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Epic fail
A couple of years ago, “epic fail” was the phrase my teenage son used as I unsuccessfully attempted to beat him in a game we were playing. At the time, I thought to myself it was a harsh, but accurate assessment of my performance. And I was certainly motivated to practice on my own so that the next time, things would be different.
That same phrase came to mind as I read an October 2015 online article published in Cancer Epidemiology, Biomarkers & Prevention titled “Quality of Physician Communication about Human Papillomavirus Vaccine: Findings from a National Survey” (Nov:24[11];1673). The article describes well the poor performance of the medical community – primarily pediatricians and family physicians – in providing this vaccine. Another source, the most recent National Immunization Survey–Teen 2014, reports another alarming trend: HPV vaccine series initiation and completion continues to lag far behind what it should be.
It came as no surprise to me that the journal article clearly showed what I have suspected for some time and what has been hinted at by previous studies. The epic failure in providing what is essentially a cancer-prevention vaccine to the recommended population of 11- to 12-year-old boys and girls lies not at the feet of the antivaccine movement or hesitant parents. Rather, the failure belongs to us.
The article describes findings from an online survey sent to 2,368 pediatricians and family physicians in 2014. Respondents (776) self-reported their own performance on strength of endorsement (saying the vaccine is important), timeliness (recommending it at ages 11 and 12 years), consistency (recommending it routinely versus using a risk-based approach), and urgency (recommending same-day vaccination).
More than one-quarter stated they did not strongly endorse the HPV vaccine, and a similar number reported they did not recommend it be given at 11-12 years of age. Amazingly, 59% stated they used a risk-based approach versus a routine approach to recommending the HPV vaccine, and only half of the respondents recommended giving the vaccine at the current encounter when discussing the HPV vaccine. Because this is self-reported data, these results represent a best-case scenario because respondents would be unlikely to paint an unflattering picture of their own performance.
Clearly, we have a major problem with physicians struggling with their own discomfort in talking about the HPV vaccine and who erroneously believe parents do not value it. The physician’s lack of competency in communicating effectively – overtly and covertly – leads to a lack of an affirmative recommendation that is so important in any preventive intervention. We are at risk of being the generation of pediatricians and family physicians who collectively failed to protect our patients from a preventable cause of cancer. Only we can fix what is wrong with us. Only we can turn around this epic failure.
Physicians and other providers of medical care to adolescents can access resources to help themselves improve their provision of the HPV vaccine to their patients. One of the best collections of resources can be found online at the American Academy of Pediatrics' Champion Toolkit. This includes material from the Centers for Disease Control and Prevention and AAP as well as some illuminating video vignettes that illustrate the do's and don'ts of communicating with families about HPV vaccination. This must become part of our mission!
Dr. Terk is a pediatrician in Keller, Tx., and is the immediate past president of the Texas Pediatric Society.
*Updated 1/26/2016
A couple of years ago, “epic fail” was the phrase my teenage son used as I unsuccessfully attempted to beat him in a game we were playing. At the time, I thought to myself it was a harsh, but accurate assessment of my performance. And I was certainly motivated to practice on my own so that the next time, things would be different.
That same phrase came to mind as I read an October 2015 online article published in Cancer Epidemiology, Biomarkers & Prevention titled “Quality of Physician Communication about Human Papillomavirus Vaccine: Findings from a National Survey” (Nov:24[11];1673). The article describes well the poor performance of the medical community – primarily pediatricians and family physicians – in providing this vaccine. Another source, the most recent National Immunization Survey–Teen 2014, reports another alarming trend: HPV vaccine series initiation and completion continues to lag far behind what it should be.
It came as no surprise to me that the journal article clearly showed what I have suspected for some time and what has been hinted at by previous studies. The epic failure in providing what is essentially a cancer-prevention vaccine to the recommended population of 11- to 12-year-old boys and girls lies not at the feet of the antivaccine movement or hesitant parents. Rather, the failure belongs to us.
The article describes findings from an online survey sent to 2,368 pediatricians and family physicians in 2014. Respondents (776) self-reported their own performance on strength of endorsement (saying the vaccine is important), timeliness (recommending it at ages 11 and 12 years), consistency (recommending it routinely versus using a risk-based approach), and urgency (recommending same-day vaccination).
More than one-quarter stated they did not strongly endorse the HPV vaccine, and a similar number reported they did not recommend it be given at 11-12 years of age. Amazingly, 59% stated they used a risk-based approach versus a routine approach to recommending the HPV vaccine, and only half of the respondents recommended giving the vaccine at the current encounter when discussing the HPV vaccine. Because this is self-reported data, these results represent a best-case scenario because respondents would be unlikely to paint an unflattering picture of their own performance.
Clearly, we have a major problem with physicians struggling with their own discomfort in talking about the HPV vaccine and who erroneously believe parents do not value it. The physician’s lack of competency in communicating effectively – overtly and covertly – leads to a lack of an affirmative recommendation that is so important in any preventive intervention. We are at risk of being the generation of pediatricians and family physicians who collectively failed to protect our patients from a preventable cause of cancer. Only we can fix what is wrong with us. Only we can turn around this epic failure.
Physicians and other providers of medical care to adolescents can access resources to help themselves improve their provision of the HPV vaccine to their patients. One of the best collections of resources can be found online at the American Academy of Pediatrics' Champion Toolkit. This includes material from the Centers for Disease Control and Prevention and AAP as well as some illuminating video vignettes that illustrate the do's and don'ts of communicating with families about HPV vaccination. This must become part of our mission!
Dr. Terk is a pediatrician in Keller, Tx., and is the immediate past president of the Texas Pediatric Society.
*Updated 1/26/2016
A couple of years ago, “epic fail” was the phrase my teenage son used as I unsuccessfully attempted to beat him in a game we were playing. At the time, I thought to myself it was a harsh, but accurate assessment of my performance. And I was certainly motivated to practice on my own so that the next time, things would be different.
That same phrase came to mind as I read an October 2015 online article published in Cancer Epidemiology, Biomarkers & Prevention titled “Quality of Physician Communication about Human Papillomavirus Vaccine: Findings from a National Survey” (Nov:24[11];1673). The article describes well the poor performance of the medical community – primarily pediatricians and family physicians – in providing this vaccine. Another source, the most recent National Immunization Survey–Teen 2014, reports another alarming trend: HPV vaccine series initiation and completion continues to lag far behind what it should be.
It came as no surprise to me that the journal article clearly showed what I have suspected for some time and what has been hinted at by previous studies. The epic failure in providing what is essentially a cancer-prevention vaccine to the recommended population of 11- to 12-year-old boys and girls lies not at the feet of the antivaccine movement or hesitant parents. Rather, the failure belongs to us.
The article describes findings from an online survey sent to 2,368 pediatricians and family physicians in 2014. Respondents (776) self-reported their own performance on strength of endorsement (saying the vaccine is important), timeliness (recommending it at ages 11 and 12 years), consistency (recommending it routinely versus using a risk-based approach), and urgency (recommending same-day vaccination).
More than one-quarter stated they did not strongly endorse the HPV vaccine, and a similar number reported they did not recommend it be given at 11-12 years of age. Amazingly, 59% stated they used a risk-based approach versus a routine approach to recommending the HPV vaccine, and only half of the respondents recommended giving the vaccine at the current encounter when discussing the HPV vaccine. Because this is self-reported data, these results represent a best-case scenario because respondents would be unlikely to paint an unflattering picture of their own performance.
Clearly, we have a major problem with physicians struggling with their own discomfort in talking about the HPV vaccine and who erroneously believe parents do not value it. The physician’s lack of competency in communicating effectively – overtly and covertly – leads to a lack of an affirmative recommendation that is so important in any preventive intervention. We are at risk of being the generation of pediatricians and family physicians who collectively failed to protect our patients from a preventable cause of cancer. Only we can fix what is wrong with us. Only we can turn around this epic failure.
Physicians and other providers of medical care to adolescents can access resources to help themselves improve their provision of the HPV vaccine to their patients. One of the best collections of resources can be found online at the American Academy of Pediatrics' Champion Toolkit. This includes material from the Centers for Disease Control and Prevention and AAP as well as some illuminating video vignettes that illustrate the do's and don'ts of communicating with families about HPV vaccination. This must become part of our mission!
Dr. Terk is a pediatrician in Keller, Tx., and is the immediate past president of the Texas Pediatric Society.
*Updated 1/26/2016
Maternal immunization during pregnancy: lessons learned, and emerging opportunities
Pediatricians and our teams are the immunization experts. We educate, advocate, and incorporate vaccines into much of our daily routine. As such, we recognize the importance of working with our colleagues in family medicine, internal medicine, and obstetrics to optimize immunization programs for high-risk individuals, including pregnant women. Recent advances in vaccine recommendations during pregnancy are a result of the collaborative efforts of the health care providers for these women, and from systematic evaluation of immunization programs, vaccine pregnancy registries, and disease epidemiology.
Vaccinating women during pregnancy should be considered when a vaccine is known to be safe and when the following apply:
• The risk of severe infection is high during or augmented by pregnancy.
• The specific infection during pregnancy threatens the fetus.
• Maternal protection against infection benefits the newborn.
• Passive transfer of antibody from mother to fetus benefits the newborn.
Examples of safe vaccines immediately come to mind that fulfill one of more of these criteria, yet substantial obstacles exist even where safety and effectiveness data are robust. Because clinical vaccine trials traditionally exclude pregnant women, safety and effectiveness data for this group and their newborns are limited and often must come through experience. In a climate of increased vaccine hesitancy in general, both among providers and patients, vaccine delivery can be fragmented and particularly difficult to streamline. Additional obstacles that exist for any immunization program, including one that targets pregnant women specifically, are immunization delivery logistics and cost.
One of the major success stories of maternal immunization that is easily forgotten or overlooked in developed parts of the world is in the prevention of maternal and neonatal tetanus (MNT). A review of recent history reminds us that between the years 2000 and 2014, 35 countries were finally successful in eliminating MNT, including China, Turkey, Egypt, and South Africa. In addition, 24 of 36 states in the country of India, 30 of 34 provinces of Indonesia, and most of Ethiopia have met with success. This has been accomplished through aggressive tetanus vaccination programs, and through education programs targeted at optimal umbilical cord stump care after delivery.
In the United States, the Advisory Committee on Immunization Practices recommends that all pregnant women should receive inactivated influenza vaccine and Tdap vaccine. In addition, several other vaccines are recommended under certain circumstances. Live attenuated vaccines are considered contraindicated, although yellow fever vaccine is an exception during epidemics, or when travel to a highly endemic area during pregnancy cannot be avoided.
Influenza vaccine administered during pregnancy reduces maternal morbidity and mortality. Moreover, safety and benefits for the fetus are clearly documented. Both retrospective cohort analysis studies and randomized controlled trials have consistently demonstrated lower risk of preterm birth and lower risk for delivering newborns small for gestational age among women who received inactivated influenza vaccine during pregnancy. The benefit extends to term healthy infants who are less likely to be hospitalized during the first months of life if their mother was vaccinated against influenza during pregnancy. Because the mother was immunized during pregnancy, it reduces her risk of infection, thereby reducing the potential that the newborn will be exposed to a mother who is contagious. Perhaps more importantly, infants born at or near term have the benefit of transplacental antibody endowment from their mother, including vaccine induced anti-influenza antibodies. This passive protection is expected to last for several months. Active immunization against influenza during infancy begins at 6 months of age.
Tdap vaccine is also recommended during each pregnancy. In the United States, MNT is eliminated. Here, as in other developed countries, Tdap is administered to reduce infant pertussis morbidity. Pertussis remains endemic to the United States, and infants who develop whooping cough during the first 2-3 months of life are at the highest risk for morbidity and mortality.
Historically, one-third of infants infected with pertussis were infected by their mother, although more recent evidence suggests that older siblings are at least as likely a source. Looking back to the paradigm for protection against influenza infection in the first few months of life, it becomes clear why the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has recommended Tdap vaccine for all mothers during each pregnancy.
The first goal is to prevent pertussis in the mother so that she will not transmit the infection to her newborn. The additional goal, and the rationale for vaccinating pregnant women during every pregnancy, is to optimize levels of anti-pertussis antibody in the mother, so that the transplacental endowment to the infant is as robust as possible.
Serologic studies have demonstrated that Tdap vaccine induces high anti-pertussis antibodies when administered during pregnancy, but that the half-life of those antibodies is brief. When Tdap is given during pregnancy, and the infant is born at or near term, the antibody transfer to the infant is expected to provide passive protection for several months. Maternal immunization during pregnancy thereby reduces the risk that the mother will develop pertussis and transmit it to her newborn, while at the same time allows a degree of passive immunoprotection to the infant during the most vulnerable period of life. Active immunization against pertussis in the infant begins between 6-8 weeks of age.
Another infection that is exceedingly common during the first several months of life is respiratory syncytial virus (RSV). RSV remains the most common reason for infant hospitalization in the United States and other developed countries. The source of the virus can be any other person with a mild or moderate respiratory tract infection as the virus is ubiquitous, and can re-infect individuals throughout their lifetime. The first infection, however, is the worst. It is estimated that between 3% and 4% of the U.S. birth cohort is hospitalized with RSV. With a U.S. birth cohort of about 4 million, the result is 120,000-160,000 infant admissions annually.
The RSV epidemic is seasonal, fairly predictable, and dreaded by primary care pediatricians and hospitalists alike. Lower respiratory tract infection with RSV, in the form of RSV bronchiolitis, presents all too commonly in the young infant with cough, coryza, tachypnea, and wheezing. When the work of breathing increases, and the cough symptoms predominate, the infant is unable to feed efficiently. Hospitalizations may be for dehydration, concerns for impending respiratory failure, or for the administration of supplemental oxygen or other respiratory support. No specific therapeutic interventions reliably reduce the symptoms or the length of hospital stay, nor do they reduce the possibility that intensive care with mechanical ventilation may be required. Treatments are only supportive. An effective vaccine remains elusive.
All other common infections that once resulted in high rates of hospitalization in the first year of life are now substantially reduced through vaccination. Why not this one? The development of a safe and effective vaccine to prevent infant RSV infection or to reduce RSV-associated hospitalizations is especially challenging for multiple reasons.
Some of these reasons have met with substantial advances quite recently, including the discovery of antigen structures needed to induce neutralizing antibody responses. There also are challenges specific to the infant group we need most to protect. Infant RSV infection itself confers only modest protection against subsequent infection. Repeated infections over time are necessary for protection against illness when re-exposed. A vaccine that is able to induce a response similar to natural infection would therefore require multiple doses, presumably over time (the so called ‘primary series’) before a substantial clinical benefit would be expected. This is particularly important because most RSV-associated hospitalizations occur during the first several months of life, reducing the timeline for which a protective vaccine series could be administered.
The challenges are parallel to the issues described earlier for protection against both influenza and pertussis. Infant protection against both of these infections are now addressed, at least to start with, by vaccinating the mother during her pregnancy. In the infant, the pertussis vaccine primary series is then initiated between 6 and 8 weeks of age, and the influenza series initiated at 6 months of age. It is the passive protection, in the form of transplacental maternal antibody, that offers the interim protection during the highest-risk first months of life.
For infants at very high risk of serious RSV infection, passive antibody protection is already administered in the form of the pharmacobiologic medication palivizumab. Its half-life dictates monthly injections for those eligible, and its cost precludes its use for any but the highest risk infants (those born prematurely, and those with chronic lung disease and/or congenital heart disease). This strategy, however, has proven effective in preventing RSV-associated hospitalization in every group in which it has been studied. This “proof of concept” strongly suggests that if the right RSV vaccine is given to women during pregnancy to induce a robust neutralizing anti-RSV antibody response, and that antibody is transferred to the fetus prior to birth, the newborn will benefit from protection against RSV for a period of time.
Several questions emerge. If RSV is ubiquitous, and can re-infect individuals throughout their lifetime, then some women will be infected during their pregnancy. Do their infants benefit? As a re-infection, the maternal symptoms would be expected to be mild, but the infection could boost the women’s natural immunity with a robust anamnestic antibody response. This possibility has not been studied systematically, but might help to explain why some healthy term infants exposed to RSV develop little or no symptoms, while others (mothers who have not recently had a natural RSV infection) develop severe illness requiring hospitalization.
There are data to support the contention that term infants born to mothers with higher naturally occurring anti-RSV neutralizing antibodies benefit from those antibodies. In a large prospective cohort study performed in Kenya, cord blood anti-RSV antibody concentrations correlated directly with the length of time before the infant’s first RSV infection. It’s therefore logical to conclude that administering an effective RSV vaccine during pregnancy could augment that natural antibody response, be transferred to the infant at birth, and offer protection against RSV when exposed.
Several candidate vaccines for study already exist and have undergone phase I testing in nonpregnant adults. Once safety is demonstrated, the next step is to identify the vaccine formulation resulting in the most robust anti-RSV neutralizing antibody concentrations. Such a candidate vaccine will be chosen for future phase III trials during pregnancy. Safety, and maternal/cord blood RSV antibody titers will be of interest during that clinical trial, but the rates and timing of RSV infection and RSV-associated hospitalizations among the infants born to those mothers will be the most instructive.
Ideally, a candidate RSV vaccine shown to be as safe and as effective during pregnancy as inactivated influenza vaccines and/or Tdap vaccines would be implemented immediately and universally. Unfortunately, substantial vaccine hesitancy for the use of influenza and Tdap vaccines continues among pregnant patients and their providers. Acceptance of an RSV vaccine for use during pregnancy will not come easily, or immediately. As with all of our successful vaccine programs, launching such an effort will require education, patience, and careful post-licensure documentation of the impact that the intervention has in the real world.
Dr. Domachowske is professor of pediatrics and professor of microbiology and immunology at the State University of New York Upstate Medical University, Syracuse, N.Y. Dr. Domachowske is performing clinical trials and has grants in the area of RSV prevention with Astra Zeneca, Regeneron, and Glaxo Smith Kline.
Pediatricians and our teams are the immunization experts. We educate, advocate, and incorporate vaccines into much of our daily routine. As such, we recognize the importance of working with our colleagues in family medicine, internal medicine, and obstetrics to optimize immunization programs for high-risk individuals, including pregnant women. Recent advances in vaccine recommendations during pregnancy are a result of the collaborative efforts of the health care providers for these women, and from systematic evaluation of immunization programs, vaccine pregnancy registries, and disease epidemiology.
Vaccinating women during pregnancy should be considered when a vaccine is known to be safe and when the following apply:
• The risk of severe infection is high during or augmented by pregnancy.
• The specific infection during pregnancy threatens the fetus.
• Maternal protection against infection benefits the newborn.
• Passive transfer of antibody from mother to fetus benefits the newborn.
Examples of safe vaccines immediately come to mind that fulfill one of more of these criteria, yet substantial obstacles exist even where safety and effectiveness data are robust. Because clinical vaccine trials traditionally exclude pregnant women, safety and effectiveness data for this group and their newborns are limited and often must come through experience. In a climate of increased vaccine hesitancy in general, both among providers and patients, vaccine delivery can be fragmented and particularly difficult to streamline. Additional obstacles that exist for any immunization program, including one that targets pregnant women specifically, are immunization delivery logistics and cost.
One of the major success stories of maternal immunization that is easily forgotten or overlooked in developed parts of the world is in the prevention of maternal and neonatal tetanus (MNT). A review of recent history reminds us that between the years 2000 and 2014, 35 countries were finally successful in eliminating MNT, including China, Turkey, Egypt, and South Africa. In addition, 24 of 36 states in the country of India, 30 of 34 provinces of Indonesia, and most of Ethiopia have met with success. This has been accomplished through aggressive tetanus vaccination programs, and through education programs targeted at optimal umbilical cord stump care after delivery.
In the United States, the Advisory Committee on Immunization Practices recommends that all pregnant women should receive inactivated influenza vaccine and Tdap vaccine. In addition, several other vaccines are recommended under certain circumstances. Live attenuated vaccines are considered contraindicated, although yellow fever vaccine is an exception during epidemics, or when travel to a highly endemic area during pregnancy cannot be avoided.
Influenza vaccine administered during pregnancy reduces maternal morbidity and mortality. Moreover, safety and benefits for the fetus are clearly documented. Both retrospective cohort analysis studies and randomized controlled trials have consistently demonstrated lower risk of preterm birth and lower risk for delivering newborns small for gestational age among women who received inactivated influenza vaccine during pregnancy. The benefit extends to term healthy infants who are less likely to be hospitalized during the first months of life if their mother was vaccinated against influenza during pregnancy. Because the mother was immunized during pregnancy, it reduces her risk of infection, thereby reducing the potential that the newborn will be exposed to a mother who is contagious. Perhaps more importantly, infants born at or near term have the benefit of transplacental antibody endowment from their mother, including vaccine induced anti-influenza antibodies. This passive protection is expected to last for several months. Active immunization against influenza during infancy begins at 6 months of age.
Tdap vaccine is also recommended during each pregnancy. In the United States, MNT is eliminated. Here, as in other developed countries, Tdap is administered to reduce infant pertussis morbidity. Pertussis remains endemic to the United States, and infants who develop whooping cough during the first 2-3 months of life are at the highest risk for morbidity and mortality.
Historically, one-third of infants infected with pertussis were infected by their mother, although more recent evidence suggests that older siblings are at least as likely a source. Looking back to the paradigm for protection against influenza infection in the first few months of life, it becomes clear why the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has recommended Tdap vaccine for all mothers during each pregnancy.
The first goal is to prevent pertussis in the mother so that she will not transmit the infection to her newborn. The additional goal, and the rationale for vaccinating pregnant women during every pregnancy, is to optimize levels of anti-pertussis antibody in the mother, so that the transplacental endowment to the infant is as robust as possible.
Serologic studies have demonstrated that Tdap vaccine induces high anti-pertussis antibodies when administered during pregnancy, but that the half-life of those antibodies is brief. When Tdap is given during pregnancy, and the infant is born at or near term, the antibody transfer to the infant is expected to provide passive protection for several months. Maternal immunization during pregnancy thereby reduces the risk that the mother will develop pertussis and transmit it to her newborn, while at the same time allows a degree of passive immunoprotection to the infant during the most vulnerable period of life. Active immunization against pertussis in the infant begins between 6-8 weeks of age.
Another infection that is exceedingly common during the first several months of life is respiratory syncytial virus (RSV). RSV remains the most common reason for infant hospitalization in the United States and other developed countries. The source of the virus can be any other person with a mild or moderate respiratory tract infection as the virus is ubiquitous, and can re-infect individuals throughout their lifetime. The first infection, however, is the worst. It is estimated that between 3% and 4% of the U.S. birth cohort is hospitalized with RSV. With a U.S. birth cohort of about 4 million, the result is 120,000-160,000 infant admissions annually.
The RSV epidemic is seasonal, fairly predictable, and dreaded by primary care pediatricians and hospitalists alike. Lower respiratory tract infection with RSV, in the form of RSV bronchiolitis, presents all too commonly in the young infant with cough, coryza, tachypnea, and wheezing. When the work of breathing increases, and the cough symptoms predominate, the infant is unable to feed efficiently. Hospitalizations may be for dehydration, concerns for impending respiratory failure, or for the administration of supplemental oxygen or other respiratory support. No specific therapeutic interventions reliably reduce the symptoms or the length of hospital stay, nor do they reduce the possibility that intensive care with mechanical ventilation may be required. Treatments are only supportive. An effective vaccine remains elusive.
All other common infections that once resulted in high rates of hospitalization in the first year of life are now substantially reduced through vaccination. Why not this one? The development of a safe and effective vaccine to prevent infant RSV infection or to reduce RSV-associated hospitalizations is especially challenging for multiple reasons.
Some of these reasons have met with substantial advances quite recently, including the discovery of antigen structures needed to induce neutralizing antibody responses. There also are challenges specific to the infant group we need most to protect. Infant RSV infection itself confers only modest protection against subsequent infection. Repeated infections over time are necessary for protection against illness when re-exposed. A vaccine that is able to induce a response similar to natural infection would therefore require multiple doses, presumably over time (the so called ‘primary series’) before a substantial clinical benefit would be expected. This is particularly important because most RSV-associated hospitalizations occur during the first several months of life, reducing the timeline for which a protective vaccine series could be administered.
The challenges are parallel to the issues described earlier for protection against both influenza and pertussis. Infant protection against both of these infections are now addressed, at least to start with, by vaccinating the mother during her pregnancy. In the infant, the pertussis vaccine primary series is then initiated between 6 and 8 weeks of age, and the influenza series initiated at 6 months of age. It is the passive protection, in the form of transplacental maternal antibody, that offers the interim protection during the highest-risk first months of life.
For infants at very high risk of serious RSV infection, passive antibody protection is already administered in the form of the pharmacobiologic medication palivizumab. Its half-life dictates monthly injections for those eligible, and its cost precludes its use for any but the highest risk infants (those born prematurely, and those with chronic lung disease and/or congenital heart disease). This strategy, however, has proven effective in preventing RSV-associated hospitalization in every group in which it has been studied. This “proof of concept” strongly suggests that if the right RSV vaccine is given to women during pregnancy to induce a robust neutralizing anti-RSV antibody response, and that antibody is transferred to the fetus prior to birth, the newborn will benefit from protection against RSV for a period of time.
Several questions emerge. If RSV is ubiquitous, and can re-infect individuals throughout their lifetime, then some women will be infected during their pregnancy. Do their infants benefit? As a re-infection, the maternal symptoms would be expected to be mild, but the infection could boost the women’s natural immunity with a robust anamnestic antibody response. This possibility has not been studied systematically, but might help to explain why some healthy term infants exposed to RSV develop little or no symptoms, while others (mothers who have not recently had a natural RSV infection) develop severe illness requiring hospitalization.
There are data to support the contention that term infants born to mothers with higher naturally occurring anti-RSV neutralizing antibodies benefit from those antibodies. In a large prospective cohort study performed in Kenya, cord blood anti-RSV antibody concentrations correlated directly with the length of time before the infant’s first RSV infection. It’s therefore logical to conclude that administering an effective RSV vaccine during pregnancy could augment that natural antibody response, be transferred to the infant at birth, and offer protection against RSV when exposed.
Several candidate vaccines for study already exist and have undergone phase I testing in nonpregnant adults. Once safety is demonstrated, the next step is to identify the vaccine formulation resulting in the most robust anti-RSV neutralizing antibody concentrations. Such a candidate vaccine will be chosen for future phase III trials during pregnancy. Safety, and maternal/cord blood RSV antibody titers will be of interest during that clinical trial, but the rates and timing of RSV infection and RSV-associated hospitalizations among the infants born to those mothers will be the most instructive.
Ideally, a candidate RSV vaccine shown to be as safe and as effective during pregnancy as inactivated influenza vaccines and/or Tdap vaccines would be implemented immediately and universally. Unfortunately, substantial vaccine hesitancy for the use of influenza and Tdap vaccines continues among pregnant patients and their providers. Acceptance of an RSV vaccine for use during pregnancy will not come easily, or immediately. As with all of our successful vaccine programs, launching such an effort will require education, patience, and careful post-licensure documentation of the impact that the intervention has in the real world.
Dr. Domachowske is professor of pediatrics and professor of microbiology and immunology at the State University of New York Upstate Medical University, Syracuse, N.Y. Dr. Domachowske is performing clinical trials and has grants in the area of RSV prevention with Astra Zeneca, Regeneron, and Glaxo Smith Kline.
Pediatricians and our teams are the immunization experts. We educate, advocate, and incorporate vaccines into much of our daily routine. As such, we recognize the importance of working with our colleagues in family medicine, internal medicine, and obstetrics to optimize immunization programs for high-risk individuals, including pregnant women. Recent advances in vaccine recommendations during pregnancy are a result of the collaborative efforts of the health care providers for these women, and from systematic evaluation of immunization programs, vaccine pregnancy registries, and disease epidemiology.
Vaccinating women during pregnancy should be considered when a vaccine is known to be safe and when the following apply:
• The risk of severe infection is high during or augmented by pregnancy.
• The specific infection during pregnancy threatens the fetus.
• Maternal protection against infection benefits the newborn.
• Passive transfer of antibody from mother to fetus benefits the newborn.
Examples of safe vaccines immediately come to mind that fulfill one of more of these criteria, yet substantial obstacles exist even where safety and effectiveness data are robust. Because clinical vaccine trials traditionally exclude pregnant women, safety and effectiveness data for this group and their newborns are limited and often must come through experience. In a climate of increased vaccine hesitancy in general, both among providers and patients, vaccine delivery can be fragmented and particularly difficult to streamline. Additional obstacles that exist for any immunization program, including one that targets pregnant women specifically, are immunization delivery logistics and cost.
One of the major success stories of maternal immunization that is easily forgotten or overlooked in developed parts of the world is in the prevention of maternal and neonatal tetanus (MNT). A review of recent history reminds us that between the years 2000 and 2014, 35 countries were finally successful in eliminating MNT, including China, Turkey, Egypt, and South Africa. In addition, 24 of 36 states in the country of India, 30 of 34 provinces of Indonesia, and most of Ethiopia have met with success. This has been accomplished through aggressive tetanus vaccination programs, and through education programs targeted at optimal umbilical cord stump care after delivery.
In the United States, the Advisory Committee on Immunization Practices recommends that all pregnant women should receive inactivated influenza vaccine and Tdap vaccine. In addition, several other vaccines are recommended under certain circumstances. Live attenuated vaccines are considered contraindicated, although yellow fever vaccine is an exception during epidemics, or when travel to a highly endemic area during pregnancy cannot be avoided.
Influenza vaccine administered during pregnancy reduces maternal morbidity and mortality. Moreover, safety and benefits for the fetus are clearly documented. Both retrospective cohort analysis studies and randomized controlled trials have consistently demonstrated lower risk of preterm birth and lower risk for delivering newborns small for gestational age among women who received inactivated influenza vaccine during pregnancy. The benefit extends to term healthy infants who are less likely to be hospitalized during the first months of life if their mother was vaccinated against influenza during pregnancy. Because the mother was immunized during pregnancy, it reduces her risk of infection, thereby reducing the potential that the newborn will be exposed to a mother who is contagious. Perhaps more importantly, infants born at or near term have the benefit of transplacental antibody endowment from their mother, including vaccine induced anti-influenza antibodies. This passive protection is expected to last for several months. Active immunization against influenza during infancy begins at 6 months of age.
Tdap vaccine is also recommended during each pregnancy. In the United States, MNT is eliminated. Here, as in other developed countries, Tdap is administered to reduce infant pertussis morbidity. Pertussis remains endemic to the United States, and infants who develop whooping cough during the first 2-3 months of life are at the highest risk for morbidity and mortality.
Historically, one-third of infants infected with pertussis were infected by their mother, although more recent evidence suggests that older siblings are at least as likely a source. Looking back to the paradigm for protection against influenza infection in the first few months of life, it becomes clear why the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has recommended Tdap vaccine for all mothers during each pregnancy.
The first goal is to prevent pertussis in the mother so that she will not transmit the infection to her newborn. The additional goal, and the rationale for vaccinating pregnant women during every pregnancy, is to optimize levels of anti-pertussis antibody in the mother, so that the transplacental endowment to the infant is as robust as possible.
Serologic studies have demonstrated that Tdap vaccine induces high anti-pertussis antibodies when administered during pregnancy, but that the half-life of those antibodies is brief. When Tdap is given during pregnancy, and the infant is born at or near term, the antibody transfer to the infant is expected to provide passive protection for several months. Maternal immunization during pregnancy thereby reduces the risk that the mother will develop pertussis and transmit it to her newborn, while at the same time allows a degree of passive immunoprotection to the infant during the most vulnerable period of life. Active immunization against pertussis in the infant begins between 6-8 weeks of age.
Another infection that is exceedingly common during the first several months of life is respiratory syncytial virus (RSV). RSV remains the most common reason for infant hospitalization in the United States and other developed countries. The source of the virus can be any other person with a mild or moderate respiratory tract infection as the virus is ubiquitous, and can re-infect individuals throughout their lifetime. The first infection, however, is the worst. It is estimated that between 3% and 4% of the U.S. birth cohort is hospitalized with RSV. With a U.S. birth cohort of about 4 million, the result is 120,000-160,000 infant admissions annually.
The RSV epidemic is seasonal, fairly predictable, and dreaded by primary care pediatricians and hospitalists alike. Lower respiratory tract infection with RSV, in the form of RSV bronchiolitis, presents all too commonly in the young infant with cough, coryza, tachypnea, and wheezing. When the work of breathing increases, and the cough symptoms predominate, the infant is unable to feed efficiently. Hospitalizations may be for dehydration, concerns for impending respiratory failure, or for the administration of supplemental oxygen or other respiratory support. No specific therapeutic interventions reliably reduce the symptoms or the length of hospital stay, nor do they reduce the possibility that intensive care with mechanical ventilation may be required. Treatments are only supportive. An effective vaccine remains elusive.
All other common infections that once resulted in high rates of hospitalization in the first year of life are now substantially reduced through vaccination. Why not this one? The development of a safe and effective vaccine to prevent infant RSV infection or to reduce RSV-associated hospitalizations is especially challenging for multiple reasons.
Some of these reasons have met with substantial advances quite recently, including the discovery of antigen structures needed to induce neutralizing antibody responses. There also are challenges specific to the infant group we need most to protect. Infant RSV infection itself confers only modest protection against subsequent infection. Repeated infections over time are necessary for protection against illness when re-exposed. A vaccine that is able to induce a response similar to natural infection would therefore require multiple doses, presumably over time (the so called ‘primary series’) before a substantial clinical benefit would be expected. This is particularly important because most RSV-associated hospitalizations occur during the first several months of life, reducing the timeline for which a protective vaccine series could be administered.
The challenges are parallel to the issues described earlier for protection against both influenza and pertussis. Infant protection against both of these infections are now addressed, at least to start with, by vaccinating the mother during her pregnancy. In the infant, the pertussis vaccine primary series is then initiated between 6 and 8 weeks of age, and the influenza series initiated at 6 months of age. It is the passive protection, in the form of transplacental maternal antibody, that offers the interim protection during the highest-risk first months of life.
For infants at very high risk of serious RSV infection, passive antibody protection is already administered in the form of the pharmacobiologic medication palivizumab. Its half-life dictates monthly injections for those eligible, and its cost precludes its use for any but the highest risk infants (those born prematurely, and those with chronic lung disease and/or congenital heart disease). This strategy, however, has proven effective in preventing RSV-associated hospitalization in every group in which it has been studied. This “proof of concept” strongly suggests that if the right RSV vaccine is given to women during pregnancy to induce a robust neutralizing anti-RSV antibody response, and that antibody is transferred to the fetus prior to birth, the newborn will benefit from protection against RSV for a period of time.
Several questions emerge. If RSV is ubiquitous, and can re-infect individuals throughout their lifetime, then some women will be infected during their pregnancy. Do their infants benefit? As a re-infection, the maternal symptoms would be expected to be mild, but the infection could boost the women’s natural immunity with a robust anamnestic antibody response. This possibility has not been studied systematically, but might help to explain why some healthy term infants exposed to RSV develop little or no symptoms, while others (mothers who have not recently had a natural RSV infection) develop severe illness requiring hospitalization.
There are data to support the contention that term infants born to mothers with higher naturally occurring anti-RSV neutralizing antibodies benefit from those antibodies. In a large prospective cohort study performed in Kenya, cord blood anti-RSV antibody concentrations correlated directly with the length of time before the infant’s first RSV infection. It’s therefore logical to conclude that administering an effective RSV vaccine during pregnancy could augment that natural antibody response, be transferred to the infant at birth, and offer protection against RSV when exposed.
Several candidate vaccines for study already exist and have undergone phase I testing in nonpregnant adults. Once safety is demonstrated, the next step is to identify the vaccine formulation resulting in the most robust anti-RSV neutralizing antibody concentrations. Such a candidate vaccine will be chosen for future phase III trials during pregnancy. Safety, and maternal/cord blood RSV antibody titers will be of interest during that clinical trial, but the rates and timing of RSV infection and RSV-associated hospitalizations among the infants born to those mothers will be the most instructive.
Ideally, a candidate RSV vaccine shown to be as safe and as effective during pregnancy as inactivated influenza vaccines and/or Tdap vaccines would be implemented immediately and universally. Unfortunately, substantial vaccine hesitancy for the use of influenza and Tdap vaccines continues among pregnant patients and their providers. Acceptance of an RSV vaccine for use during pregnancy will not come easily, or immediately. As with all of our successful vaccine programs, launching such an effort will require education, patience, and careful post-licensure documentation of the impact that the intervention has in the real world.
Dr. Domachowske is professor of pediatrics and professor of microbiology and immunology at the State University of New York Upstate Medical University, Syracuse, N.Y. Dr. Domachowske is performing clinical trials and has grants in the area of RSV prevention with Astra Zeneca, Regeneron, and Glaxo Smith Kline.
Why you need a new SVS tie or scarf
Congratulations! You noticed that Vascular Specialist has a new look. And with your well-honed powers of observation you also noticed the inauguration of the new logo for the Society for Vascular Surgery. However, you may be somewhat nonplussed. Because of the new logo you may have to buy a whole new wardrobe of SVS garments. I must admit I was confused as to the rationale behind changing the logo.
Surely it wasn’t because patients went elsewhere for treatment because they didn’t approve of the old one. I had never heard “Sorry Dr. Samson, I’m going to a cardiologist, I prefer the American College of Cardiology logo,” However, I now understand the reason behind this change is not so trivial. Rather, the new logo and Vascular Specialist’s appearance portends momentous changes in the aspirations and objectives of SVS and its publications.
Let me start with SVS. Long considered a staid, conservative organization geared mainly to promote academic and research achievements, it now fully embraces a commitment to the entire field of vascular surgery, its practitioners and patients. Under the leadership of current President Bruce Perler, the Executive Committee realized it is an imperative that government, health industries, and other medical specialists recognize the uniqueness of the spectrum of vascular surgeons’ services. Further, that this message is conveyed by SVS as our official mouthpiece.
You may ask how changing the logo conveys such a message. Simply put, the old logo does not work well with different color backgrounds and modern electronic media. It does not scale in updated websites, web browsers, or mobile apps. The new logo overcomes all these problems and by so doing confirms a change in direction for SVS. It acknowledges that our Society is part of the “Now” generation that understands the importance of all these new forms of communication. It affirms that branding and marketing the Society and its member vascular surgeons has become a priority.
Also, SVS recognized that this could only be achieved through an aggressive marketing campaign utilizing all that modern media has to offer. The first item on the Executive’s agenda was updating the SVS web site and for this a more workable logo was essential. The new website is in development and will debut soon. Concurrently, all aspects of branding will be revamped and the new logo will become omnipresent. It will now appear proudly on position papers, the JVS, SVS guidelines and all documents authored by the Society. I admit that to bolster this effort I have championed a complete name change to the American College of Vascular Surgery – but I have come to believe that this would be time consuming and entail so much cajoling that it would delay the SVS’s program. The website is a priority and our Society needs to move forward with its marketing campaign. The new logo is symbolic of the new SVS and it looks great!
The new design for Vascular Specialist begins as it enters its second decade as the official newspaper of SVS. Like SVS, our newspaper has also changed with the times. Although print has become very expensive, through the generosity of our many industry supporters, we have been able to expand the print editions to at least 20 pages every month and it is now mailed to over 5,000 members and affiliates worldwide.
A recent survey of SVS members confirmed that Vascular Specialist is the most widely read of all the vascular related periodicals. Importantly, Vascular Specialist also takes advantage of all the new methods of communication. It is now not only presented in print, but has an electronic presence with a website (www.vascularspecialistonline.com) and a mobile app containing many articles beyond those you will read in the print edition. We hope that vascular specialistonline.com will become your go to site for news and conversation related to all things vascular. One of my goals as Medical editor is to encourage you to not only be an avid reader, but also a contributor.
There are many ways you can help grow Vascular Specialist. Write a letter to the editor, contribute a Tips and Tricks, volunteer to write a Point/Counter Point column, submit an Opinion piece or simply respond to one of our online polls. Perhaps you wrote an article or made a presentation that you would like to reach a wider audience. You could send it to us and our reporters will convert it into newsworthy reports that can be printed or added to our online edition. Don’t fret over the chore of grammar and style; our writing staff will help make you seem like Shakespeare!
Of course patients did not avoid us because of our old logo and members read Vascular Specialist even though the font was old fashioned. However, these are important and exciting times and we want you to take part. We hope you will continue to read about your accomplishments and SVS achievements in print and electronic versions of Vascular Specialist. And yes, you may have to spring for a new SVS tie or scarf because the old ones are no longer current.
But, hopefully, the powers that be will recognize that a document or electronic media emblazoned with speaks authoritatively on behalf of vascular surgeons and our patients.
Dr. Samson is clinical professor of surgery (vascular) at Florida State University Medical School, is president of Mote Vascular Foundation, and an attending vascular surgeon, Sarasota (Fla.) Vascular Specialists.
Congratulations! You noticed that Vascular Specialist has a new look. And with your well-honed powers of observation you also noticed the inauguration of the new logo for the Society for Vascular Surgery. However, you may be somewhat nonplussed. Because of the new logo you may have to buy a whole new wardrobe of SVS garments. I must admit I was confused as to the rationale behind changing the logo.
Surely it wasn’t because patients went elsewhere for treatment because they didn’t approve of the old one. I had never heard “Sorry Dr. Samson, I’m going to a cardiologist, I prefer the American College of Cardiology logo,” However, I now understand the reason behind this change is not so trivial. Rather, the new logo and Vascular Specialist’s appearance portends momentous changes in the aspirations and objectives of SVS and its publications.
Let me start with SVS. Long considered a staid, conservative organization geared mainly to promote academic and research achievements, it now fully embraces a commitment to the entire field of vascular surgery, its practitioners and patients. Under the leadership of current President Bruce Perler, the Executive Committee realized it is an imperative that government, health industries, and other medical specialists recognize the uniqueness of the spectrum of vascular surgeons’ services. Further, that this message is conveyed by SVS as our official mouthpiece.
You may ask how changing the logo conveys such a message. Simply put, the old logo does not work well with different color backgrounds and modern electronic media. It does not scale in updated websites, web browsers, or mobile apps. The new logo overcomes all these problems and by so doing confirms a change in direction for SVS. It acknowledges that our Society is part of the “Now” generation that understands the importance of all these new forms of communication. It affirms that branding and marketing the Society and its member vascular surgeons has become a priority.
Also, SVS recognized that this could only be achieved through an aggressive marketing campaign utilizing all that modern media has to offer. The first item on the Executive’s agenda was updating the SVS web site and for this a more workable logo was essential. The new website is in development and will debut soon. Concurrently, all aspects of branding will be revamped and the new logo will become omnipresent. It will now appear proudly on position papers, the JVS, SVS guidelines and all documents authored by the Society. I admit that to bolster this effort I have championed a complete name change to the American College of Vascular Surgery – but I have come to believe that this would be time consuming and entail so much cajoling that it would delay the SVS’s program. The website is a priority and our Society needs to move forward with its marketing campaign. The new logo is symbolic of the new SVS and it looks great!
The new design for Vascular Specialist begins as it enters its second decade as the official newspaper of SVS. Like SVS, our newspaper has also changed with the times. Although print has become very expensive, through the generosity of our many industry supporters, we have been able to expand the print editions to at least 20 pages every month and it is now mailed to over 5,000 members and affiliates worldwide.
A recent survey of SVS members confirmed that Vascular Specialist is the most widely read of all the vascular related periodicals. Importantly, Vascular Specialist also takes advantage of all the new methods of communication. It is now not only presented in print, but has an electronic presence with a website (www.vascularspecialistonline.com) and a mobile app containing many articles beyond those you will read in the print edition. We hope that vascular specialistonline.com will become your go to site for news and conversation related to all things vascular. One of my goals as Medical editor is to encourage you to not only be an avid reader, but also a contributor.
There are many ways you can help grow Vascular Specialist. Write a letter to the editor, contribute a Tips and Tricks, volunteer to write a Point/Counter Point column, submit an Opinion piece or simply respond to one of our online polls. Perhaps you wrote an article or made a presentation that you would like to reach a wider audience. You could send it to us and our reporters will convert it into newsworthy reports that can be printed or added to our online edition. Don’t fret over the chore of grammar and style; our writing staff will help make you seem like Shakespeare!
Of course patients did not avoid us because of our old logo and members read Vascular Specialist even though the font was old fashioned. However, these are important and exciting times and we want you to take part. We hope you will continue to read about your accomplishments and SVS achievements in print and electronic versions of Vascular Specialist. And yes, you may have to spring for a new SVS tie or scarf because the old ones are no longer current.
But, hopefully, the powers that be will recognize that a document or electronic media emblazoned with speaks authoritatively on behalf of vascular surgeons and our patients.
Dr. Samson is clinical professor of surgery (vascular) at Florida State University Medical School, is president of Mote Vascular Foundation, and an attending vascular surgeon, Sarasota (Fla.) Vascular Specialists.
Congratulations! You noticed that Vascular Specialist has a new look. And with your well-honed powers of observation you also noticed the inauguration of the new logo for the Society for Vascular Surgery. However, you may be somewhat nonplussed. Because of the new logo you may have to buy a whole new wardrobe of SVS garments. I must admit I was confused as to the rationale behind changing the logo.
Surely it wasn’t because patients went elsewhere for treatment because they didn’t approve of the old one. I had never heard “Sorry Dr. Samson, I’m going to a cardiologist, I prefer the American College of Cardiology logo,” However, I now understand the reason behind this change is not so trivial. Rather, the new logo and Vascular Specialist’s appearance portends momentous changes in the aspirations and objectives of SVS and its publications.
Let me start with SVS. Long considered a staid, conservative organization geared mainly to promote academic and research achievements, it now fully embraces a commitment to the entire field of vascular surgery, its practitioners and patients. Under the leadership of current President Bruce Perler, the Executive Committee realized it is an imperative that government, health industries, and other medical specialists recognize the uniqueness of the spectrum of vascular surgeons’ services. Further, that this message is conveyed by SVS as our official mouthpiece.
You may ask how changing the logo conveys such a message. Simply put, the old logo does not work well with different color backgrounds and modern electronic media. It does not scale in updated websites, web browsers, or mobile apps. The new logo overcomes all these problems and by so doing confirms a change in direction for SVS. It acknowledges that our Society is part of the “Now” generation that understands the importance of all these new forms of communication. It affirms that branding and marketing the Society and its member vascular surgeons has become a priority.
Also, SVS recognized that this could only be achieved through an aggressive marketing campaign utilizing all that modern media has to offer. The first item on the Executive’s agenda was updating the SVS web site and for this a more workable logo was essential. The new website is in development and will debut soon. Concurrently, all aspects of branding will be revamped and the new logo will become omnipresent. It will now appear proudly on position papers, the JVS, SVS guidelines and all documents authored by the Society. I admit that to bolster this effort I have championed a complete name change to the American College of Vascular Surgery – but I have come to believe that this would be time consuming and entail so much cajoling that it would delay the SVS’s program. The website is a priority and our Society needs to move forward with its marketing campaign. The new logo is symbolic of the new SVS and it looks great!
The new design for Vascular Specialist begins as it enters its second decade as the official newspaper of SVS. Like SVS, our newspaper has also changed with the times. Although print has become very expensive, through the generosity of our many industry supporters, we have been able to expand the print editions to at least 20 pages every month and it is now mailed to over 5,000 members and affiliates worldwide.
A recent survey of SVS members confirmed that Vascular Specialist is the most widely read of all the vascular related periodicals. Importantly, Vascular Specialist also takes advantage of all the new methods of communication. It is now not only presented in print, but has an electronic presence with a website (www.vascularspecialistonline.com) and a mobile app containing many articles beyond those you will read in the print edition. We hope that vascular specialistonline.com will become your go to site for news and conversation related to all things vascular. One of my goals as Medical editor is to encourage you to not only be an avid reader, but also a contributor.
There are many ways you can help grow Vascular Specialist. Write a letter to the editor, contribute a Tips and Tricks, volunteer to write a Point/Counter Point column, submit an Opinion piece or simply respond to one of our online polls. Perhaps you wrote an article or made a presentation that you would like to reach a wider audience. You could send it to us and our reporters will convert it into newsworthy reports that can be printed or added to our online edition. Don’t fret over the chore of grammar and style; our writing staff will help make you seem like Shakespeare!
Of course patients did not avoid us because of our old logo and members read Vascular Specialist even though the font was old fashioned. However, these are important and exciting times and we want you to take part. We hope you will continue to read about your accomplishments and SVS achievements in print and electronic versions of Vascular Specialist. And yes, you may have to spring for a new SVS tie or scarf because the old ones are no longer current.
But, hopefully, the powers that be will recognize that a document or electronic media emblazoned with speaks authoritatively on behalf of vascular surgeons and our patients.
Dr. Samson is clinical professor of surgery (vascular) at Florida State University Medical School, is president of Mote Vascular Foundation, and an attending vascular surgeon, Sarasota (Fla.) Vascular Specialists.
A dermatologist’s bad dream?
My plane doesn’t leave till 2:30. Glad I cut off seeing patients at 11, which should give me plenty of time. I’m getting smarter in my old age.
Smooth morning, paperwork pretty much done. Just one patient left. Look, a nice little old man. He has such a sweet smile.
“How can I help you, Mr. Goldfarb?”
“It’s complicated. This letter explains everything that’s happened the past 3 years,”
Oh-oh, that doesn’t sound good. “OK, let’s have a look.”
“My, you read fast, Doctor.”
When the first line says, ‘The lice all over my body don’t go away even after I apply bug shampoo every day,’ I’m pretty much done.
“Doctor, this bag has everything I’ve used: lice shampoo, insect spray, itch lotion. I forgot to bring in all the little bugs I collected from my combs and sheets.”
No! This can’t be happening! How do I negotiate with a delusion and still make my plane?
“Sometimes it feels like bugs are crawling on my skin.”
“Itching often feels that way ... ”
“I brought pictures. Want to see?”
No! Not an album! Snap after snap: scabs on the scalp, scaling at the corners of the mouth, linear scratches on the extremities.
“You know, Mr. Goldfarb – maybe firm confidence will let me regain control of this interview – what you’re describing does not sound like lice or bugs of any kind ... ”
“But Doctor, how do you explain this?” Another photo, this of a comb filled with brownish epidermal fragments. “I meant to bring some in, but I forgot.”
Enough. Time to look grim and speak briskly. “Mr. Goldfarb, this cannot be lice because ... ”
“I see them coming out of all my pores ... ”
“Mr. Goldfarb!” Now it’s my turn to interrupt. “I would appreciate it if you would let me finish my sentence.”
“Yes, Doctor. If it’s not lice, what do you think it is?”
Must think fast. “Sensitivity. Sensitive skin, especially if you’ve scratched it, can certainly feel as though there are things crawling on you. Patients often say that the skin feels this way. I will therefore treat this sensitivity with anti-inflammatory creams and lotion you will apply to the scalp, face, and the rest of your body respectively.”
Goldfarb is still listening. I’m almost there.
“I want you to use this medication for 2 weeks without stopping, and not use any more of the bug shampoos and creams because they can be irritating and increase itch and sensitivity. Please call me on my private extension at that point with your progress.” Easier to deny a delusion when not standing face to face.
“That’s good news, Doctor. I’ll pick up the medication and let you know.”
At most, he’ll stop scratching for a while. By the time he starts again, I’ll have made my plane and come back to the office. Meantime: Depart exam room briskly!
I can still make it if I leave right away. One last check of my office e-mail. There’s one from Zelda. She has a small scaly patch on one forearm. Claims it’s responded neither to topical antifungals nor steroids.
Here’s the text of her e-mail: “Doctor, I showed my rash to my neighbor Mary. She did some Internet research, and she’s convinced it’s chromoblastomycosis. I’m pretty sure she’s right. What do you think?”
I think I better leave right now.
My reply: “Dear Zelda, pretty unlikely. Try the new cream I’m going to prescribe for 2 weeks, and let me check on how you’re doing.”
How does evil dermatologic karma know that I’m trying to leave town? Parasitosis and chromoblastomycosis! Can this be a bad dream? If so, why don’t I wake up?
Mr. Goldfarb, still looking sweet and mild, sits in the waiting room, awaiting the elder shuttle to take him home.
Walk fast. Do not smile and meet his gaze. This is no time for politeness.
No, sir. I am outta here.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at dermnews@frontlinemedcom.com.
My plane doesn’t leave till 2:30. Glad I cut off seeing patients at 11, which should give me plenty of time. I’m getting smarter in my old age.
Smooth morning, paperwork pretty much done. Just one patient left. Look, a nice little old man. He has such a sweet smile.
“How can I help you, Mr. Goldfarb?”
“It’s complicated. This letter explains everything that’s happened the past 3 years,”
Oh-oh, that doesn’t sound good. “OK, let’s have a look.”
“My, you read fast, Doctor.”
When the first line says, ‘The lice all over my body don’t go away even after I apply bug shampoo every day,’ I’m pretty much done.
“Doctor, this bag has everything I’ve used: lice shampoo, insect spray, itch lotion. I forgot to bring in all the little bugs I collected from my combs and sheets.”
No! This can’t be happening! How do I negotiate with a delusion and still make my plane?
“Sometimes it feels like bugs are crawling on my skin.”
“Itching often feels that way ... ”
“I brought pictures. Want to see?”
No! Not an album! Snap after snap: scabs on the scalp, scaling at the corners of the mouth, linear scratches on the extremities.
“You know, Mr. Goldfarb – maybe firm confidence will let me regain control of this interview – what you’re describing does not sound like lice or bugs of any kind ... ”
“But Doctor, how do you explain this?” Another photo, this of a comb filled with brownish epidermal fragments. “I meant to bring some in, but I forgot.”
Enough. Time to look grim and speak briskly. “Mr. Goldfarb, this cannot be lice because ... ”
“I see them coming out of all my pores ... ”
“Mr. Goldfarb!” Now it’s my turn to interrupt. “I would appreciate it if you would let me finish my sentence.”
“Yes, Doctor. If it’s not lice, what do you think it is?”
Must think fast. “Sensitivity. Sensitive skin, especially if you’ve scratched it, can certainly feel as though there are things crawling on you. Patients often say that the skin feels this way. I will therefore treat this sensitivity with anti-inflammatory creams and lotion you will apply to the scalp, face, and the rest of your body respectively.”
Goldfarb is still listening. I’m almost there.
“I want you to use this medication for 2 weeks without stopping, and not use any more of the bug shampoos and creams because they can be irritating and increase itch and sensitivity. Please call me on my private extension at that point with your progress.” Easier to deny a delusion when not standing face to face.
“That’s good news, Doctor. I’ll pick up the medication and let you know.”
At most, he’ll stop scratching for a while. By the time he starts again, I’ll have made my plane and come back to the office. Meantime: Depart exam room briskly!
I can still make it if I leave right away. One last check of my office e-mail. There’s one from Zelda. She has a small scaly patch on one forearm. Claims it’s responded neither to topical antifungals nor steroids.
Here’s the text of her e-mail: “Doctor, I showed my rash to my neighbor Mary. She did some Internet research, and she’s convinced it’s chromoblastomycosis. I’m pretty sure she’s right. What do you think?”
I think I better leave right now.
My reply: “Dear Zelda, pretty unlikely. Try the new cream I’m going to prescribe for 2 weeks, and let me check on how you’re doing.”
How does evil dermatologic karma know that I’m trying to leave town? Parasitosis and chromoblastomycosis! Can this be a bad dream? If so, why don’t I wake up?
Mr. Goldfarb, still looking sweet and mild, sits in the waiting room, awaiting the elder shuttle to take him home.
Walk fast. Do not smile and meet his gaze. This is no time for politeness.
No, sir. I am outta here.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at dermnews@frontlinemedcom.com.
My plane doesn’t leave till 2:30. Glad I cut off seeing patients at 11, which should give me plenty of time. I’m getting smarter in my old age.
Smooth morning, paperwork pretty much done. Just one patient left. Look, a nice little old man. He has such a sweet smile.
“How can I help you, Mr. Goldfarb?”
“It’s complicated. This letter explains everything that’s happened the past 3 years,”
Oh-oh, that doesn’t sound good. “OK, let’s have a look.”
“My, you read fast, Doctor.”
When the first line says, ‘The lice all over my body don’t go away even after I apply bug shampoo every day,’ I’m pretty much done.
“Doctor, this bag has everything I’ve used: lice shampoo, insect spray, itch lotion. I forgot to bring in all the little bugs I collected from my combs and sheets.”
No! This can’t be happening! How do I negotiate with a delusion and still make my plane?
“Sometimes it feels like bugs are crawling on my skin.”
“Itching often feels that way ... ”
“I brought pictures. Want to see?”
No! Not an album! Snap after snap: scabs on the scalp, scaling at the corners of the mouth, linear scratches on the extremities.
“You know, Mr. Goldfarb – maybe firm confidence will let me regain control of this interview – what you’re describing does not sound like lice or bugs of any kind ... ”
“But Doctor, how do you explain this?” Another photo, this of a comb filled with brownish epidermal fragments. “I meant to bring some in, but I forgot.”
Enough. Time to look grim and speak briskly. “Mr. Goldfarb, this cannot be lice because ... ”
“I see them coming out of all my pores ... ”
“Mr. Goldfarb!” Now it’s my turn to interrupt. “I would appreciate it if you would let me finish my sentence.”
“Yes, Doctor. If it’s not lice, what do you think it is?”
Must think fast. “Sensitivity. Sensitive skin, especially if you’ve scratched it, can certainly feel as though there are things crawling on you. Patients often say that the skin feels this way. I will therefore treat this sensitivity with anti-inflammatory creams and lotion you will apply to the scalp, face, and the rest of your body respectively.”
Goldfarb is still listening. I’m almost there.
“I want you to use this medication for 2 weeks without stopping, and not use any more of the bug shampoos and creams because they can be irritating and increase itch and sensitivity. Please call me on my private extension at that point with your progress.” Easier to deny a delusion when not standing face to face.
“That’s good news, Doctor. I’ll pick up the medication and let you know.”
At most, he’ll stop scratching for a while. By the time he starts again, I’ll have made my plane and come back to the office. Meantime: Depart exam room briskly!
I can still make it if I leave right away. One last check of my office e-mail. There’s one from Zelda. She has a small scaly patch on one forearm. Claims it’s responded neither to topical antifungals nor steroids.
Here’s the text of her e-mail: “Doctor, I showed my rash to my neighbor Mary. She did some Internet research, and she’s convinced it’s chromoblastomycosis. I’m pretty sure she’s right. What do you think?”
I think I better leave right now.
My reply: “Dear Zelda, pretty unlikely. Try the new cream I’m going to prescribe for 2 weeks, and let me check on how you’re doing.”
How does evil dermatologic karma know that I’m trying to leave town? Parasitosis and chromoblastomycosis! Can this be a bad dream? If so, why don’t I wake up?
Mr. Goldfarb, still looking sweet and mild, sits in the waiting room, awaiting the elder shuttle to take him home.
Walk fast. Do not smile and meet his gaze. This is no time for politeness.
No, sir. I am outta here.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. Write to him at dermnews@frontlinemedcom.com.
Caring for gender-nonconforming youth in a primary care setting – Part 2
Gender identity typically develops in early childhood, and by age 4 years, most children consistently refer to themselves as a girl or a boy.1 For the majority of children, natal sex or sex assigned at birth, aligns with gender identity (a person’s innate sense of feeling male, female, or somewhere in between). However, this is not always the case. Gender identity can be understood as a spectrum with youth identifying as a gender that aligns with their natal sex (cisgender), is opposite of their natal sex (transgender), no gender (agender), or somewhere in between (genderqueer). The distress that can result from an incongruence between natal sex and gender identity is called gender dysphoria. Youth with gender dysphoria are at increased risk for a number of conditions, including suicide and self-harm. Early identification and appropriate care of these youth can reduce these risks. This month’s column will briefly review assessment of these youth in the pediatric setting.
Many youth who have a gender-nonconforming identity in childhood will not go on to have one in adulthood.2,3 Those who have a consistent, insistent, and persistent nonconforming identity are more likely to have this identity persist into adulthood. Youth who experience increased gender dysphoria with the onset of puberty rarely have this subside.
As it can be difficult to predict the trajectory of gender identity from childhood to adolescence, the approach to the prepubertal and pubertal gender nonconforming patient is different. It is important to note that research suggests that gender identity is innate and cannot be changed with interventions. The goals of care for gender-nonconforming (GN) youth include providing a safe environment where youth can explore their identities, and individualizing treatment to meet the needs of each patient and family.
Care for prepubertal GN youth
For parents:
Have you noticed, or are you concerned about your child’s:
• Preference or rejection of particular toys/games?
• Hair and clothing preferences or rejections?
• Preferred (if any) gender of playmates?
Has your child ever expressed:
• A desire to be or insistence that they are the other gender?
• A dislike of their sexual anatomy?
• A desire for primary (penis, vagina) or secondary (periods, facial hair) sex characteristics of the other gender?
Are you concerned about bullying ?
Do you have any concerns about your child’s mood or concerns for self-harm?
For children:
• Do you feel more like a girl, boy, neither, both?
• How would you like to play, cut your hair, dress?
• What name or pronoun (she for girl, he for boy) fits you?4
The goal for prepubertal youth with nonconforming identities is to ensure that they are safe at home, school, and at play. Some youth may express a desire to “transition” or live as their identified gender by changing their name and dressing as their identified gender. Some youth and families may choose to transition only in certain settings (at home, but not at school). Some youth and families may want a safe space where the child can grow, develop, and continue to explore their identity without transitioning. Mental health providers trained in the care of GN youth can help patients and families decide if transition is appropriate for them and support them with the process and timing of transitioning. For youth who experience depression, anxiety, bullying, or thoughts of self-harm related to their gender identity, care by an experienced mental health provider is essential. It is important to recognize that each patient and family will need an individualized approach based on their needs.
Care for pubertal GN youth
The development of secondary sex characteristics can be particularly distressing for GN youth. Some youth may first experience gender dysphoria at this time. This distress combined with the psychosocial stressors of adolescent development can lead to depression, anxiety, suicidal ideation, self-harm, and other risk taking behaviors. Visits with pubertal GN youth, as with any adolescent, should include confidential time alone with the medical provider to discuss any concerns. Youth should be informed that information will be kept confidential, but parents will need to be notified of any safety concerns (such as suicidality or self-harm). As with prepubertal youth, a history related to hair and clothing preferences; distress related to genital anatomy; and the desire to be the other gender should be obtained. A pubertal history and any related symptoms of distress also should be obtained.
DO
• Ask preferred name and pronoun.
• Perform confidential strength and risk assessment.
• Assess for family and social support.
• Refer to appropriate mental health and transgender providers.
DON’T
• Assume names and pronouns.
• Interview patient only with parent in the room.
• Disclose identity without patient consent.
• Dismiss parents as sources of support.
• Refer for reparative therapy.4
Youth who are suspected to have a diagnosis of gender dysphoria should be referred to mental health and medical providers with experience caring for transgender youth. These specialists can work with patients and families, and determine when and if youth are eligible for puberty blocking therapy with GnRH analogues and/or hormone therapy. GnRH analogues, if appropriate, can be prescribed after patients have reached sexual maturity rating stage 2. The rationale for this treatment is to prevent the development of unwanted secondary sex characteristics while giving the youth a chance to continue with psychotherapy and explore their gender identity.5 Hormone therapy, if appropriate, can be prescribed a few years later under the care of a transgender specialist and mental health provider.
Summary
It is normal to experiment with gender roles and expression in childhood. Providing a safe space to do this is important.
Individuals who have a persistent, consistent, and insistent gender-nonconforming identification and who have increased distress with puberty are unlikely to have this subside.
Pediatricians can assess for gender dysphoria and screen for related mood disorders and behaviors in the primary care setting. Appropriate referral to trained professionals is important.
Care should be individualized and focused on the health and safety of the patient.
Resources
For health care professionals
• World Professional Association for Transgender Health: Standards of care on care of transgender patients and provider directory. www.wpath.org• Physicians for Reproductive Health’s adolescent reproductive and sexual health education program (ARSHEP): Best practices for adolescent and reproductive health: Module on caring for transgender adolescent patients. prh.org/teen-reproductive-health/arshep-downloads/
For patients and families
• Family Acceptance Project: familyproject.sfsu.edu/
• Healthychildren.org: Parenting website supported by the American Academy of Pediatrics. Links to articles on gender nonconforming and transgender children; gender identity development in children. www.healthychildren.org
References
1. Caring for Your School Age Child: Ages 5-12 by the American Academy of Pediatrics (New York: Bantam Books, 1995).
2. Dev Psychol. 2008 Jan;44(1):34-45.
3. J Am Acad Child and Adolesc Psychiatry. 2008;47(12):1413-23
4. Caring for Transgender Adolescent Patients. Physicians for Reproductive Health’s Adolescent Reproductive and Sexual Health Education Program (ARSHEP): Best practices for adolescent and reproductive health: prh.org/teen-reproductive-health/arshep-downloads/
5. World Professional Association of Transgender Health, Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, 7th Edition (International Journal of Transgenderism. 2011;13:165-232)
Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.
Gender identity typically develops in early childhood, and by age 4 years, most children consistently refer to themselves as a girl or a boy.1 For the majority of children, natal sex or sex assigned at birth, aligns with gender identity (a person’s innate sense of feeling male, female, or somewhere in between). However, this is not always the case. Gender identity can be understood as a spectrum with youth identifying as a gender that aligns with their natal sex (cisgender), is opposite of their natal sex (transgender), no gender (agender), or somewhere in between (genderqueer). The distress that can result from an incongruence between natal sex and gender identity is called gender dysphoria. Youth with gender dysphoria are at increased risk for a number of conditions, including suicide and self-harm. Early identification and appropriate care of these youth can reduce these risks. This month’s column will briefly review assessment of these youth in the pediatric setting.
Many youth who have a gender-nonconforming identity in childhood will not go on to have one in adulthood.2,3 Those who have a consistent, insistent, and persistent nonconforming identity are more likely to have this identity persist into adulthood. Youth who experience increased gender dysphoria with the onset of puberty rarely have this subside.
As it can be difficult to predict the trajectory of gender identity from childhood to adolescence, the approach to the prepubertal and pubertal gender nonconforming patient is different. It is important to note that research suggests that gender identity is innate and cannot be changed with interventions. The goals of care for gender-nonconforming (GN) youth include providing a safe environment where youth can explore their identities, and individualizing treatment to meet the needs of each patient and family.
Care for prepubertal GN youth
For parents:
Have you noticed, or are you concerned about your child’s:
• Preference or rejection of particular toys/games?
• Hair and clothing preferences or rejections?
• Preferred (if any) gender of playmates?
Has your child ever expressed:
• A desire to be or insistence that they are the other gender?
• A dislike of their sexual anatomy?
• A desire for primary (penis, vagina) or secondary (periods, facial hair) sex characteristics of the other gender?
Are you concerned about bullying ?
Do you have any concerns about your child’s mood or concerns for self-harm?
For children:
• Do you feel more like a girl, boy, neither, both?
• How would you like to play, cut your hair, dress?
• What name or pronoun (she for girl, he for boy) fits you?4
The goal for prepubertal youth with nonconforming identities is to ensure that they are safe at home, school, and at play. Some youth may express a desire to “transition” or live as their identified gender by changing their name and dressing as their identified gender. Some youth and families may choose to transition only in certain settings (at home, but not at school). Some youth and families may want a safe space where the child can grow, develop, and continue to explore their identity without transitioning. Mental health providers trained in the care of GN youth can help patients and families decide if transition is appropriate for them and support them with the process and timing of transitioning. For youth who experience depression, anxiety, bullying, or thoughts of self-harm related to their gender identity, care by an experienced mental health provider is essential. It is important to recognize that each patient and family will need an individualized approach based on their needs.
Care for pubertal GN youth
The development of secondary sex characteristics can be particularly distressing for GN youth. Some youth may first experience gender dysphoria at this time. This distress combined with the psychosocial stressors of adolescent development can lead to depression, anxiety, suicidal ideation, self-harm, and other risk taking behaviors. Visits with pubertal GN youth, as with any adolescent, should include confidential time alone with the medical provider to discuss any concerns. Youth should be informed that information will be kept confidential, but parents will need to be notified of any safety concerns (such as suicidality or self-harm). As with prepubertal youth, a history related to hair and clothing preferences; distress related to genital anatomy; and the desire to be the other gender should be obtained. A pubertal history and any related symptoms of distress also should be obtained.
DO
• Ask preferred name and pronoun.
• Perform confidential strength and risk assessment.
• Assess for family and social support.
• Refer to appropriate mental health and transgender providers.
DON’T
• Assume names and pronouns.
• Interview patient only with parent in the room.
• Disclose identity without patient consent.
• Dismiss parents as sources of support.
• Refer for reparative therapy.4
Youth who are suspected to have a diagnosis of gender dysphoria should be referred to mental health and medical providers with experience caring for transgender youth. These specialists can work with patients and families, and determine when and if youth are eligible for puberty blocking therapy with GnRH analogues and/or hormone therapy. GnRH analogues, if appropriate, can be prescribed after patients have reached sexual maturity rating stage 2. The rationale for this treatment is to prevent the development of unwanted secondary sex characteristics while giving the youth a chance to continue with psychotherapy and explore their gender identity.5 Hormone therapy, if appropriate, can be prescribed a few years later under the care of a transgender specialist and mental health provider.
Summary
It is normal to experiment with gender roles and expression in childhood. Providing a safe space to do this is important.
Individuals who have a persistent, consistent, and insistent gender-nonconforming identification and who have increased distress with puberty are unlikely to have this subside.
Pediatricians can assess for gender dysphoria and screen for related mood disorders and behaviors in the primary care setting. Appropriate referral to trained professionals is important.
Care should be individualized and focused on the health and safety of the patient.
Resources
For health care professionals
• World Professional Association for Transgender Health: Standards of care on care of transgender patients and provider directory. www.wpath.org• Physicians for Reproductive Health’s adolescent reproductive and sexual health education program (ARSHEP): Best practices for adolescent and reproductive health: Module on caring for transgender adolescent patients. prh.org/teen-reproductive-health/arshep-downloads/
For patients and families
• Family Acceptance Project: familyproject.sfsu.edu/
• Healthychildren.org: Parenting website supported by the American Academy of Pediatrics. Links to articles on gender nonconforming and transgender children; gender identity development in children. www.healthychildren.org
References
1. Caring for Your School Age Child: Ages 5-12 by the American Academy of Pediatrics (New York: Bantam Books, 1995).
2. Dev Psychol. 2008 Jan;44(1):34-45.
3. J Am Acad Child and Adolesc Psychiatry. 2008;47(12):1413-23
4. Caring for Transgender Adolescent Patients. Physicians for Reproductive Health’s Adolescent Reproductive and Sexual Health Education Program (ARSHEP): Best practices for adolescent and reproductive health: prh.org/teen-reproductive-health/arshep-downloads/
5. World Professional Association of Transgender Health, Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, 7th Edition (International Journal of Transgenderism. 2011;13:165-232)
Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.
Gender identity typically develops in early childhood, and by age 4 years, most children consistently refer to themselves as a girl or a boy.1 For the majority of children, natal sex or sex assigned at birth, aligns with gender identity (a person’s innate sense of feeling male, female, or somewhere in between). However, this is not always the case. Gender identity can be understood as a spectrum with youth identifying as a gender that aligns with their natal sex (cisgender), is opposite of their natal sex (transgender), no gender (agender), or somewhere in between (genderqueer). The distress that can result from an incongruence between natal sex and gender identity is called gender dysphoria. Youth with gender dysphoria are at increased risk for a number of conditions, including suicide and self-harm. Early identification and appropriate care of these youth can reduce these risks. This month’s column will briefly review assessment of these youth in the pediatric setting.
Many youth who have a gender-nonconforming identity in childhood will not go on to have one in adulthood.2,3 Those who have a consistent, insistent, and persistent nonconforming identity are more likely to have this identity persist into adulthood. Youth who experience increased gender dysphoria with the onset of puberty rarely have this subside.
As it can be difficult to predict the trajectory of gender identity from childhood to adolescence, the approach to the prepubertal and pubertal gender nonconforming patient is different. It is important to note that research suggests that gender identity is innate and cannot be changed with interventions. The goals of care for gender-nonconforming (GN) youth include providing a safe environment where youth can explore their identities, and individualizing treatment to meet the needs of each patient and family.
Care for prepubertal GN youth
For parents:
Have you noticed, or are you concerned about your child’s:
• Preference or rejection of particular toys/games?
• Hair and clothing preferences or rejections?
• Preferred (if any) gender of playmates?
Has your child ever expressed:
• A desire to be or insistence that they are the other gender?
• A dislike of their sexual anatomy?
• A desire for primary (penis, vagina) or secondary (periods, facial hair) sex characteristics of the other gender?
Are you concerned about bullying ?
Do you have any concerns about your child’s mood or concerns for self-harm?
For children:
• Do you feel more like a girl, boy, neither, both?
• How would you like to play, cut your hair, dress?
• What name or pronoun (she for girl, he for boy) fits you?4
The goal for prepubertal youth with nonconforming identities is to ensure that they are safe at home, school, and at play. Some youth may express a desire to “transition” or live as their identified gender by changing their name and dressing as their identified gender. Some youth and families may choose to transition only in certain settings (at home, but not at school). Some youth and families may want a safe space where the child can grow, develop, and continue to explore their identity without transitioning. Mental health providers trained in the care of GN youth can help patients and families decide if transition is appropriate for them and support them with the process and timing of transitioning. For youth who experience depression, anxiety, bullying, or thoughts of self-harm related to their gender identity, care by an experienced mental health provider is essential. It is important to recognize that each patient and family will need an individualized approach based on their needs.
Care for pubertal GN youth
The development of secondary sex characteristics can be particularly distressing for GN youth. Some youth may first experience gender dysphoria at this time. This distress combined with the psychosocial stressors of adolescent development can lead to depression, anxiety, suicidal ideation, self-harm, and other risk taking behaviors. Visits with pubertal GN youth, as with any adolescent, should include confidential time alone with the medical provider to discuss any concerns. Youth should be informed that information will be kept confidential, but parents will need to be notified of any safety concerns (such as suicidality or self-harm). As with prepubertal youth, a history related to hair and clothing preferences; distress related to genital anatomy; and the desire to be the other gender should be obtained. A pubertal history and any related symptoms of distress also should be obtained.
DO
• Ask preferred name and pronoun.
• Perform confidential strength and risk assessment.
• Assess for family and social support.
• Refer to appropriate mental health and transgender providers.
DON’T
• Assume names and pronouns.
• Interview patient only with parent in the room.
• Disclose identity without patient consent.
• Dismiss parents as sources of support.
• Refer for reparative therapy.4
Youth who are suspected to have a diagnosis of gender dysphoria should be referred to mental health and medical providers with experience caring for transgender youth. These specialists can work with patients and families, and determine when and if youth are eligible for puberty blocking therapy with GnRH analogues and/or hormone therapy. GnRH analogues, if appropriate, can be prescribed after patients have reached sexual maturity rating stage 2. The rationale for this treatment is to prevent the development of unwanted secondary sex characteristics while giving the youth a chance to continue with psychotherapy and explore their gender identity.5 Hormone therapy, if appropriate, can be prescribed a few years later under the care of a transgender specialist and mental health provider.
Summary
It is normal to experiment with gender roles and expression in childhood. Providing a safe space to do this is important.
Individuals who have a persistent, consistent, and insistent gender-nonconforming identification and who have increased distress with puberty are unlikely to have this subside.
Pediatricians can assess for gender dysphoria and screen for related mood disorders and behaviors in the primary care setting. Appropriate referral to trained professionals is important.
Care should be individualized and focused on the health and safety of the patient.
Resources
For health care professionals
• World Professional Association for Transgender Health: Standards of care on care of transgender patients and provider directory. www.wpath.org• Physicians for Reproductive Health’s adolescent reproductive and sexual health education program (ARSHEP): Best practices for adolescent and reproductive health: Module on caring for transgender adolescent patients. prh.org/teen-reproductive-health/arshep-downloads/
For patients and families
• Family Acceptance Project: familyproject.sfsu.edu/
• Healthychildren.org: Parenting website supported by the American Academy of Pediatrics. Links to articles on gender nonconforming and transgender children; gender identity development in children. www.healthychildren.org
References
1. Caring for Your School Age Child: Ages 5-12 by the American Academy of Pediatrics (New York: Bantam Books, 1995).
2. Dev Psychol. 2008 Jan;44(1):34-45.
3. J Am Acad Child and Adolesc Psychiatry. 2008;47(12):1413-23
4. Caring for Transgender Adolescent Patients. Physicians for Reproductive Health’s Adolescent Reproductive and Sexual Health Education Program (ARSHEP): Best practices for adolescent and reproductive health: prh.org/teen-reproductive-health/arshep-downloads/
5. World Professional Association of Transgender Health, Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, 7th Edition (International Journal of Transgenderism. 2011;13:165-232)
Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.
Examining the medical needs of military women
A supplement recently published in Military Medicine seeks to examine how the Defense Department meets the medical needs of its women warriors. Called “Combat: Framing the Issues of Health and Health Research for America’s Servicewomen,” the articles go a long way toward shining a light on an important issue.
Several of the articles in the supplement highlight mental health issues for women in the military. They include the pieces about sexual harassment, the many faces of military families, alcohol use, and the corrosive effects of ostracism.
One of the articles by Kate McGraw, Ph.D., of the Deployment Health Clinical Center, Silver Spring, Md., focuses on the mental well-being of servicewomen and sexual trauma. Underlying the supplement is the recognition that the most robust mental health research repeatedly conducted in Afghanistan, for example, did not include a single woman because of the sampling methodology. A dedicated group addressing service women’s health and inclusion in health research would have prevented this oversight.
The health of female service members has long been an interest of mine, partly because I was in the Army for 28 years and deployed to a lot of austere environments. They included the rice fields of Camp Edwards, near the DMZ in Korea; Mogadishu and other “cities” in Somalia; and various Forward Operating Bases in Iraq.
Many years ago, I published an article on health concerns of deployed women. That focused on concerns about how to avoid urinary tract infections (UTIs) while in the field – where bathrooms are often scarce and dirty – and other seemingly mundane issues.
Mundane unless you have a UTI, or are trying to figure out how to manage your menses with no tampons or places to wash your hands.
Since then the literature has grown. For example, I published a volume called “Women at War” (Oxford University Press, 2015) last spring. This recent supplement advances those discussions, including articles on avoiding anemia and stress fractures.
But the way forward has been spotty. Many political issues delay an open discussion, especially on reproductive concerns. Further, there is no driving function within the Department of Defense that focuses on funding research in support of service women and reporting back to the department and civilian leadership.
For example: Female service members have a rate of unintended pregnancy twice that of the civilian world. This leads to early attrition from the military, and in turn, to young female veterans with children who are homeless.
Some have said, highlighting these concerns, that females should not be in the military because our presence is a risk to operational readiness. However, this is not an issue without tested solutions.
Taking this one issue further, consider that all service women are included in the Military Health System and have access to a variety of forms of birth control. If female service members can be put on oral contraceptives, that would both suppress their menses and avoid unwanted pregnancies. However, longer lasting methods of birth control would enable service women to enjoy decreased menses, avoid unwanted pregnancies, and avoid access issues during deployment.
The supplement contains numerous health policy and research recommendations as well as a detailed look at the unique health and lifestyle challenges of service women. Other issues include: the reproductive health of women in austere environments, nutritional factors, avoiding musculoskeletal injuries, combat-related injuries, designing military equipment (including uniforms) for optimal performance, and the role of leadership. It concludes with 20 research gaps and accompanying recommendations.
The number of women serving in the military is increasing, while all jobs, particularly those in the ground combat element, are now open to women. The time is now to focus on establishing and tracking health and well-being issues to ensure the success of this population – and the Military Medicine special issue is just a first step.
Dr. Ritchie serves as professor of psychiatry at the Uniformed Services University of the Health Services in Bethesda, Md., and at Georgetown University in Washington. She helped write one of the articles in the supplement with Dr. McGraw and Tracey Perez Koehlmoos, Ph.D., an associate professor with the Uniformed Services University.
A supplement recently published in Military Medicine seeks to examine how the Defense Department meets the medical needs of its women warriors. Called “Combat: Framing the Issues of Health and Health Research for America’s Servicewomen,” the articles go a long way toward shining a light on an important issue.
Several of the articles in the supplement highlight mental health issues for women in the military. They include the pieces about sexual harassment, the many faces of military families, alcohol use, and the corrosive effects of ostracism.
One of the articles by Kate McGraw, Ph.D., of the Deployment Health Clinical Center, Silver Spring, Md., focuses on the mental well-being of servicewomen and sexual trauma. Underlying the supplement is the recognition that the most robust mental health research repeatedly conducted in Afghanistan, for example, did not include a single woman because of the sampling methodology. A dedicated group addressing service women’s health and inclusion in health research would have prevented this oversight.
The health of female service members has long been an interest of mine, partly because I was in the Army for 28 years and deployed to a lot of austere environments. They included the rice fields of Camp Edwards, near the DMZ in Korea; Mogadishu and other “cities” in Somalia; and various Forward Operating Bases in Iraq.
Many years ago, I published an article on health concerns of deployed women. That focused on concerns about how to avoid urinary tract infections (UTIs) while in the field – where bathrooms are often scarce and dirty – and other seemingly mundane issues.
Mundane unless you have a UTI, or are trying to figure out how to manage your menses with no tampons or places to wash your hands.
Since then the literature has grown. For example, I published a volume called “Women at War” (Oxford University Press, 2015) last spring. This recent supplement advances those discussions, including articles on avoiding anemia and stress fractures.
But the way forward has been spotty. Many political issues delay an open discussion, especially on reproductive concerns. Further, there is no driving function within the Department of Defense that focuses on funding research in support of service women and reporting back to the department and civilian leadership.
For example: Female service members have a rate of unintended pregnancy twice that of the civilian world. This leads to early attrition from the military, and in turn, to young female veterans with children who are homeless.
Some have said, highlighting these concerns, that females should not be in the military because our presence is a risk to operational readiness. However, this is not an issue without tested solutions.
Taking this one issue further, consider that all service women are included in the Military Health System and have access to a variety of forms of birth control. If female service members can be put on oral contraceptives, that would both suppress their menses and avoid unwanted pregnancies. However, longer lasting methods of birth control would enable service women to enjoy decreased menses, avoid unwanted pregnancies, and avoid access issues during deployment.
The supplement contains numerous health policy and research recommendations as well as a detailed look at the unique health and lifestyle challenges of service women. Other issues include: the reproductive health of women in austere environments, nutritional factors, avoiding musculoskeletal injuries, combat-related injuries, designing military equipment (including uniforms) for optimal performance, and the role of leadership. It concludes with 20 research gaps and accompanying recommendations.
The number of women serving in the military is increasing, while all jobs, particularly those in the ground combat element, are now open to women. The time is now to focus on establishing and tracking health and well-being issues to ensure the success of this population – and the Military Medicine special issue is just a first step.
Dr. Ritchie serves as professor of psychiatry at the Uniformed Services University of the Health Services in Bethesda, Md., and at Georgetown University in Washington. She helped write one of the articles in the supplement with Dr. McGraw and Tracey Perez Koehlmoos, Ph.D., an associate professor with the Uniformed Services University.
A supplement recently published in Military Medicine seeks to examine how the Defense Department meets the medical needs of its women warriors. Called “Combat: Framing the Issues of Health and Health Research for America’s Servicewomen,” the articles go a long way toward shining a light on an important issue.
Several of the articles in the supplement highlight mental health issues for women in the military. They include the pieces about sexual harassment, the many faces of military families, alcohol use, and the corrosive effects of ostracism.
One of the articles by Kate McGraw, Ph.D., of the Deployment Health Clinical Center, Silver Spring, Md., focuses on the mental well-being of servicewomen and sexual trauma. Underlying the supplement is the recognition that the most robust mental health research repeatedly conducted in Afghanistan, for example, did not include a single woman because of the sampling methodology. A dedicated group addressing service women’s health and inclusion in health research would have prevented this oversight.
The health of female service members has long been an interest of mine, partly because I was in the Army for 28 years and deployed to a lot of austere environments. They included the rice fields of Camp Edwards, near the DMZ in Korea; Mogadishu and other “cities” in Somalia; and various Forward Operating Bases in Iraq.
Many years ago, I published an article on health concerns of deployed women. That focused on concerns about how to avoid urinary tract infections (UTIs) while in the field – where bathrooms are often scarce and dirty – and other seemingly mundane issues.
Mundane unless you have a UTI, or are trying to figure out how to manage your menses with no tampons or places to wash your hands.
Since then the literature has grown. For example, I published a volume called “Women at War” (Oxford University Press, 2015) last spring. This recent supplement advances those discussions, including articles on avoiding anemia and stress fractures.
But the way forward has been spotty. Many political issues delay an open discussion, especially on reproductive concerns. Further, there is no driving function within the Department of Defense that focuses on funding research in support of service women and reporting back to the department and civilian leadership.
For example: Female service members have a rate of unintended pregnancy twice that of the civilian world. This leads to early attrition from the military, and in turn, to young female veterans with children who are homeless.
Some have said, highlighting these concerns, that females should not be in the military because our presence is a risk to operational readiness. However, this is not an issue without tested solutions.
Taking this one issue further, consider that all service women are included in the Military Health System and have access to a variety of forms of birth control. If female service members can be put on oral contraceptives, that would both suppress their menses and avoid unwanted pregnancies. However, longer lasting methods of birth control would enable service women to enjoy decreased menses, avoid unwanted pregnancies, and avoid access issues during deployment.
The supplement contains numerous health policy and research recommendations as well as a detailed look at the unique health and lifestyle challenges of service women. Other issues include: the reproductive health of women in austere environments, nutritional factors, avoiding musculoskeletal injuries, combat-related injuries, designing military equipment (including uniforms) for optimal performance, and the role of leadership. It concludes with 20 research gaps and accompanying recommendations.
The number of women serving in the military is increasing, while all jobs, particularly those in the ground combat element, are now open to women. The time is now to focus on establishing and tracking health and well-being issues to ensure the success of this population – and the Military Medicine special issue is just a first step.
Dr. Ritchie serves as professor of psychiatry at the Uniformed Services University of the Health Services in Bethesda, Md., and at Georgetown University in Washington. She helped write one of the articles in the supplement with Dr. McGraw and Tracey Perez Koehlmoos, Ph.D., an associate professor with the Uniformed Services University.
Fertility preservation in early cervical cancer
Historically, the standard of care for women diagnosed with early cervical cancer has been radical hysterectomy. Thus, young women are not only being confronted with a cancer diagnosis, but may also be forced to cope with the loss of their fertility.
As many young women with cervical cancer were not accepting of this treatment, Dr. Daniel Dargent pioneered the vaginal radical trachelectomy as a fertility-preserving treatment option for early cervical cancer in 1994. There have now been more than 900 vaginal radical trachelectomies performed and they have been shown to have oncologic outcomes similar to those of traditional radical hysterectomy, while sparing a woman’s fertility (Int J Gynecol Cancer. 2013 Jul;23[6]:982-9).
Obstetric outcomes following vaginal radical trachelectomy are acceptable with 17% miscarriage rate in the first trimester (compared to 10%-20% in the general population) and 8% in the second trimester (compared to 1%-5% in the general population) (Am Fam Physician. 2007 Nov 1;76[9]:1341-6). Following vaginal radical trachelectomy, 64% of pregnancies deliver at term.
The usual criteria required to undergo radical trachelectomy include:
1) Reproductive age with desire for fertility.
2) Stage IA1 with LVSI (lymphovascular space invasion), IA2, or IB1 with tumor less than 2 cm.
3) Limited endocervical involvement via preoperative MRI.
4) Negative pelvic lymph nodes.
Preoperative PET scan can be used to evaluate nodal status, but suspicious lymph nodes should be evaluated on frozen section at the time of surgery. The presence of LVSI alone is not a contraindication to trachelectomy.
A key limitation of vaginal radical trachelectomy is the specialized training required to perform this technically challenging procedure. Few surgeons in the United States are trained to perform vaginal radical trachelectomy. In response to this limitation, surgeons began to attempt radical trachelectomy via laparotomy (Gynecol Oncol. 2006 Dec;103[3]:807-13). Oncologic outcomes following fertility-sparing abdominal radical trachelectomy have been reported to be equivalent to radical hysterectomy. Concerns regarding the abdominal approach to radical trachelectomy include higher rates of second trimester loss (19%) when compared to the vaginal approach (8%), higher rate of loss of fertility (30%), and risk of postoperative adhesions.
The advent of minimally invasive surgery, particularly robotic surgery, now offers surgeons the ability to perform a procedure technically similar to radical hysterectomy using a minimally invasive approach. Given the similarity of procedural steps of radical trachelectomy to radical hysterectomy using the robotic platform, this procedure is gaining acceptance in the United States with an associated improved surgeon learning curve (Gynecol Oncol. 2008 Nov;111[2]:255-60). In addition, the use of minimally invasive surgery should result in less adhesion formation facilitating natural fertility options postoperatively.
Obstetric and fertility outcomes are limited following minimally invasive radical trachelectomy via laparoscopy or robotic surgery given the novelty of this procedure. Emerging obstetric outcomes appear reassuring, but further data are needed to fully understand the effects of this procedure on pregnancy outcomes and the need for assisted reproductive techniques to achieve pregnancy.
The management of pregnancies following radical trachelectomy is also an area with limited data, which presents a clinical challenge to obstetricians. Many gynecologic oncologists perform a permanent cerclage at the time of trachelectomy and recommend delivery via scheduled cesarean at term for all subsequent pregnancies prior to labor (usually 37-38 weeks).
At our institution, we recommend the use of progesterone from 16 to 36 weeks despite no clear evidence on the role of progesterone in this setting. Maternal-fetal medicine consultation should be considered to either follow these patients during their pregnancies or to perform a single consultative visit to guide antepartum care.
Some have advocated for less radical surgery, such as simple trachelectomy or large cold knife conization, as the risk of parametrial extension in these patients is low (Gynecol Oncol. 2011 Dec;123[3]:557-60). More data are needed to determine if this is a safe approach. Further, the use of neoadjuvant chemotherapy followed by cold knife conization for fertility preservation in women with larger tumors has been proposed. This may be a feasible option in women with chemo-sensitive tumors, but progression on chemotherapy and increased recurrences have been reported with this approach (Gynecol Oncol. 2008 Dec;111[3]:438-43).
Women of reproductive age diagnosed with early cervical cancer now have multiple options for fertility preservation. Ongoing research regarding obstetric and fertility outcomes is needed; however, oncologic outcomes appear to be equivalent.
Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina, Chapel Hill. Dr. Boggess is an expert in robotic surgery in gynecologic oncology and is a professor in the division of gynecologic oncology at UNC–Chapel Hill. They reported having no financial disclosures relevant to this column. Email them at obnews@frontlinemedcom.com.
Historically, the standard of care for women diagnosed with early cervical cancer has been radical hysterectomy. Thus, young women are not only being confronted with a cancer diagnosis, but may also be forced to cope with the loss of their fertility.
As many young women with cervical cancer were not accepting of this treatment, Dr. Daniel Dargent pioneered the vaginal radical trachelectomy as a fertility-preserving treatment option for early cervical cancer in 1994. There have now been more than 900 vaginal radical trachelectomies performed and they have been shown to have oncologic outcomes similar to those of traditional radical hysterectomy, while sparing a woman’s fertility (Int J Gynecol Cancer. 2013 Jul;23[6]:982-9).
Obstetric outcomes following vaginal radical trachelectomy are acceptable with 17% miscarriage rate in the first trimester (compared to 10%-20% in the general population) and 8% in the second trimester (compared to 1%-5% in the general population) (Am Fam Physician. 2007 Nov 1;76[9]:1341-6). Following vaginal radical trachelectomy, 64% of pregnancies deliver at term.
The usual criteria required to undergo radical trachelectomy include:
1) Reproductive age with desire for fertility.
2) Stage IA1 with LVSI (lymphovascular space invasion), IA2, or IB1 with tumor less than 2 cm.
3) Limited endocervical involvement via preoperative MRI.
4) Negative pelvic lymph nodes.
Preoperative PET scan can be used to evaluate nodal status, but suspicious lymph nodes should be evaluated on frozen section at the time of surgery. The presence of LVSI alone is not a contraindication to trachelectomy.
A key limitation of vaginal radical trachelectomy is the specialized training required to perform this technically challenging procedure. Few surgeons in the United States are trained to perform vaginal radical trachelectomy. In response to this limitation, surgeons began to attempt radical trachelectomy via laparotomy (Gynecol Oncol. 2006 Dec;103[3]:807-13). Oncologic outcomes following fertility-sparing abdominal radical trachelectomy have been reported to be equivalent to radical hysterectomy. Concerns regarding the abdominal approach to radical trachelectomy include higher rates of second trimester loss (19%) when compared to the vaginal approach (8%), higher rate of loss of fertility (30%), and risk of postoperative adhesions.
The advent of minimally invasive surgery, particularly robotic surgery, now offers surgeons the ability to perform a procedure technically similar to radical hysterectomy using a minimally invasive approach. Given the similarity of procedural steps of radical trachelectomy to radical hysterectomy using the robotic platform, this procedure is gaining acceptance in the United States with an associated improved surgeon learning curve (Gynecol Oncol. 2008 Nov;111[2]:255-60). In addition, the use of minimally invasive surgery should result in less adhesion formation facilitating natural fertility options postoperatively.
Obstetric and fertility outcomes are limited following minimally invasive radical trachelectomy via laparoscopy or robotic surgery given the novelty of this procedure. Emerging obstetric outcomes appear reassuring, but further data are needed to fully understand the effects of this procedure on pregnancy outcomes and the need for assisted reproductive techniques to achieve pregnancy.
The management of pregnancies following radical trachelectomy is also an area with limited data, which presents a clinical challenge to obstetricians. Many gynecologic oncologists perform a permanent cerclage at the time of trachelectomy and recommend delivery via scheduled cesarean at term for all subsequent pregnancies prior to labor (usually 37-38 weeks).
At our institution, we recommend the use of progesterone from 16 to 36 weeks despite no clear evidence on the role of progesterone in this setting. Maternal-fetal medicine consultation should be considered to either follow these patients during their pregnancies or to perform a single consultative visit to guide antepartum care.
Some have advocated for less radical surgery, such as simple trachelectomy or large cold knife conization, as the risk of parametrial extension in these patients is low (Gynecol Oncol. 2011 Dec;123[3]:557-60). More data are needed to determine if this is a safe approach. Further, the use of neoadjuvant chemotherapy followed by cold knife conization for fertility preservation in women with larger tumors has been proposed. This may be a feasible option in women with chemo-sensitive tumors, but progression on chemotherapy and increased recurrences have been reported with this approach (Gynecol Oncol. 2008 Dec;111[3]:438-43).
Women of reproductive age diagnosed with early cervical cancer now have multiple options for fertility preservation. Ongoing research regarding obstetric and fertility outcomes is needed; however, oncologic outcomes appear to be equivalent.
Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina, Chapel Hill. Dr. Boggess is an expert in robotic surgery in gynecologic oncology and is a professor in the division of gynecologic oncology at UNC–Chapel Hill. They reported having no financial disclosures relevant to this column. Email them at obnews@frontlinemedcom.com.
Historically, the standard of care for women diagnosed with early cervical cancer has been radical hysterectomy. Thus, young women are not only being confronted with a cancer diagnosis, but may also be forced to cope with the loss of their fertility.
As many young women with cervical cancer were not accepting of this treatment, Dr. Daniel Dargent pioneered the vaginal radical trachelectomy as a fertility-preserving treatment option for early cervical cancer in 1994. There have now been more than 900 vaginal radical trachelectomies performed and they have been shown to have oncologic outcomes similar to those of traditional radical hysterectomy, while sparing a woman’s fertility (Int J Gynecol Cancer. 2013 Jul;23[6]:982-9).
Obstetric outcomes following vaginal radical trachelectomy are acceptable with 17% miscarriage rate in the first trimester (compared to 10%-20% in the general population) and 8% in the second trimester (compared to 1%-5% in the general population) (Am Fam Physician. 2007 Nov 1;76[9]:1341-6). Following vaginal radical trachelectomy, 64% of pregnancies deliver at term.
The usual criteria required to undergo radical trachelectomy include:
1) Reproductive age with desire for fertility.
2) Stage IA1 with LVSI (lymphovascular space invasion), IA2, or IB1 with tumor less than 2 cm.
3) Limited endocervical involvement via preoperative MRI.
4) Negative pelvic lymph nodes.
Preoperative PET scan can be used to evaluate nodal status, but suspicious lymph nodes should be evaluated on frozen section at the time of surgery. The presence of LVSI alone is not a contraindication to trachelectomy.
A key limitation of vaginal radical trachelectomy is the specialized training required to perform this technically challenging procedure. Few surgeons in the United States are trained to perform vaginal radical trachelectomy. In response to this limitation, surgeons began to attempt radical trachelectomy via laparotomy (Gynecol Oncol. 2006 Dec;103[3]:807-13). Oncologic outcomes following fertility-sparing abdominal radical trachelectomy have been reported to be equivalent to radical hysterectomy. Concerns regarding the abdominal approach to radical trachelectomy include higher rates of second trimester loss (19%) when compared to the vaginal approach (8%), higher rate of loss of fertility (30%), and risk of postoperative adhesions.
The advent of minimally invasive surgery, particularly robotic surgery, now offers surgeons the ability to perform a procedure technically similar to radical hysterectomy using a minimally invasive approach. Given the similarity of procedural steps of radical trachelectomy to radical hysterectomy using the robotic platform, this procedure is gaining acceptance in the United States with an associated improved surgeon learning curve (Gynecol Oncol. 2008 Nov;111[2]:255-60). In addition, the use of minimally invasive surgery should result in less adhesion formation facilitating natural fertility options postoperatively.
Obstetric and fertility outcomes are limited following minimally invasive radical trachelectomy via laparoscopy or robotic surgery given the novelty of this procedure. Emerging obstetric outcomes appear reassuring, but further data are needed to fully understand the effects of this procedure on pregnancy outcomes and the need for assisted reproductive techniques to achieve pregnancy.
The management of pregnancies following radical trachelectomy is also an area with limited data, which presents a clinical challenge to obstetricians. Many gynecologic oncologists perform a permanent cerclage at the time of trachelectomy and recommend delivery via scheduled cesarean at term for all subsequent pregnancies prior to labor (usually 37-38 weeks).
At our institution, we recommend the use of progesterone from 16 to 36 weeks despite no clear evidence on the role of progesterone in this setting. Maternal-fetal medicine consultation should be considered to either follow these patients during their pregnancies or to perform a single consultative visit to guide antepartum care.
Some have advocated for less radical surgery, such as simple trachelectomy or large cold knife conization, as the risk of parametrial extension in these patients is low (Gynecol Oncol. 2011 Dec;123[3]:557-60). More data are needed to determine if this is a safe approach. Further, the use of neoadjuvant chemotherapy followed by cold knife conization for fertility preservation in women with larger tumors has been proposed. This may be a feasible option in women with chemo-sensitive tumors, but progression on chemotherapy and increased recurrences have been reported with this approach (Gynecol Oncol. 2008 Dec;111[3]:438-43).
Women of reproductive age diagnosed with early cervical cancer now have multiple options for fertility preservation. Ongoing research regarding obstetric and fertility outcomes is needed; however, oncologic outcomes appear to be equivalent.
Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina, Chapel Hill. Dr. Boggess is an expert in robotic surgery in gynecologic oncology and is a professor in the division of gynecologic oncology at UNC–Chapel Hill. They reported having no financial disclosures relevant to this column. Email them at obnews@frontlinemedcom.com.
Understanding stillbirth
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
Research adds insight on stillbirth risk factors
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Biologic treatment in pregnancy requires balancing risks
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 obnews@frontlinemedcom.com.
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 obnews@frontlinemedcom.com.
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 obnews@frontlinemedcom.com.
