Anti-TNF Safety in Pregnant and Breastfeeding Women With IBD
Anti-TNF Safety in Pregnant and Breastfeeding Women With IBD
Although the American Academy of Pediatrics recommends breastfeeding for at least 6 months after birth, many women who require drug therapy initiate breastfeeding less frequently, discontinue breastfeeding earlier than women who are not receiving medication, or do not breastfeed at all. Breastfeeding provides significant health benefits to infants, including transmission of protective antibodies.
It is traditionally recommended that breastfeeding is probably best avoided while receiving anti-TNF drugs. However, theoretically, breastfeeding should be safe during anti-TNF therapy, as IgA is the predominant immunoglobulin in human milk; therefore, secretion of TNF inhibitors (IgG) is likely to be very limited. Furthermore, large protein molecules such as biologics are probably broken down or inactivated by digestive enzymes in the gastrointestinal tract.
Several case reports have shown that infliximab levels in breast milk are consistently below detectable limits. Furthermore, case reports of women who breastfed while on infliximab do not suggest toxicity; therefore, this drug has been considered compatible with breastfeeding. In a recent study on whether infliximab is transferred in utero or through breast milk from women with Crohn's disease. Three patients who received infliximab during and after pregnancy were followed prospectively. The patients received infliximab (5 mg/kg) at regular intervals until approximately gestational week 30, and resumed infliximab within 3 to 14 days after delivery. The drug was detected in the mothers' sera, but not in their breast milk or in the sera of the newborns. Data from this small series of patients suggest that infliximab was not transferred from mother to child, either in utero or through breast milk, and that mothers receiving infliximab should not be discouraged from breastfeeding their children (at least if they have abstained from infusions after week 32 of pregnancy).
It is noteworthy that the studies in which infliximab (or adalimumab) was not detected in breast milk used a commercial kit standardized according to blood levels. In contrast, other researchers who used control breast milk samples for calibration of the standard curve recorded detectable levels of infliximab or adalimumab in breast milk, although in concentrations that were significantly lower than in serum; nevertheless, miniscule amounts of these anti-TNF drugs were detected in the milks tested. Consequently, the authors evaluated the presence of infliximab in the breast milk of nursing IBD patients: serum and breast milk were obtained after delivery from three patients with Crohn's disease. Infliximab levels in breast milk rose to 101 ng/ml within 2–3 days of the infusion; this level was roughly 1/200th of the level in blood. These findings were recently confirmed by Fritzsche et al., who prospectively followed breastfed children under maternal treatment with infliximab or adalimumab; the concentration range of infliximab in the breast milk of two patients was similar to the levels measured by Ben-Horin et al., peaking at ~100 ng/ml.
Therefore, in contrast with previous reports, anti-TNF drugs have been detected in the breast milk of nursing mothers. These findings suggest that infliximab (and adalimumab) might be absorbed from the gut. The mechanism of absorption is not yet clear, but might involve FcRn, which is expressed in a variety of neonatal tissues and in the intestinal cells of adults and fetuses.
The miniscule amounts of infliximab/adalimumab transferred in breast milk are unlikely to result in systemic immune suppression in the infant; in addition, this small quantity most probably undergoes proteolysis in the stomach and intestine after ingestion. Nevertheless, local effects of exposure on the neonates' intestine cannot be excluded and merit further investigation.
The preliminary results of the PIANO study were recently presented. To date, 102 women have been treated with anti-TNF drugs. Most newborns (72%) were breastfed. Although a significant increase in infant infections was detected at 12 months of age in the combination therapy group (thiopurines plus anti-TNFs), breastfeeding was not associated with an increased risk of infection among patients exposed to the drugs.
Finally, it remains to be determined whether neonatal exposure to the drug can sensitize the infant to exogenous anti-TNF antibody. The offspring of a patient with Crohn's disease has a risk of developing IBD of up to 9%, and it is currently estimated that 20–30% of Crohn's disease patients are or have been treated with anti-TNF agents. Consequently, 1 out of 37–55 nursing infants of anti-TNF-treated mothers may require these drugs for IBD at some point during their life, thus highlighting the importance of breastfeeding-mediated sensitization. While these considerations need to be borne in mind, they should also be weighed against the proven benefits of breastfeeding for the newborn when discussing with patients the pros and cons of ongoing anti-TNF therapy during this period.
Anti-TNF Treatment and Breastfeeding
Although the American Academy of Pediatrics recommends breastfeeding for at least 6 months after birth, many women who require drug therapy initiate breastfeeding less frequently, discontinue breastfeeding earlier than women who are not receiving medication, or do not breastfeed at all. Breastfeeding provides significant health benefits to infants, including transmission of protective antibodies.
It is traditionally recommended that breastfeeding is probably best avoided while receiving anti-TNF drugs. However, theoretically, breastfeeding should be safe during anti-TNF therapy, as IgA is the predominant immunoglobulin in human milk; therefore, secretion of TNF inhibitors (IgG) is likely to be very limited. Furthermore, large protein molecules such as biologics are probably broken down or inactivated by digestive enzymes in the gastrointestinal tract.
Several case reports have shown that infliximab levels in breast milk are consistently below detectable limits. Furthermore, case reports of women who breastfed while on infliximab do not suggest toxicity; therefore, this drug has been considered compatible with breastfeeding. In a recent study on whether infliximab is transferred in utero or through breast milk from women with Crohn's disease. Three patients who received infliximab during and after pregnancy were followed prospectively. The patients received infliximab (5 mg/kg) at regular intervals until approximately gestational week 30, and resumed infliximab within 3 to 14 days after delivery. The drug was detected in the mothers' sera, but not in their breast milk or in the sera of the newborns. Data from this small series of patients suggest that infliximab was not transferred from mother to child, either in utero or through breast milk, and that mothers receiving infliximab should not be discouraged from breastfeeding their children (at least if they have abstained from infusions after week 32 of pregnancy).
It is noteworthy that the studies in which infliximab (or adalimumab) was not detected in breast milk used a commercial kit standardized according to blood levels. In contrast, other researchers who used control breast milk samples for calibration of the standard curve recorded detectable levels of infliximab or adalimumab in breast milk, although in concentrations that were significantly lower than in serum; nevertheless, miniscule amounts of these anti-TNF drugs were detected in the milks tested. Consequently, the authors evaluated the presence of infliximab in the breast milk of nursing IBD patients: serum and breast milk were obtained after delivery from three patients with Crohn's disease. Infliximab levels in breast milk rose to 101 ng/ml within 2–3 days of the infusion; this level was roughly 1/200th of the level in blood. These findings were recently confirmed by Fritzsche et al., who prospectively followed breastfed children under maternal treatment with infliximab or adalimumab; the concentration range of infliximab in the breast milk of two patients was similar to the levels measured by Ben-Horin et al., peaking at ~100 ng/ml.
Therefore, in contrast with previous reports, anti-TNF drugs have been detected in the breast milk of nursing mothers. These findings suggest that infliximab (and adalimumab) might be absorbed from the gut. The mechanism of absorption is not yet clear, but might involve FcRn, which is expressed in a variety of neonatal tissues and in the intestinal cells of adults and fetuses.
The miniscule amounts of infliximab/adalimumab transferred in breast milk are unlikely to result in systemic immune suppression in the infant; in addition, this small quantity most probably undergoes proteolysis in the stomach and intestine after ingestion. Nevertheless, local effects of exposure on the neonates' intestine cannot be excluded and merit further investigation.
The preliminary results of the PIANO study were recently presented. To date, 102 women have been treated with anti-TNF drugs. Most newborns (72%) were breastfed. Although a significant increase in infant infections was detected at 12 months of age in the combination therapy group (thiopurines plus anti-TNFs), breastfeeding was not associated with an increased risk of infection among patients exposed to the drugs.
Finally, it remains to be determined whether neonatal exposure to the drug can sensitize the infant to exogenous anti-TNF antibody. The offspring of a patient with Crohn's disease has a risk of developing IBD of up to 9%, and it is currently estimated that 20–30% of Crohn's disease patients are or have been treated with anti-TNF agents. Consequently, 1 out of 37–55 nursing infants of anti-TNF-treated mothers may require these drugs for IBD at some point during their life, thus highlighting the importance of breastfeeding-mediated sensitization. While these considerations need to be borne in mind, they should also be weighed against the proven benefits of breastfeeding for the newborn when discussing with patients the pros and cons of ongoing anti-TNF therapy during this period.
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