30 wks: n = 1 – unknown: n = 3 |
1 – at < 10 weeks |
| Miscarriages in pts receiving infliximab within 3 mo of conception | 12 (4 in patients with additional 1st trimester exposure) |
The expected number of live births, miscarriages, and therapeutic terminations (from data compiled by the U.S. National Center for Health Statistics from 1976 to 1996) was 67%, 17%, and 16% respectively. The expected number of live births, miscarriages, and therapeutic terminations from pregnancies in women with Crohns disease from a prior publication was 67%, 13%, and 20% respectively. Comparing only the infliximab exposed subjects with Crohns disease to these historical controls revealed no statistically significant differences.
Fetal complications were reported in five births: preterm birth with fetal demise at 24 weeks gestation; neonatal respiratory distress, jaundice, and seizure with full resolution by 9 months; Tetralogy of Fallot; intestinal malrotation; and delayed development and hypothyroidism in one of a set of full-term twins. Timing of infliximab exposure and concomitant medications varied between these cases.
Conclusion:
Pregnancy outcomes in infliximab exposed women voluntarily reported to the manufacturer are consistent with those of the U.S. general population and women with Crohns disease without exposure to infliximab.
Editorial Comment:
Due to the obvious difficulties associated with conducting controlled trials of pharmaceuticals in pregnant women, conclusions about the safety of many medications are often based solely on animal data and small case series of humans inadvertently exposed during pregnancy. While several methodological imperfections of the present study are notable (namely, the reliance on voluntary report of cases, missing data, and comparison to historical controls), this report is the largest and most thorough to date. Even so, these results can only speak directly to outcomes related to inadvertent exposures to infliximab at preconception and very early in pregnancy and cannot necessarily be applied to support the active use of infliximab later in pregnancy. As most pregnant women with RA who are inadvertently exposed to infliximab will also be exposed to methotrexate, a known teratogen and abortofacient, dissecting out the independent role of infliximab in these patients is more challenging. At present, no studies examining pregnancy outcomes in women exposed to other TNF inhibitors, etanercept or adalimumab, have been published, though an abstract presented in poster form at the recent 2004 ACR Annual Scientific Meeting found similar results as the present study in women with RA treated with etanercept (n=29) compared to women with RA not treated with etanercept, or non-RA controls (Arthritis Rheum 2004;50(9)suppl:S479).
