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The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].
The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].
The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at [email protected].
