Pediatrics

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

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.

©Dr. Craig Lyerla/CDC

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.

©Dr. Craig Lyerla/CDC

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.

©Dr. Craig Lyerla/CDC

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.

Repeated exposure to physical pain can have both short-term and long-term adverse effects in newborns, yet providers too inconsistently assess and adequately manage pain in neonates, the American Academy of Pediatrics said in an updated policy statement on preventing and managing procedural pain in these infants.

“Neonates are frequently subjected to painful procedures, with the most immature infants receiving the highest number of painful events,” wrote the AAP Committee on Fetus and Newborn and the AAP Section on Anesthesiology and Pain Medicine. Premature infants also are at the highest risk for long-term sequelae, the committees noted. “These sequelae include physiologic instability; altered brain development; and abnormal neurodevelopment, somatosensory, and stress response systems, which can persist into childhood” (Pediatrics. 2016 Jan 25. doi: 10.1542/peds.2015-4271).

The statement nicely summarizes current evidence on the evaluation and management of pain in neonates, as well as potential short-term and long-term negative effects, said Dr. Clay T. Jones, a neonatal hospitalist at Newton-Wellesley Hospital in Newton, Mass., who was not involved in drafting the statement.

“It is a nice testament to how far we’ve come since the days of performing major surgeries in newborns without the use of analgesic medications, but there is still considerable room for improvement,” Dr. Jones said in an interview. “Although we’ve learned a lot about pain in this population over the past few decades, the authors go to great lengths to make it clear that the optimal way to treat pain hasn’t been established yet, and that the evaluation of risk versus benefit in regards to management using pharmaceutical agents is ongoing.”

The statement described the challenges of effective pain management, including foremost the newborn’s inability to communicate and the dearth of information about effective pain assessments and management in this population.

“Contextual factors such as gestational age and behavioral state may play a significant role in pain assessment and are beginning to be included in some assessment tools,” the committees wrote. “New and emerging technologies to measure pain responses, such as near-infrared spectroscopy, amplitude-integrated electroencephalography, functional MRI, skin conductance, and heart rate variability assessment, are being investigated.”

In the meantime, however, all facilities caring for newborns should implement a pain prevention program that takes advantage of what pain management strategies do exist. In addition to reviewing these strategies, the statement recommended all providers implement and use pain assessment and management plans that include both pharmacologic and nonpharmacologic therapies for major procedures and routine minor interventions that might still cause pain.

“Where this report might have the largest impact is in the outpatient offices of pediatric medical providers and in newborn nurseries,” Dr. Jones said. “It is not uncommon for young infants to undergo painful medical procedures, such as heel sticks and circumcisions, without a systematic approach to pain evaluation and inconsistent efforts to prevent or reduce pain.”

Yet there is no excuse for this lack of a consistent approach, he said.

“Nonpharmaceutical interventions are safe, easy to implement, [and] inexpensive, and there is good evidence that they reduce physiologic surrogate markers for pain such as blood pressure, heart rate, and respiratory rate,” Dr. Jones said.

The statement’s first recommendation is that all institutions have written guidelines for a stepwise plan of pain prevention and treatment in newborns. This plan also should include use of currently available and validated neonatal assessment tools “before, during, and after painful procedures to monitor the effectiveness of pain relief interventions.”

Another recommendation urged pediatricians and other neonatal health care providers and family members to receive ongoing education about recognizing and assessing pain in newborns and then managing it as much as current knowledge and evidence allow. The committees called for more research into pain assessment tools and pain prevention and amelioration strategies, including pharmacologic options.

The nonpharmacologic strategies shown to be effective for reducing pain during short-term mild or moderately painful procedures include facilitated tucking, sensorial stimulation, nonnutritive sucking, and breastfeeding or providing expressed human milk.

“Anything we can do to ease pain will improve a baby’s quality of life,” said Dr. Nathan Boonstra of Blank Children’s Hospital pediatric clinic in Des Moines, Iowa, who was not involved in writing the statement.

“Pediatricians should always be judicious when deciding to draw blood, but when we need to, we should reflexively think about what can keep the procedure’s pain at a minimum,” he said in an interview. “Many of my patients’ mothers instinctively want to breastfeed to help their newborns through something painful, and their instinct serves them well.”

The policy statement mentioned oral sucrose and/or glucose solutions as effective analgesic options for mild to moderately painful procedures, but recommended these be prescribed and tracked as medication.

This strategy carries risks and other drawbacks, however, Dr. Thomas M Seman, a pediatrician in group practice in Danvers, Mass., said in an interview

“Having sucrose or glucose solutions in the office can be dangerous because of the risk of overuse and hyperglycemia as well as the cost of these items,” said Dr. Seman, who was not involved with drafting the AAP statement. His office policy primarily focuses on the parents holding their children and talking, singing, or humming to them during procedures, followed by feeding and/or acetaminophen, he said.

“The other medications used are prohibitive for a number of reasons,” said Dr. Seman, although he added that most of the procedures described in the statement are performed on premature infants in a NICU with only a few done in private practices.

For example, opioids such as fentanyl and morphine are most frequently used for persistent pain, yet the data on appropriate dosing and long-term effects in the newborn period are “woefully lacking and/or conflicting,” the statement noted. The evidence for benzodiazepines, often used for sedation in the neonatal intensive care, shows little additional analgesic benefit, but these agents can potentiate the risk of respiratory depression and hypotension associated with opioid use. Caution should particularly be exercised before using methadone, ketamine, propofol, and dexmedetomidine because so little is known about safe and effective dosing of these medications in neonates. They also carry various potential risks ranging from neurotoxicity to bradycardia, desaturations, and prolonged hypotension.

While NSAIDs are not recommended at this young age, oral or intravenous acetaminophen has sufficient preliminary safety and efficacy to be considered for postoperative pain relief, according to the statement.

The AAP did not report disclosures for committee members. Dr. Boonstra, Dr. Jones, and Dr. Seman had no relevant financial disclosures.

Repeated exposure to physical pain can have both short-term and long-term adverse effects in newborns, yet providers too inconsistently assess and adequately manage pain in neonates, the American Academy of Pediatrics said in an updated policy statement on preventing and managing procedural pain in these infants.

“Neonates are frequently subjected to painful procedures, with the most immature infants receiving the highest number of painful events,” wrote the AAP Committee on Fetus and Newborn and the AAP Section on Anesthesiology and Pain Medicine. Premature infants also are at the highest risk for long-term sequelae, the committees noted. “These sequelae include physiologic instability; altered brain development; and abnormal neurodevelopment, somatosensory, and stress response systems, which can persist into childhood” (Pediatrics. 2016 Jan 25. doi: 10.1542/peds.2015-4271).

The statement nicely summarizes current evidence on the evaluation and management of pain in neonates, as well as potential short-term and long-term negative effects, said Dr. Clay T. Jones, a neonatal hospitalist at Newton-Wellesley Hospital in Newton, Mass., who was not involved in drafting the statement.

“It is a nice testament to how far we’ve come since the days of performing major surgeries in newborns without the use of analgesic medications, but there is still considerable room for improvement,” Dr. Jones said in an interview. “Although we’ve learned a lot about pain in this population over the past few decades, the authors go to great lengths to make it clear that the optimal way to treat pain hasn’t been established yet, and that the evaluation of risk versus benefit in regards to management using pharmaceutical agents is ongoing.”

The statement described the challenges of effective pain management, including foremost the newborn’s inability to communicate and the dearth of information about effective pain assessments and management in this population.

“Contextual factors such as gestational age and behavioral state may play a significant role in pain assessment and are beginning to be included in some assessment tools,” the committees wrote. “New and emerging technologies to measure pain responses, such as near-infrared spectroscopy, amplitude-integrated electroencephalography, functional MRI, skin conductance, and heart rate variability assessment, are being investigated.”

In the meantime, however, all facilities caring for newborns should implement a pain prevention program that takes advantage of what pain management strategies do exist. In addition to reviewing these strategies, the statement recommended all providers implement and use pain assessment and management plans that include both pharmacologic and nonpharmacologic therapies for major procedures and routine minor interventions that might still cause pain.

“Where this report might have the largest impact is in the outpatient offices of pediatric medical providers and in newborn nurseries,” Dr. Jones said. “It is not uncommon for young infants to undergo painful medical procedures, such as heel sticks and circumcisions, without a systematic approach to pain evaluation and inconsistent efforts to prevent or reduce pain.”

Yet there is no excuse for this lack of a consistent approach, he said.

“Nonpharmaceutical interventions are safe, easy to implement, [and] inexpensive, and there is good evidence that they reduce physiologic surrogate markers for pain such as blood pressure, heart rate, and respiratory rate,” Dr. Jones said.

The statement’s first recommendation is that all institutions have written guidelines for a stepwise plan of pain prevention and treatment in newborns. This plan also should include use of currently available and validated neonatal assessment tools “before, during, and after painful procedures to monitor the effectiveness of pain relief interventions.”

Another recommendation urged pediatricians and other neonatal health care providers and family members to receive ongoing education about recognizing and assessing pain in newborns and then managing it as much as current knowledge and evidence allow. The committees called for more research into pain assessment tools and pain prevention and amelioration strategies, including pharmacologic options.

The nonpharmacologic strategies shown to be effective for reducing pain during short-term mild or moderately painful procedures include facilitated tucking, sensorial stimulation, nonnutritive sucking, and breastfeeding or providing expressed human milk.

“Anything we can do to ease pain will improve a baby’s quality of life,” said Dr. Nathan Boonstra of Blank Children’s Hospital pediatric clinic in Des Moines, Iowa, who was not involved in writing the statement.

“Pediatricians should always be judicious when deciding to draw blood, but when we need to, we should reflexively think about what can keep the procedure’s pain at a minimum,” he said in an interview. “Many of my patients’ mothers instinctively want to breastfeed to help their newborns through something painful, and their instinct serves them well.”

The policy statement mentioned oral sucrose and/or glucose solutions as effective analgesic options for mild to moderately painful procedures, but recommended these be prescribed and tracked as medication.

This strategy carries risks and other drawbacks, however, Dr. Thomas M Seman, a pediatrician in group practice in Danvers, Mass., said in an interview

“Having sucrose or glucose solutions in the office can be dangerous because of the risk of overuse and hyperglycemia as well as the cost of these items,” said Dr. Seman, who was not involved with drafting the AAP statement. His office policy primarily focuses on the parents holding their children and talking, singing, or humming to them during procedures, followed by feeding and/or acetaminophen, he said.

“The other medications used are prohibitive for a number of reasons,” said Dr. Seman, although he added that most of the procedures described in the statement are performed on premature infants in a NICU with only a few done in private practices.

For example, opioids such as fentanyl and morphine are most frequently used for persistent pain, yet the data on appropriate dosing and long-term effects in the newborn period are “woefully lacking and/or conflicting,” the statement noted. The evidence for benzodiazepines, often used for sedation in the neonatal intensive care, shows little additional analgesic benefit, but these agents can potentiate the risk of respiratory depression and hypotension associated with opioid use. Caution should particularly be exercised before using methadone, ketamine, propofol, and dexmedetomidine because so little is known about safe and effective dosing of these medications in neonates. They also carry various potential risks ranging from neurotoxicity to bradycardia, desaturations, and prolonged hypotension.

While NSAIDs are not recommended at this young age, oral or intravenous acetaminophen has sufficient preliminary safety and efficacy to be considered for postoperative pain relief, according to the statement.

The AAP did not report disclosures for committee members. Dr. Boonstra, Dr. Jones, and Dr. Seman had no relevant financial disclosures.

Repeated exposure to physical pain can have both short-term and long-term adverse effects in newborns, yet providers too inconsistently assess and adequately manage pain in neonates, the American Academy of Pediatrics said in an updated policy statement on preventing and managing procedural pain in these infants.

“Neonates are frequently subjected to painful procedures, with the most immature infants receiving the highest number of painful events,” wrote the AAP Committee on Fetus and Newborn and the AAP Section on Anesthesiology and Pain Medicine. Premature infants also are at the highest risk for long-term sequelae, the committees noted. “These sequelae include physiologic instability; altered brain development; and abnormal neurodevelopment, somatosensory, and stress response systems, which can persist into childhood” (Pediatrics. 2016 Jan 25. doi: 10.1542/peds.2015-4271).

The statement nicely summarizes current evidence on the evaluation and management of pain in neonates, as well as potential short-term and long-term negative effects, said Dr. Clay T. Jones, a neonatal hospitalist at Newton-Wellesley Hospital in Newton, Mass., who was not involved in drafting the statement.

“It is a nice testament to how far we’ve come since the days of performing major surgeries in newborns without the use of analgesic medications, but there is still considerable room for improvement,” Dr. Jones said in an interview. “Although we’ve learned a lot about pain in this population over the past few decades, the authors go to great lengths to make it clear that the optimal way to treat pain hasn’t been established yet, and that the evaluation of risk versus benefit in regards to management using pharmaceutical agents is ongoing.”

The statement described the challenges of effective pain management, including foremost the newborn’s inability to communicate and the dearth of information about effective pain assessments and management in this population.

“Contextual factors such as gestational age and behavioral state may play a significant role in pain assessment and are beginning to be included in some assessment tools,” the committees wrote. “New and emerging technologies to measure pain responses, such as near-infrared spectroscopy, amplitude-integrated electroencephalography, functional MRI, skin conductance, and heart rate variability assessment, are being investigated.”

In the meantime, however, all facilities caring for newborns should implement a pain prevention program that takes advantage of what pain management strategies do exist. In addition to reviewing these strategies, the statement recommended all providers implement and use pain assessment and management plans that include both pharmacologic and nonpharmacologic therapies for major procedures and routine minor interventions that might still cause pain.

“Where this report might have the largest impact is in the outpatient offices of pediatric medical providers and in newborn nurseries,” Dr. Jones said. “It is not uncommon for young infants to undergo painful medical procedures, such as heel sticks and circumcisions, without a systematic approach to pain evaluation and inconsistent efforts to prevent or reduce pain.”

Yet there is no excuse for this lack of a consistent approach, he said.

“Nonpharmaceutical interventions are safe, easy to implement, [and] inexpensive, and there is good evidence that they reduce physiologic surrogate markers for pain such as blood pressure, heart rate, and respiratory rate,” Dr. Jones said.

The statement’s first recommendation is that all institutions have written guidelines for a stepwise plan of pain prevention and treatment in newborns. This plan also should include use of currently available and validated neonatal assessment tools “before, during, and after painful procedures to monitor the effectiveness of pain relief interventions.”

Another recommendation urged pediatricians and other neonatal health care providers and family members to receive ongoing education about recognizing and assessing pain in newborns and then managing it as much as current knowledge and evidence allow. The committees called for more research into pain assessment tools and pain prevention and amelioration strategies, including pharmacologic options.

The nonpharmacologic strategies shown to be effective for reducing pain during short-term mild or moderately painful procedures include facilitated tucking, sensorial stimulation, nonnutritive sucking, and breastfeeding or providing expressed human milk.

“Anything we can do to ease pain will improve a baby’s quality of life,” said Dr. Nathan Boonstra of Blank Children’s Hospital pediatric clinic in Des Moines, Iowa, who was not involved in writing the statement.

“Pediatricians should always be judicious when deciding to draw blood, but when we need to, we should reflexively think about what can keep the procedure’s pain at a minimum,” he said in an interview. “Many of my patients’ mothers instinctively want to breastfeed to help their newborns through something painful, and their instinct serves them well.”

The policy statement mentioned oral sucrose and/or glucose solutions as effective analgesic options for mild to moderately painful procedures, but recommended these be prescribed and tracked as medication.

This strategy carries risks and other drawbacks, however, Dr. Thomas M Seman, a pediatrician in group practice in Danvers, Mass., said in an interview

“Having sucrose or glucose solutions in the office can be dangerous because of the risk of overuse and hyperglycemia as well as the cost of these items,” said Dr. Seman, who was not involved with drafting the AAP statement. His office policy primarily focuses on the parents holding their children and talking, singing, or humming to them during procedures, followed by feeding and/or acetaminophen, he said.

“The other medications used are prohibitive for a number of reasons,” said Dr. Seman, although he added that most of the procedures described in the statement are performed on premature infants in a NICU with only a few done in private practices.

For example, opioids such as fentanyl and morphine are most frequently used for persistent pain, yet the data on appropriate dosing and long-term effects in the newborn period are “woefully lacking and/or conflicting,” the statement noted. The evidence for benzodiazepines, often used for sedation in the neonatal intensive care, shows little additional analgesic benefit, but these agents can potentiate the risk of respiratory depression and hypotension associated with opioid use. Caution should particularly be exercised before using methadone, ketamine, propofol, and dexmedetomidine because so little is known about safe and effective dosing of these medications in neonates. They also carry various potential risks ranging from neurotoxicity to bradycardia, desaturations, and prolonged hypotension.

While NSAIDs are not recommended at this young age, oral or intravenous acetaminophen has sufficient preliminary safety and efficacy to be considered for postoperative pain relief, according to the statement.

The AAP did not report disclosures for committee members. Dr. Boonstra, Dr. Jones, and Dr. Seman had no relevant financial disclosures.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, appears generally safe for young children with cystic fibrosis and a CFTR gating mutation, an open-label, single-arm study shows.

The study, published online Jan. 20, is the first to assess ivacaftor in children aged 2-5 years, suggests that the drug is well tolerated, somewhat improves sweat chloride and nutritional measures, and also might improve pancreatic function, reported Dr. Jane C. Davies of the National Heart & Lung Institute of Imperial College London, and her associates. “Reported side effects are similar to those in the general cystic fibrosis population, although children with previous cystic fibrosis liver disease might have transient rises in transaminase concentrations,” they added.

© CTRPhotos / ThinkStockPhotos.com

Ivacaftor is approved by the Food and Drug Administration for children aged 6 years and older with cystic fibrosis, and it should be even more beneficial if given before patients develop infections and inflammation as a result of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, the researchers noted.

The investigators enrolled children aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the United States, the United Kingdom, and Canada. To establish short-term safety and pharmacokinetics of ivacaftor and its metabolites, nine patients received an oral dose of 50 mg (if they weighed less than 14 kg) or 75 mg (if they weighed 14 kg or more) every 12 hours for 4 days.

To assess longer-term safety, 34 patients received these doses for 24 weeks, followed by an open-label extension study that remains underway (Lancet Respir Med. 2016 Jan 20. doi: 10.1016/S2213-2600[15]00545-7).

The pharmacokinetic analyses indicated that exposure was similar to that reported in adults, the researchers reported. The median Cmin was 536 ng per mL for the 50-mg dose and 580 ng per mL for the 75-mg dose, and median ivacaftor AUC values were 9,840 ng×h/mL and 10,200 ngxh/mL, respectively. The most common adverse events over 6 weeks of treatment included cough (56% of patients) and vomiting (29%). In addition five (15%) patients had liver function test results that were more than eight-fold higher than the upper limit of normal. As a result, four had the study drug interrupted and one discontinued. Hypertransaminasemia was the only serious adverse event considered related to ivacaftor, and the only adverse event leading to treatment discontinuation. By week 24, sweat chloride levels had dropped an average of 47 mmol per L from baseline (standard deviation, 26.2, P less than .0001), weight had dropped by a z score factor of 0.2 (P less than .0001), and BMI had fallen by a factor of 0.4 (P less than .0001).

“Unfortunately, this study could not generate meaningful data on pulmonary function, because only three patients produced research-quality measurements, and we did not provide specific training or quality control in preschool lung function testing,” the investigators said. The results “confirmed a safe and tolerable dose of an acceptable formulation of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation, although liver function seems to require closer monitoring in this age range than in adults, particularly among those with a history of elevated [liver function tests].”

Vertex Pharmaceuticals funded the study. Dr. Davies reported serving on advisory boards for Proteostasis, Pharmaxis, Pulmocide, Novartis, and Vertex Pharmaceuticals, and participating in educational activities for which her institution received payment. Seven coinvestigators also reported financial relationships with Vertex, including three who reported employment with the company.

Both single-dose and two-dose meningococcal CRM-conjugate vaccine series (MenACWY-CRM) were immunogenic, but antibody responses were greater in patients after two doses, especially for patients aged 2-5 years old, according to a new study.

The multicenter, randomized, observer-blind, placebo-controlled study, conducted in the United States between October 2012 and May 2014, included 713 subjects who were up to date with their routine childhood immunizations. The subjects were broken into two age groups: children aged 2-5 years and children aged 6-10 years. The two age groups were randomized 1:1 to receive two doses of MenACWY-CRM or one dose of placebo followed by one dose of MenACWY-CRM, 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement.

©DesignPics/Thinkstock.com

The researchers’ primary objective was to assess the noninferiority and superiority of antibody responses of the two doses, compared with the single dose against Neisseria meningitidis serogroups A,C, W, and Y, at 1-month after the last vaccination. Among the exclusion criteria for participation in the study were previous or suspected disease caused by N. meningitidis or immunization with any investigational or licensed vaccines containing meningococcal antigens.

Noninferiority of two doses of MenACWY-CRM, compared with a single dose, was demonstrated for all four serogroups. Additionally, at 1 month after the last vaccination, the superiority of receiving the two doses over the single dose was demonstrated for serogroups C and Y, for patients in the 2- to 5-year-old age cohort, while the superiority of two doses over one dose was demonstrated for the serogroup Y, for patients in the 6- to 10-year-old cohort.

The safety profile of the vaccine was similar in both groups. Medically attended adverse events that were considered to have been “possibly or probably related to the study vaccine” occurred in five subjects (as six events) in the 2- to 5-year-old age cohort and three subjects (as three events) in the 6- to 10-year-age cohort. One subject in the cohort aged 6-10 years withdrew from the study, because of vomiting and diarrhea, “which were considered to be unrelated to the study vaccine.” Eight serious adverse events were reported by five subjects, with one of the events “considered to be possibly related to the study vaccine.” That event was idiopathic thrombocytopenia, which occurred in a 6-year-old who received the single dose.

“[B]oth the single-dose and the two-dose primary series of MenACWY-CRM are immunogenic and have an acceptable safety profile in 2- to 10-year-old children. The two-dose primary series induced a higher immune response than [did] a single dose, although this difference in response decreases over time,” Dr. William Johnston Jr. of Alabama Clinical Therapeutics in Birmingham and his colleagues said.

Read the study in the Pediatric Infectious Disease Journal (doi: 10.1097/INF.0000000000000931).

klennon@frontlinemedcom.com

Both single-dose and two-dose meningococcal CRM-conjugate vaccine series (MenACWY-CRM) were immunogenic, but antibody responses were greater in patients after two doses, especially for patients aged 2-5 years old, according to a new study.

The multicenter, randomized, observer-blind, placebo-controlled study, conducted in the United States between October 2012 and May 2014, included 713 subjects who were up to date with their routine childhood immunizations. The subjects were broken into two age groups: children aged 2-5 years and children aged 6-10 years. The two age groups were randomized 1:1 to receive two doses of MenACWY-CRM or one dose of placebo followed by one dose of MenACWY-CRM, 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement.

©DesignPics/Thinkstock.com

The researchers’ primary objective was to assess the noninferiority and superiority of antibody responses of the two doses, compared with the single dose against Neisseria meningitidis serogroups A,C, W, and Y, at 1-month after the last vaccination. Among the exclusion criteria for participation in the study were previous or suspected disease caused by N. meningitidis or immunization with any investigational or licensed vaccines containing meningococcal antigens.

Noninferiority of two doses of MenACWY-CRM, compared with a single dose, was demonstrated for all four serogroups. Additionally, at 1 month after the last vaccination, the superiority of receiving the two doses over the single dose was demonstrated for serogroups C and Y, for patients in the 2- to 5-year-old age cohort, while the superiority of two doses over one dose was demonstrated for the serogroup Y, for patients in the 6- to 10-year-old cohort.

The safety profile of the vaccine was similar in both groups. Medically attended adverse events that were considered to have been “possibly or probably related to the study vaccine” occurred in five subjects (as six events) in the 2- to 5-year-old age cohort and three subjects (as three events) in the 6- to 10-year-age cohort. One subject in the cohort aged 6-10 years withdrew from the study, because of vomiting and diarrhea, “which were considered to be unrelated to the study vaccine.” Eight serious adverse events were reported by five subjects, with one of the events “considered to be possibly related to the study vaccine.” That event was idiopathic thrombocytopenia, which occurred in a 6-year-old who received the single dose.

“[B]oth the single-dose and the two-dose primary series of MenACWY-CRM are immunogenic and have an acceptable safety profile in 2- to 10-year-old children. The two-dose primary series induced a higher immune response than [did] a single dose, although this difference in response decreases over time,” Dr. William Johnston Jr. of Alabama Clinical Therapeutics in Birmingham and his colleagues said.

Read the study in the Pediatric Infectious Disease Journal (doi: 10.1097/INF.0000000000000931).

klennon@frontlinemedcom.com

Both single-dose and two-dose meningococcal CRM-conjugate vaccine series (MenACWY-CRM) were immunogenic, but antibody responses were greater in patients after two doses, especially for patients aged 2-5 years old, according to a new study.

The multicenter, randomized, observer-blind, placebo-controlled study, conducted in the United States between October 2012 and May 2014, included 713 subjects who were up to date with their routine childhood immunizations. The subjects were broken into two age groups: children aged 2-5 years and children aged 6-10 years. The two age groups were randomized 1:1 to receive two doses of MenACWY-CRM or one dose of placebo followed by one dose of MenACWY-CRM, 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement.

©DesignPics/Thinkstock.com

The researchers’ primary objective was to assess the noninferiority and superiority of antibody responses of the two doses, compared with the single dose against Neisseria meningitidis serogroups A,C, W, and Y, at 1-month after the last vaccination. Among the exclusion criteria for participation in the study were previous or suspected disease caused by N. meningitidis or immunization with any investigational or licensed vaccines containing meningococcal antigens.

Noninferiority of two doses of MenACWY-CRM, compared with a single dose, was demonstrated for all four serogroups. Additionally, at 1 month after the last vaccination, the superiority of receiving the two doses over the single dose was demonstrated for serogroups C and Y, for patients in the 2- to 5-year-old age cohort, while the superiority of two doses over one dose was demonstrated for the serogroup Y, for patients in the 6- to 10-year-old cohort.

The safety profile of the vaccine was similar in both groups. Medically attended adverse events that were considered to have been “possibly or probably related to the study vaccine” occurred in five subjects (as six events) in the 2- to 5-year-old age cohort and three subjects (as three events) in the 6- to 10-year-age cohort. One subject in the cohort aged 6-10 years withdrew from the study, because of vomiting and diarrhea, “which were considered to be unrelated to the study vaccine.” Eight serious adverse events were reported by five subjects, with one of the events “considered to be possibly related to the study vaccine.” That event was idiopathic thrombocytopenia, which occurred in a 6-year-old who received the single dose.

“[B]oth the single-dose and the two-dose primary series of MenACWY-CRM are immunogenic and have an acceptable safety profile in 2- to 10-year-old children. The two-dose primary series induced a higher immune response than [did] a single dose, although this difference in response decreases over time,” Dr. William Johnston Jr. of Alabama Clinical Therapeutics in Birmingham and his colleagues said.

Read the study in the Pediatric Infectious Disease Journal (doi: 10.1097/INF.0000000000000931).

klennon@frontlinemedcom.com