Pediatrics

Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.

The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.

In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.

Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.

By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.

The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.

However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.

In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
 

Accepting simple intervention could have great impact

This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.

“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.

Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.

“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.  

However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.

“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.

Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.

Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.

The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.

Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.

The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.

In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.

Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.

By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.

The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.

However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.

In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
 

Accepting simple intervention could have great impact

This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.

“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.

Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.

“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.  

However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.

“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.

Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.

Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.

The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.

Delayed umbilical cord clamping for at least 60 seconds after birth significantly reduced death or disability in infants of less than 30 weeks’ gestation, according to data from nearly 1,500 infants.

The burden of disability and mortality for babies born before 30 weeks’ gestation remains high, especially in low- and middle-income countries, wrote Kristy P. Robledo, PhD, of the University of Sydney, Australia, and colleagues. Delayed clamping of the umbilical cord is a simple procedure that may improve mortality in this population, but more research is needed; recommended times to delayed clamping range from 30 seconds to 3 minutes, they noted.

In a study published in The Lancet Child & Adolescent Health, the researchers randomized 767 very preterm infants to delayed clamping at least 60 seconds after birth and 764 to immediate clamping. Of these, 384 were multiple births (who were individually randomized), 862 were male, and 505 were born before 27 weeks’ gestation. The primary outcome was death or disability at 2 years of age. Major disability was defined as cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay at 2 years corrected age. The median time to clamping was 60 seconds in the delayed group and 5 seconds in the immediate group.

Primary outcome data were available for 1,419 infants. Death or major disability occurred in 29% of infants assigned to delayed clamping compared to 34% of those assigned to immediate clamping (relative risk 0.83, P = .010). The infants were part of the APTS Childhood Follow-Up Study, an open-label superiority trial conducted in Australia and New Zealand.

By age 2 years, 8% of infants in the delayed group and 11% of those in the immediate group had died; 23% and 26%, respectively, met criteria for major disability. The impact of delayed clamping translates to a 30% reduction in relative risk of mortality at 2 years of age, but no significant impact on major disability, the researchers wrote.

The findings were limited by several factors including the unblinded study design, lack of data on heart rate or time to first breath, and the clamping prior to 60 seconds in 26% of infants in the delayed group based on clinical concerns for these specific infants, the researchers noted.

However, the results were strengthened by the large size, low risk of bias, and specific primary outcome, they said. The data support findings from recent systematic reviews and highlight the need for further trials to evaluate delayed clamping at different time points, with larger populations, inclusion of time to first breath and heart rate, and improved measures of disability, the researchers added.

In clinical practice, “Given that aiming to delay cord clamping for 60 seconds or more improved 2-year outcomes and short-term hematological measures with no evidence of significant harm, it seems reasonable to conclude that delayed clamping is appropriate as standard care in very preterm infants,” they concluded.
 

Accepting simple intervention could have great impact

This study is important in light of the overwhelming burden of preterm birth on the health care system and society as a whole, Lisette D. Tanner, MD, of Emory University, Atlanta, said in an interview.

“Preterm birth is associated with billions in health care costs each year, and a large portion of that money is directed to the complications associated with preterm birth, such as early intervention services, educational support, and ongoing medical care,” Dr. Tanner said. “This study is particularly timely, as we are quickly approaching 2030, the deadline for achieving the United Nations Sustainable Development Goal of ending preventable deaths of newborns and children under 5 years of age,” she said. The goal involves “all countries aiming to reduce neonatal mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as low as 25 per 1,000 live births. Effective treatments to reduce infant and child mortality would make strong inroads toward this goal,” she explained.

Dr. Tanner said she was not surprised by the findings because previous studies have shown similar results. “However, the large, multicenter nature of this study provides additional weight to recommendations to delay cord clamping as standard practice,” she said.

“The findings of this study support the recommendations of a number of large organizations,” said Dr. Tanner. “The World Health Organization recommends that the umbilical cord not be clamped earlier than 1 minute after birth in term or preterm infants who do not require positive pressure ventilation. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics now recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30–60 seconds after birth,” she said. “The Royal College of Obstetricians and Gynaecologists also recommends deferring umbilical cord clamping for healthy term and preterm infants for at least 2 minutes after birth,” she added.  

However, “the delay in adoption of this guidelines in practice appears to be related to some concerns regarding universal adoption of this approach,” Dr. Tanner noted. “Some clinicians have suggested that delayed cord clamping could delay vital neonatal resuscitative efforts, leading to worse neonatal outcomes, but this concern has not been borne out in the data, as all guidelines specifically state that this intervention is for vigorous newborns,” she said. “In fact, in preterm infants, delayed cord clamping is associated with improved transitional circulation, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage,” Dr. Tanner emphasized. “Additionally, concerns persist that delayed cord clamping could lead to excessive transfusion with resultant polycythemia. Again, no data have supported this claim to date,” she said.

“Finally, some clinicians are concerned that delayed clamping could lead to delay in addressing maternal complications of birth such as hemorrhage, but studies have shown the opposite; delayed umbilical cord clamping has not been associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor has it been with a difference in the need for blood transfusion,” said Dr. Tanner.

Ideally, practitioners will become more comfortable in delaying cord clamping as a routine practice as more data demonstrating the safety and benefit of this easy intervention are disseminated, she said.

Additional research delineating which gestational ages benefit most from delayed cord clamping would help direct education efforts to implement this intervention, Dr. Tanner noted.

The study was funded by the Australian National Health and Medical Research Council. The researchers and Dr. Tanner had no financial conflicts to disclose.

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

Tumor biology and socioeconomics only partly explain why acute lymphoblastic leukemia survival outcomes are worse for young Hispanic and Black patients than White patients, but they don’t explain it entirely, according to a report at the American Society of Hematology annual meeting.

Among almost 25,000 children and young adults up to 31 years old, all of whom participated in Children’s Oncology Group studies since 2004, 5-year event free survival (EFS) was 87.4% for White patients, 82.8% for Hispanic patients, and 81.9% for Black patients.

When socioeconomics and disease characteristics such as CNS involvement, white blood cell lineage, and induction status were taken into account, the risk of having a survival event fell from 37% to 11% higher for Hispanic patients versus White patients but from 45% to 32% for Black patients versus White patients.

However, there was no explicit adjustment in the study for acuity at presentation, body mass index, adherence to protocols, or Philadelphia chromosome (PH)-like disease, which is more common among Hispanic patients.

Even so, lead investigator Sumit Gupta, MD, a pediatric blood cancer specialist at the University of Toronto, said that even with the potential confounders, lingering differences in outcomes raise questions about equal access to care and other matters, and suggest that there are still “uncomfortable things to consider, things like ... structural racism” and a system that delivers “systemically different care to patients across racial” groups.

Another report presented at the meeting with 295 patients 18-40 years old found that Hispanic patients had 3-year overall survival comparable to that of White patients despite a higher prevalence of PH-like disease, perhaps because Hispanic patients had higher treatment adherence than did White patients at 76% versus 56%, said lead investigator Lori Muffly, MD, a bone and marrow transplant specialist at Stanford (Calif.) University.

However, Hispanic ALL patients were underrepresented in the study because the investigators didn’t recruit in Texas and Florida, states with higher percentages of young Hispanic ALL patients, and recruitment in California fell short of the prevalence of young Hispanic patients in that state. The work was a substudy of CALGB 10403, a trial of pediatric regimens in adolescents and young adults.

“It’s a relatively easy maneuver, going to where the patients are. When groups are thinking about multicenter trials, it has to be part of the dialogue from the beginning,” Dr. Muffly said.

Black patients in the review had fewer days in treatment and a higher prevalence of T-cell disease, and didn’t do as well as other groups.

Together, the studies “offer insight into the magnitude of racial and ethnic disparities in care among young people with” ALL, said Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, who moderated the presentations.

Dr. Gupta and his team found outcome differences only in relapsed B-cell ALL, not T-cell disease. B-cell disease has a more rigorous maintenance schedule, so it could be that there’s a difference in sticking to follow-up between various groups or less rigorous monitoring by pediatric oncologists in some groups, he said.

Dr. Gupta’s study was funded by the National Cancer Institute and others. Dr. Muffly didn’t report a funding source, but reported ties to Pfizer, Amgen, and other companies. Dr. Gupta is involved with Jazz Pharmaceuticals.

[email protected]

In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.

The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.

The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.

Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.

Adaptive versus conventional therapy

The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.

The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.

The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.

Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.

Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.

“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.¹

Poor survival with advanced disease

Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.

The overall 5-year survival rate is approximately 71%.¹

However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).

“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.

Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.

“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.

The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.

“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.

This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.

“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.

For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.

“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.

He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.

A life too brief

Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.

“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.

Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.

In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.

An evolutionary primer (cancer edition)

To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.

“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.

These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.

“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.

The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.

“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.

Survival of the fittest

The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.

And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.

“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.

The endangered species list

As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.

The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.

In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.

Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.

Strike two and the MVP

Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.

Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.

“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.

The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.²

“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”

Adaptive therapy

As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.

Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.

They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.

“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.

Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.

In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.

Putting it to the test

The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.

“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.

Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.

“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”

Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.

“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.

Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.

Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.

A change in thinking

Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”

“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”

The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.

“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”

Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”

The common refrain was that adaptive therapy was “giving up.”

But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2

Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.

Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.

“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”

The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.

“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.

“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”

If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.

And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.

“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”

Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”

References

1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2

In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.

The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.

The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.

Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.

Adaptive versus conventional therapy

The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.

The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.

The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.

Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.

Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.

“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.¹

Poor survival with advanced disease

Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.

The overall 5-year survival rate is approximately 71%.¹

However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).

“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.

Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.

“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.

The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.

“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.

This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.

“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.

For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.

“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.

He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.

A life too brief

Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.

“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.

Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.

In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.

An evolutionary primer (cancer edition)

To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.

“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.

These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.

“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.

The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.

“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.

Survival of the fittest

The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.

And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.

“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.

The endangered species list

As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.

The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.

In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.

Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.

Strike two and the MVP

Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.

Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.

“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.

The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.²

“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”

Adaptive therapy

As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.

Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.

They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.

“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.

Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.

In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.

Putting it to the test

The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.

“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.

Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.

“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”

Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.

“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.

Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.

Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.

A change in thinking

Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”

“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”

The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.

“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”

Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”

The common refrain was that adaptive therapy was “giving up.”

But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2

Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.

Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.

“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”

The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.

“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.

“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”

If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.

And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.

“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”

Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”

References

1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2

In 1859, Charles Darwin published “On the Origin of Species,” which outlined his world-shaking theory of evolution and its core principle of natural selection caused by environmental pressures that may determine whether an organism adapts and survives, or remains static, languishes, and eventually dies out.

The same forces that have influenced the size and shape of the beaks of finches in the Galapagos Islands, the length of giraffe necks in Africa, and the intestinal microbiomes of the nearly 8 billion human inhabitants of this planet also control whether malignant cells thrive and multiply, wither and die when assaulted by chemotherapy, or go into hiding, mutating and waiting for their next opportunity to erupt again and metastasize.

The ability of malignant cells to adapt to environmental pressures is “cancer’s most lethal and sophisticated property,” said Damon R. Reed, MD, program leader of the adolescent/young adult program at Moffitt Cancer Center in Tampa, Fla.

Dr. Reed and colleagues are developing methods to meet cancer on its own terms, applying evolutionary principles to the treatment of childhood fusion-positive rhabdomyosarcoma in an innovative, and some would say audacious, clinical trial.

Adaptive versus conventional therapy

The trial, now recruiting, is designed to evaluate each of four different strategies for chemotherapy schedules in patients with newly diagnosed metastatic fusion-positive rhabdomyosarcoma.

The trial contains four arms, three of which consist of either conventional chemotherapy based on published clinical trials, moving a second-line therapy to the first line, or adding maintenance therapy, all of which have the goal of inducing as many complete remissions as possible.

The remaining adaptive therapy arm, however, is entirely novel in approach, with therapy using a combination of chemotherapy drugs that will be started and interrupted based on tumor responses, with resumption of therapy on an adaptive schedule unique to each patient. The goal of treatment for patients enrolled in this arm will be prolongation of the time to disease progression, rather than complete remission.

Although some people might consider the adaptive therapy approach to be sacrificing the hope for a cure in exchange for palliation, the hard truth is that patients with fusion-positive rhabdomyosarcoma (in contrast to those with fusion-negative disease) have a dismal prognosis following relapse after up-front intensified therapy.

Instead, because a cure is exceedingly unlikely in patients with metastatic disease, the conventional idea of delivering the maximum tolerated dose of chemotherapy until disease progression could be replaced by an approach based on understanding of the evolution of cancer cells under selective pressures, Dr. Reed and colleagues contend.

“Although adaptive therapy would represent a major paradigm shift in pediatric oncology, this approach would exploit the chemotherapy-sensitive population to prevent the emergence of resistant populations, optimizing tumor control with less toxicity,” they wrote in a commentary published online in the journal Cancer.¹

Poor survival with advanced disease

Childhood rhabdomyosarcoma (RMS) is a form of soft tissue sarcoma of mesenchymal origin. Approximately 25% of cases are parameningeal, arising from sites adjacent to the meninges of the nasopharynx, middle ear, paranasal sinuses, orbit, and other regions of the head and neck. Approximately 31% of cases arise in the genitourinary tract and 13% in the extremities, and other tumors occur less commonly in the trunk, chest wall, perineal/anal region, and abdomen.

The overall 5-year survival rate is approximately 71%.¹

However, for patients with high-risk disease, a group that includes children 10 years of age or older with widespread disease with or without an activating PAX/FOX01 gene fusion, 5-year survival ranges from just 20% to 30% (Cancer Facts & Figures 2020).

“Among patients with metastatic disease, there is a clear difference in overall survival between those who have fusion-positive disease, where the 5-year overall survival is about 19%, and patients with fusion-negative disease,” said Douglas S. Hawkins, MD, chair of the children’s oncology group and professor of pediatrics at the University of Washington, Seattle, and associate chief in the division of hematology/oncology at Seattle Children’s Hospital.

Patients with fusion-negative disease can be further classified into those with multiple metastatic sites, with a 5-year overall survival rate of approximately 45%, and those with a single metastatic site, with a 5-year overall survival rate of 70%, he said in an interview.

“So when we talk about metastatic rhabdomyosarcoma, there actually is a diversity of outcomes, between really bad – those with fusion-positive disease – and not terrible – not great, but not terrible – for a selected group of patients with fusion-negative disease,” Dr. Hawkins said.

The poor prognosis for patients with metastatic fusion-positive disease prompted Dr. Reed and colleagues to rethink the entire approach to advanced cancers.

“If someone has a sarcoma, we know that we need to do surgery and radiation to the area, we know that localized disease does better than metastatic disease, and we generally hit it with some kind of chemotherapy that we call ‘standard of care,’ ” he said in an interview.

This approach is largely effective in some forms of cancer of bone and soft tissues, such as Ewing sarcoma, he notes, which has 5-year survival rates below 20% when treated with surgery and radiation only, but with the addition of chemotherapy has 5-year overall survival rates as high as 80%.

“At other times, with other sarcomas, the cure rate is abysmal, but we still call it standard of care,” Dr. Reed said.

For example, patients with metastatic fusion-positive RMS may have an initial response to chemotherapy, but most will eventually experience relapse and die of the disease.

“With some of the most common treatments, 70% of patients will have their cancers shrink by more than 50%, which is a major response, but the vast majority of them will have a recurrence later on,” Dr. Hawkins said.

He noted that the standard of care for patients with metastatic rhabdomyosarcoma, both with and without the PAX/FOX01 fusion, is chemotherapy, generally with the VAC regimen (vincristine, actinomycin D, and cyclophosphamide), although other agents such as doxorubicin, ifosfamide, etoposide, or irinotecan have also been tried, with little effect on event-free survival or overall survival rates.

A life too brief

Ricky Huff and his family know the course that the disease can take only too well. In 2015, his 5-month-old son, Theo, was diagnosed with metastatic rhabdomyosarcoma and put under the care of Damon Reed at Moffitt.

“During the whole course of treatment – I’m sure like many other parents – apart from relying on Damon and his treatment expertise to try to determine the best treatment options, I was reading everything under the sun to try to get a working knowledge of what Theo was up against, what his treatment and clinical trial options were, and what was the state of the science,” Mr. Huff says.

Unfortunately, the characteristics of Theo’s disease, including his very young age at onset and diagnosis of stage 4 metastatic disease, conspired against him, and despite undergoing 14 months of chemotherapy, Theo died of the disease in October 2016, 5 months shy of what would have been his second birthday.

In their grief, Mr. Huff, a real estate lawyer with a practice in Clearwater, Fla., and his wife, Leah, were determined to help other families of children with cancer and settled on the National Pediatric Cancer Foundation. Mr. Huff joined the board of directors of the foundation, which is collaborating with Moffitt Cancer Center on the adaptive therapy trial.

An evolutionary primer (cancer edition)

To get a better idea of just how adaptive therapy works, it is helpful to view cancer cells through the lens of species development, adaptation, extinction, and evolution.

“Cancer cells compete against each other in a dynamic environment. Their tumor ecosystems exhibit spatial and temporal fluctuations in blood-borne nutrients, oxygen, growth factors, immune cells, and hormones,” Dr. Reed and colleagues wrote.

These influences can affect genetically identical cancer cells, which may begin to diverge from one another depending on their location in a tumor and the availability of nutrients, which in turn can result in two once-identical cells exhibiting different transcription rates for growth factors.

“Ultimately, this may affect the rate of progression through the cell cycle, leading to distinct rates of proliferation and mutational acquisition,” they wrote.

The diverging subpopulations will begin to develop different methods for adapting to the tumor microenvironment, with unique strategies for both accelerating growth and avoiding hazards such as chemotherapy drugs or radiation, the investigators explained.

“By the time a cancer becomes clinically apparent, cancer cells have transformed from a single clone into a diverse community of cell types evolving in response to a spatially and temporally heterogeneous tumor environment. Theoretically, a 10-gram cancer may contain the same order of magnitude of cancer cells as there are humans on earth, with tremendous diversity of phenotypes and environments,” they wrote.

Survival of the fittest

The competition of individuals within and between species described by Darwin also applies to cancer cells, in their interactions both with each other and with stromal cells and immune cells resulting in “the progressive replacement of less fit phenotypes by those that are more fit,” Dr. Reed and colleagues explained.

And just like the old joke about two hikers trying to escape from a charging grizzly bear (one says, “This is futile – we can’t outrun a grizzly,” and the other says, “I only have to outrun you!”), cancer cells only need to be more resistant to therapeutic attack than normal cells that are critical to function.

“This may explain why initial responses in certain solid tumors (notably rhabdomyosarcoma) do not predict eventual survival. The sensitivities of the dominant cancer cell populations dictate the initial response, but it is the ecology and evolution of the rare and more resistant populations that determine cure or relapse,” they wrote.

The endangered species list

As with many types of cancer, the current approach to treating pediatric sarcomas with curative intent is with a “first strike” approach, treating patients with surgery, radiation, and cytotoxic chemotherapy at the maximum tolerated dose for as long as needed or until unacceptable toxicities occur, with the intention of wiping out all cancer cells without permanently injuring normal cells.

The evolutionary analogy to this approach is a mass extinction event such as the meteor strike that is believed to have wiped out the dinosaurs roughly 66 million years ago. Fossil evidence suggests that the cataclysmic event resulted in the atmosphere being blanketed with dust particles that blocked sunlight and caused massive die-off of plants that dinosaurs needed to survive and were ill-adapted to do without.

In contrast, populations of smaller, more adaptable species of microbes, insects, and animals, including our mammalian ancestors, were able to survive and eventually flourish.

Many patients with localized cancers may be cured with up-front therapy, but others will have residual disease from populations of cells that are intrinsically resistant to therapy or have developed new evasion strategies.

Strike two and the MVP

Dr. Reed and colleagues liken the approach of second-line therapy for treatment of relapsed or refractory disease to the concept of “background extinctions,” using the fate of the passenger pigeon as an example of how a second-strike therapeutic strategy works.

Although the popular conception is that the passenger pigeon was hunted to extinction by humans, the species in fact died out because of many different factors, including loss of habitat, isolation of populations leading to a loss of genetic diversity, and disruption of breeding habits.

“Once first strikes of deforestation and hunting reduced the birds to small, fragmented populations, a series of what would otherwise have been minor second strikes pushed the passenger pigeon below its extinction threshold, or minimum viable population,” they said.

The analogy, as it applies to cancer therapy, is the use of second-line or follow-on therapy with one or more agents that the residual cells are at least in theory not resistant to. In the case of fusion-positive rhabdomyosarcoma, the drug most commonly added in the second-strike approach is vinorelbine.²

“Second strikes should be timed to occur around the time when the first strike has achieved its greatest effect, presumably at the point when the disease becomes clinically undetectable or at a measurable nadir,” Dr. Reed and colleagues wrote. “Ideally, second-strike therapies should have modes of action that require different resistance strategies by the cancer cells than those needed for resistance to the first strike.”

Adaptive therapy

As Dr. Reed and colleagues note, despite optimal therapy, 94% of patients with metastatic fusion-positive rhabdomyosarcoma will experience a relapse within 3 years of diagnosis.1 Clearly the scorched earth or “throw everything you have it” approach no longer works, and that’s where adaptive therapy comes in.

Here again, the authors rely on nature, or rather human interaction with nature, to devise a strategy for keeping the disease at bay when extinction of all cancerous cells cannot be achieved.

They cite the example of agricultural integrated pest management, which seeks to keep harmful insects in check by treating them to suppress but not completely destroy a population, then stopping the use of pesticides, and resuming only when the insect population spikes and again becomes a threat to crops.

“The goal is to limit crop damage while retaining the sensitivity of the insects to the pesticides. Resistance most often comes at a cost. In the absence of the pesticide, sensitive individuals will outcompete resistant individuals,” they wrote.

Adaptive therapy uses the same approach to reduce selection pressures that foster resistance, with patients treated only until a specific, predetermined response is achieved in the dominant population of chemosensitive cells. The treatment is then interrupted and reintroduced only when the tumor rebounds to a certain predetermined size.

In this scenario, cells that retain sensitivity to chemotherapy will be able to reproduce and proliferate more rapidly than drug-resistant cells, and the therapy can then be reintroduced. This strategy is less likely to cause the development and proliferation of resistant cells than conventional intensified chemotherapy, Dr. Reed and colleagues contend.

Putting it to the test

The clinical trial that Dr. Reed and colleagues have initiated, officially titled “Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma,” (NCT04388839) contains four arms: three experimental and one active comparator arm.

“We won’t randomize; we don’t feel that it would be fair to randomize patients, because these arms are so different from each other,” Dr. Reed said.

Arm A is the experimental first-strike arm, a 42-week course containing cyclophosphamide delivered intravenously over 60 minutes at a dose ranging from 220 mg to 1200 mg, vinorelbine delivered in an IV push over 6-10 minutes with a dose ranging from 4 mg to 25 mg, and actinomycin D administered via IV over 3-5 minutes at a dose ranging from 0.025 mg to 0.04 mg.

“The idea is that we take the standard of care, and we add a drug – vinorelbine – to make it stronger,” Dr. Reed said. “The idea is that the resistant cell, the cell that escapes, if we start hitting it on day 1 with vinorelbine, we might be able to drive it to extinction.”

Arm B, the second experimental arm, is the second-strike and maintenance arm, in which patients will receive conventional doses of vincristine, actinomycin D, and cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks, and will then be switched to up to 2 years of maintenance with vinorelbine and oral cyclophosphamide.

“Vinorelbine will be added when the cancer is declining or first goes into remission. We try not to wait 42 weeks, which is too long we think, by which time the cancer may be fully adapted and resistant,” he explained.

Arm C is the adaptive therapy arm, in which patients will receive VAC that starts and stops based on response, with the goal of prolonging time to disease progression rather than achieving CR.

Arm D is the active comparator arm, consisting of conventional chemotherapy based on published clinical trials, such as VAC for 42 weeks, or other standard-of-care regimens that may include irinotecan, doxorubicin, ifosfamide, and/or etoposide.

A change in thinking

Dr. Reed acknowledges that Arm C, the adaptive therapy arm, “definitely represents a change in thinking for pediatric oncology.”

“The idea is that if you could do this perfectly well, you would be able to take a patient who is diagnosed today and essentially ‘pause’ their disease for a while. Then 5 years from now, if there is a better medicine, you would have gotten that patient to that medicine.”

The optimal approach to treating metastatic fusion-positive rhabdomyosarcoma may be similar to that used for treatment of acute lymphoblastic leukemia, with induction, consolidation, and maintenance and the option of delayed intensification, he said.

“But we’re so far away from knowing which series to do that we just need to show that any series – any changing it up – is helpful.”

Dr. Reed said that when he started presenting the concept of adaptive therapy in clinical meetings in 2017, “I was told to come up with a better idea. There were several people who instantly got it, but most people would instantly get angry.”

The common refrain was that adaptive therapy was “giving up.”

But minds began to change in 2018, following presentation at the annual meeting of the American Society of Clinical Oncology of a European study showing that adding 6 months of low-dose chemotherapy maintenance to standard therapy improved the 5-year overall survival rate of pediatric rhabdomyosarcoma from 73.7% to 86.6%.2

Before presenting the idea of adaptive therapy to his colleagues, he ran it by the parents of children with advanced sarcomas, and many were on board with it, he said.

Ricky Huff said that had the option of adaptive therapy been available for Theo, he and his wife would have been willing to try it.

“Of course, everyone has the ability in hindsight to apply critical thinking to decisions that you made or could have made,” he said. “I think is true for many parents, who if they’re presented with information about options will say ‘well if there’s a 1 percent chance, I want that chance for my child, especially for a 5-month-old.”

The decision to choose adaptive therapy is a difficult decision to make, whether for oneself or for one’s son, because it isn’t curative.

“My wife and I have since had a conversation about this, and I do think we would have considered it, although through a lot of difficult conversations,” he said.

“After we got the pathology, knowing that it was metastatic, fusion-positive, and given his age, just doing a brief literature review on my own, I knew what we were up against using 20-year-old treatments, and that the chance of a cure was very, very small.”

If parents of children with metastatic, poor-prognosis rhabdomyosarcoma could be made to understand that adaptive therapy would entail shorter and fewer hospital stays, and cumulatively less toxic chemotherapy, and could prolong the lives of their children, the option might be more acceptable, he said.

And as Dr. Reed mentioned, prolonging time to progression offers hope of additional therapies to come.

“The whole time that my son was being treated, I hoped that there was going to be something else that came out, that a new trial would be launched because they found a way to drug a mutation, or treat it with immunotherapy – something that was going to give us a better option.”

Asked whether he would be willing to share his experiences in this article, Mr. Huff said that “I am willing to, in whatever small way I can, make an impact, and hopefully save another family from what we experienced.”

References

1. Reed DR et al. Cancer. 2020 Jun 1;126(11):2577-87 2. Bisogno G et al. J Clin Oncol. 2018;36:18_suppl,LBA-2

They say you are what you eat, but scientists have long wondered whether breastfeeding babies are what their mothers eat, too. Their question: How much of a nursing mother’s diet eventually plays a role in a child’s food preferences later in life?

The aroma, taste, and makeup of breast milk change from day to day, based mostly on the mother’s diet. But previous research has already shown that the foods a mother eats do not directly translate into the same smells and tastes of that food in breast milk. Some substances from the mother’s diet enter her breast milk, some don’t, and even ones that do may have a different scent or flavor than what the mother experiences.

But a new study suggests that the active ingredient in black pepper makes its way into breast milk and may help the infant develop a tolerance to pepper later. The researchers published their findings in the journal Molecular Nutrition & Food Research.
 

Pinch of pepper

The study authors thought that maybe some food preferences could result from sensory programming that occurs through breast milk in the first few months of life. Though past studies have looked at which odor-producing substances transfer into breast milk, not many have explored specific substances that give food its distinctive flavor, or even what makes up the taste of breast milk. So they decided to investigate what happens when a mother consumes a meal containing three specific compounds: those that give pepper, chili, and ginger their particularly pungent flavors.

The researchers recruited 18 healthy, nonsmoking, nursing mothers who were producing more than enough milk for their baby’s needs. Their breastfeeding children ranged in age from 8 weeks to 1 year old. The women all ate a curry dish after having spent 2 days avoiding onion, garlic, and the spices in the curry. Then they provided pumped breast milk samples at 1, 2, and 3 hours after eating the curry.

Within an hour of the women eating the curry, the scientists were able to detect piperine, the compound that gives black pepper its bite, in the mothers’ breast milk. They did not find the compounds from ginger, chili, or curcumin – the main active ingredient in turmeric – in the breast milk. The piperine remained there for several hours, but there wasn’t enough for an adult to be able to taste it. It wasn’t possible to reliably tell whether the infants could consciously detect the flavor, but the researchers don’t think it’s likely they did.

But the scientists do suggest it’s possible that the piperine in breast milk could regularly activate a protein that detects pungent or potentially harmful substances. This is the same protein that produces the sensation of heat when eating a spicy food. If the piperine frequently activates that protein in a nursing baby at levels too low for the baby to notice, it may increase the baby’s tolerance for similar spicy substances later in life.

Ultimately, the findings suggest that some compounds in a mother’s diet have the potential to influence a child’s taste preferences later.

A version of this story first appeared on WebMD.com.

They say you are what you eat, but scientists have long wondered whether breastfeeding babies are what their mothers eat, too. Their question: How much of a nursing mother’s diet eventually plays a role in a child’s food preferences later in life?

The aroma, taste, and makeup of breast milk change from day to day, based mostly on the mother’s diet. But previous research has already shown that the foods a mother eats do not directly translate into the same smells and tastes of that food in breast milk. Some substances from the mother’s diet enter her breast milk, some don’t, and even ones that do may have a different scent or flavor than what the mother experiences.

But a new study suggests that the active ingredient in black pepper makes its way into breast milk and may help the infant develop a tolerance to pepper later. The researchers published their findings in the journal Molecular Nutrition & Food Research.
 

Pinch of pepper

The study authors thought that maybe some food preferences could result from sensory programming that occurs through breast milk in the first few months of life. Though past studies have looked at which odor-producing substances transfer into breast milk, not many have explored specific substances that give food its distinctive flavor, or even what makes up the taste of breast milk. So they decided to investigate what happens when a mother consumes a meal containing three specific compounds: those that give pepper, chili, and ginger their particularly pungent flavors.

The researchers recruited 18 healthy, nonsmoking, nursing mothers who were producing more than enough milk for their baby’s needs. Their breastfeeding children ranged in age from 8 weeks to 1 year old. The women all ate a curry dish after having spent 2 days avoiding onion, garlic, and the spices in the curry. Then they provided pumped breast milk samples at 1, 2, and 3 hours after eating the curry.

Within an hour of the women eating the curry, the scientists were able to detect piperine, the compound that gives black pepper its bite, in the mothers’ breast milk. They did not find the compounds from ginger, chili, or curcumin – the main active ingredient in turmeric – in the breast milk. The piperine remained there for several hours, but there wasn’t enough for an adult to be able to taste it. It wasn’t possible to reliably tell whether the infants could consciously detect the flavor, but the researchers don’t think it’s likely they did.

But the scientists do suggest it’s possible that the piperine in breast milk could regularly activate a protein that detects pungent or potentially harmful substances. This is the same protein that produces the sensation of heat when eating a spicy food. If the piperine frequently activates that protein in a nursing baby at levels too low for the baby to notice, it may increase the baby’s tolerance for similar spicy substances later in life.

Ultimately, the findings suggest that some compounds in a mother’s diet have the potential to influence a child’s taste preferences later.

A version of this story first appeared on WebMD.com.

They say you are what you eat, but scientists have long wondered whether breastfeeding babies are what their mothers eat, too. Their question: How much of a nursing mother’s diet eventually plays a role in a child’s food preferences later in life?

The aroma, taste, and makeup of breast milk change from day to day, based mostly on the mother’s diet. But previous research has already shown that the foods a mother eats do not directly translate into the same smells and tastes of that food in breast milk. Some substances from the mother’s diet enter her breast milk, some don’t, and even ones that do may have a different scent or flavor than what the mother experiences.

But a new study suggests that the active ingredient in black pepper makes its way into breast milk and may help the infant develop a tolerance to pepper later. The researchers published their findings in the journal Molecular Nutrition & Food Research.
 

Pinch of pepper

The study authors thought that maybe some food preferences could result from sensory programming that occurs through breast milk in the first few months of life. Though past studies have looked at which odor-producing substances transfer into breast milk, not many have explored specific substances that give food its distinctive flavor, or even what makes up the taste of breast milk. So they decided to investigate what happens when a mother consumes a meal containing three specific compounds: those that give pepper, chili, and ginger their particularly pungent flavors.

The researchers recruited 18 healthy, nonsmoking, nursing mothers who were producing more than enough milk for their baby’s needs. Their breastfeeding children ranged in age from 8 weeks to 1 year old. The women all ate a curry dish after having spent 2 days avoiding onion, garlic, and the spices in the curry. Then they provided pumped breast milk samples at 1, 2, and 3 hours after eating the curry.

Within an hour of the women eating the curry, the scientists were able to detect piperine, the compound that gives black pepper its bite, in the mothers’ breast milk. They did not find the compounds from ginger, chili, or curcumin – the main active ingredient in turmeric – in the breast milk. The piperine remained there for several hours, but there wasn’t enough for an adult to be able to taste it. It wasn’t possible to reliably tell whether the infants could consciously detect the flavor, but the researchers don’t think it’s likely they did.

But the scientists do suggest it’s possible that the piperine in breast milk could regularly activate a protein that detects pungent or potentially harmful substances. This is the same protein that produces the sensation of heat when eating a spicy food. If the piperine frequently activates that protein in a nursing baby at levels too low for the baby to notice, it may increase the baby’s tolerance for similar spicy substances later in life.

Ultimately, the findings suggest that some compounds in a mother’s diet have the potential to influence a child’s taste preferences later.

A version of this story first appeared on WebMD.com.

After a brief lull in activity, weekly COVID-19 cases in children returned to the upward trend that began in early November, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Vaccinations in children, however, continued to do the opposite by falling for the fourth consecutive week, with the largest decline for the week of Dec. 7-13 coming from those most recently eligible, according to the Centers for Disease Control and Prevention.

New COVID-19 cases were up by 23.5% for the week of Dec. 3-9, after a 2-week period that saw a drop and then just a slight increase, the AAP and CHA said in their latest weekly COVID report. There were 164,000 new cases from Dec. 3 to Dec. 9 in 46 states (Alabama, Nebraska, and Texas stopped reporting over the summer of 2021 and New York has never reported by age), the District of Columbia, New York City, Puerto Rico, and Guam.

The increase occurred across all four regions of the country, but the largest share came in the Midwest, with over 65,000 new cases, followed by the West (just over 35,000), the Northeast (just under 35,000), and the South (close to 28,000), the AAP/CHA data show.

The 7.2 million cumulative cases in children as of Dec. 9 represent 17.2% of all cases reported in the United States since the start of the pandemic, with available state reports showing that proportion ranges from 12.3% in Florida to 26.1% in Vermont. Alaska has the highest incidence of COVID at 19,000 cases per 100,000 children, and Hawaii has the lowest (5,300 per 100,000) among the states currently reporting, the AAP and CHA said.

State reporting on vaccinations shows that 37% of children aged 5-11 years in Massachusetts have received at least one dose, the highest of any state, while West Virginia is lowest at just 4%. The highest vaccination rate for children aged 12-17 goes to Massachusetts at 84%, with Wyoming lowest at 37%, the AAP said in a separate report.

Nationally, new vaccinations fell by a third during the week of Dec. 7-13, compared with the previous week, with the largest decline (34.7%) coming from the 5- to 11-year-olds, who still represented the majority (almost 84%) of the 430,000 new child vaccinations received, according to the CDC’s COVID Data Tracker. Corresponding declines for the last week were 27.5% for 12- to 15-year-olds and 22.7% for those aged 16-17.

Altogether, 21.2 million children aged 5-17 had received at least one dose and 16.0 million were fully vaccinated as of Dec. 13. By age group, 19.2% of children aged 5-11 years have gotten at least one dose and 9.6% are fully vaccinated, compared with 62.1% and 52.3%, respectively, among children aged 12-17, the CDC said.

[email protected]

After a brief lull in activity, weekly COVID-19 cases in children returned to the upward trend that began in early November, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Vaccinations in children, however, continued to do the opposite by falling for the fourth consecutive week, with the largest decline for the week of Dec. 7-13 coming from those most recently eligible, according to the Centers for Disease Control and Prevention.

New COVID-19 cases were up by 23.5% for the week of Dec. 3-9, after a 2-week period that saw a drop and then just a slight increase, the AAP and CHA said in their latest weekly COVID report. There were 164,000 new cases from Dec. 3 to Dec. 9 in 46 states (Alabama, Nebraska, and Texas stopped reporting over the summer of 2021 and New York has never reported by age), the District of Columbia, New York City, Puerto Rico, and Guam.

The increase occurred across all four regions of the country, but the largest share came in the Midwest, with over 65,000 new cases, followed by the West (just over 35,000), the Northeast (just under 35,000), and the South (close to 28,000), the AAP/CHA data show.

The 7.2 million cumulative cases in children as of Dec. 9 represent 17.2% of all cases reported in the United States since the start of the pandemic, with available state reports showing that proportion ranges from 12.3% in Florida to 26.1% in Vermont. Alaska has the highest incidence of COVID at 19,000 cases per 100,000 children, and Hawaii has the lowest (5,300 per 100,000) among the states currently reporting, the AAP and CHA said.

State reporting on vaccinations shows that 37% of children aged 5-11 years in Massachusetts have received at least one dose, the highest of any state, while West Virginia is lowest at just 4%. The highest vaccination rate for children aged 12-17 goes to Massachusetts at 84%, with Wyoming lowest at 37%, the AAP said in a separate report.

Nationally, new vaccinations fell by a third during the week of Dec. 7-13, compared with the previous week, with the largest decline (34.7%) coming from the 5- to 11-year-olds, who still represented the majority (almost 84%) of the 430,000 new child vaccinations received, according to the CDC’s COVID Data Tracker. Corresponding declines for the last week were 27.5% for 12- to 15-year-olds and 22.7% for those aged 16-17.

Altogether, 21.2 million children aged 5-17 had received at least one dose and 16.0 million were fully vaccinated as of Dec. 13. By age group, 19.2% of children aged 5-11 years have gotten at least one dose and 9.6% are fully vaccinated, compared with 62.1% and 52.3%, respectively, among children aged 12-17, the CDC said.

[email protected]

After a brief lull in activity, weekly COVID-19 cases in children returned to the upward trend that began in early November, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Vaccinations in children, however, continued to do the opposite by falling for the fourth consecutive week, with the largest decline for the week of Dec. 7-13 coming from those most recently eligible, according to the Centers for Disease Control and Prevention.

New COVID-19 cases were up by 23.5% for the week of Dec. 3-9, after a 2-week period that saw a drop and then just a slight increase, the AAP and CHA said in their latest weekly COVID report. There were 164,000 new cases from Dec. 3 to Dec. 9 in 46 states (Alabama, Nebraska, and Texas stopped reporting over the summer of 2021 and New York has never reported by age), the District of Columbia, New York City, Puerto Rico, and Guam.

The increase occurred across all four regions of the country, but the largest share came in the Midwest, with over 65,000 new cases, followed by the West (just over 35,000), the Northeast (just under 35,000), and the South (close to 28,000), the AAP/CHA data show.

The 7.2 million cumulative cases in children as of Dec. 9 represent 17.2% of all cases reported in the United States since the start of the pandemic, with available state reports showing that proportion ranges from 12.3% in Florida to 26.1% in Vermont. Alaska has the highest incidence of COVID at 19,000 cases per 100,000 children, and Hawaii has the lowest (5,300 per 100,000) among the states currently reporting, the AAP and CHA said.

State reporting on vaccinations shows that 37% of children aged 5-11 years in Massachusetts have received at least one dose, the highest of any state, while West Virginia is lowest at just 4%. The highest vaccination rate for children aged 12-17 goes to Massachusetts at 84%, with Wyoming lowest at 37%, the AAP said in a separate report.

Nationally, new vaccinations fell by a third during the week of Dec. 7-13, compared with the previous week, with the largest decline (34.7%) coming from the 5- to 11-year-olds, who still represented the majority (almost 84%) of the 430,000 new child vaccinations received, according to the CDC’s COVID Data Tracker. Corresponding declines for the last week were 27.5% for 12- to 15-year-olds and 22.7% for those aged 16-17.

Altogether, 21.2 million children aged 5-17 had received at least one dose and 16.0 million were fully vaccinated as of Dec. 13. By age group, 19.2% of children aged 5-11 years have gotten at least one dose and 9.6% are fully vaccinated, compared with 62.1% and 52.3%, respectively, among children aged 12-17, the CDC said.

[email protected]

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

A version of this article first appeared on Medscape.com.

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

A version of this article first appeared on Medscape.com.

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

A version of this article first appeared on Medscape.com.

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

A version of this article first appeared on WebMD.com.

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

A version of this article first appeared on WebMD.com.

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

A version of this article first appeared on WebMD.com.

In recent weeks, the Centers for Disease Control and Prevention has greatly expanded recommendations for boosters for vaccinations against COVID-19.

These recommendations have been widened because of the continued emergence of new variants of the virus and the wane of protection over time for both vaccinations and previous disease.

The new recommendations take away some of the questions surrounding eligibility for booster vaccinations while potentially leaving some additional questions. All in all, they provide flexibility for individuals to help protect themselves against the COVID-19 virus, as many are considering celebrating the holidays with friends and family.

The first item that has become clear is that all individuals over 18 are now not only eligible for a booster vaccination a certain time after they have completed their series, but have a recommendation for one.¹

But what about a fourth dose?  There is a possibility that some patients should be receiving one.  For those who require a three-dose series due to a condition that makes them immunocompromised, they should receive their booster vaccination six months after completion of the three-dose series.  This distinction  may cause confusion for some, but is important for those immunocompromised.

Boosters in women who are pregnant

The recommendations also include specific comments about individuals who are pregnant. Although initial studies did not include pregnant individuals, there has been increasing real world data that vaccination against COVID, including booster vaccinations, is safe and recommended. As pregnancy increases the risk of severe disease if infected by COVID-19, both the CDC and the American College of Obstetricians and Gynecologists,² along with other specialty organizations, such as the Royal College of Obstetricians and Gynaecologists, recommend vaccinations for pregnant individuals.

The CDC goes on to describe that there is no evidence of vaccination increasing the risk of infertility. The vaccine protects the pregnant individual and also provides protection to the baby once born. The same is true of breastfeeding individuals.³

I hope that this information allows physicians to feel comfortable recommending vaccinations and boosters to those who are pregnant and breast feeding.
 

Expanded recommendations for those aged 16-17 years

Recently, the CDC also expanded booster recommendations to include those aged 16-17 years, 6 months after completing their vaccine series.

Those under 18 are currently only able to receive the Pfizer-BioNtech vaccine. This new guidance has left some parents wondering if there will also be approval for booster vaccinations soon for those aged 12-16 who are approaching or have reached six months past the initial vaccine.¹

Booster brand for those over 18 years?

Although the recommendation has been simplified for all over age 18 years, there is still a decision to be made about which vaccine to use as the booster.

The recommendations allow individuals to decide which brand of vaccine they would like to have as a booster. They may choose to be vaccinated with the same vaccine they originally received or with a different vaccine. This vaccine flexibility may cause confusion, but ultimately is a good thing as it allows individuals to receive whatever vaccine is available and most convenient. This also allows individuals who have been vaccinated outside of the United States by a different brand of vaccine to also receive a booster vaccination with one of the options available here.
 

Take home message

Overall, the expansion of booster recommendations will help everyone avoid severe disease from COVID-19 infections. Physicians now have more clarity on who should be receiving these vaccines. Along with testing, masking, and appropriate distancing, these recommendations should help prevent severe disease and death from COVID-19.

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program, also in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. COVID-19 Vaccine Booster Shots. Centers for Disease Control and Prevention. 2021 Dec 9.

2. COVID-19 Vaccines and Pregnancy: Conversation Guide. American College of Obstetricians and Gynecologists. 2021 November.

3. COVID-19 Vaccines While Pregnant or Breastfeeding. Centers for Disease Control and Prevention. 2021 Dec 6.

In recent weeks, the Centers for Disease Control and Prevention has greatly expanded recommendations for boosters for vaccinations against COVID-19.

These recommendations have been widened because of the continued emergence of new variants of the virus and the wane of protection over time for both vaccinations and previous disease.

The new recommendations take away some of the questions surrounding eligibility for booster vaccinations while potentially leaving some additional questions. All in all, they provide flexibility for individuals to help protect themselves against the COVID-19 virus, as many are considering celebrating the holidays with friends and family.

The first item that has become clear is that all individuals over 18 are now not only eligible for a booster vaccination a certain time after they have completed their series, but have a recommendation for one.¹

But what about a fourth dose?  There is a possibility that some patients should be receiving one.  For those who require a three-dose series due to a condition that makes them immunocompromised, they should receive their booster vaccination six months after completion of the three-dose series.  This distinction  may cause confusion for some, but is important for those immunocompromised.

Boosters in women who are pregnant

The recommendations also include specific comments about individuals who are pregnant. Although initial studies did not include pregnant individuals, there has been increasing real world data that vaccination against COVID, including booster vaccinations, is safe and recommended. As pregnancy increases the risk of severe disease if infected by COVID-19, both the CDC and the American College of Obstetricians and Gynecologists,² along with other specialty organizations, such as the Royal College of Obstetricians and Gynaecologists, recommend vaccinations for pregnant individuals.

The CDC goes on to describe that there is no evidence of vaccination increasing the risk of infertility. The vaccine protects the pregnant individual and also provides protection to the baby once born. The same is true of breastfeeding individuals.³

I hope that this information allows physicians to feel comfortable recommending vaccinations and boosters to those who are pregnant and breast feeding.
 

Expanded recommendations for those aged 16-17 years

Recently, the CDC also expanded booster recommendations to include those aged 16-17 years, 6 months after completing their vaccine series.

Those under 18 are currently only able to receive the Pfizer-BioNtech vaccine. This new guidance has left some parents wondering if there will also be approval for booster vaccinations soon for those aged 12-16 who are approaching or have reached six months past the initial vaccine.¹

Booster brand for those over 18 years?

Although the recommendation has been simplified for all over age 18 years, there is still a decision to be made about which vaccine to use as the booster.

The recommendations allow individuals to decide which brand of vaccine they would like to have as a booster. They may choose to be vaccinated with the same vaccine they originally received or with a different vaccine. This vaccine flexibility may cause confusion, but ultimately is a good thing as it allows individuals to receive whatever vaccine is available and most convenient. This also allows individuals who have been vaccinated outside of the United States by a different brand of vaccine to also receive a booster vaccination with one of the options available here.
 

Take home message

Overall, the expansion of booster recommendations will help everyone avoid severe disease from COVID-19 infections. Physicians now have more clarity on who should be receiving these vaccines. Along with testing, masking, and appropriate distancing, these recommendations should help prevent severe disease and death from COVID-19.

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program, also in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. COVID-19 Vaccine Booster Shots. Centers for Disease Control and Prevention. 2021 Dec 9.

2. COVID-19 Vaccines and Pregnancy: Conversation Guide. American College of Obstetricians and Gynecologists. 2021 November.

3. COVID-19 Vaccines While Pregnant or Breastfeeding. Centers for Disease Control and Prevention. 2021 Dec 6.

In recent weeks, the Centers for Disease Control and Prevention has greatly expanded recommendations for boosters for vaccinations against COVID-19.

These recommendations have been widened because of the continued emergence of new variants of the virus and the wane of protection over time for both vaccinations and previous disease.

The new recommendations take away some of the questions surrounding eligibility for booster vaccinations while potentially leaving some additional questions. All in all, they provide flexibility for individuals to help protect themselves against the COVID-19 virus, as many are considering celebrating the holidays with friends and family.

The first item that has become clear is that all individuals over 18 are now not only eligible for a booster vaccination a certain time after they have completed their series, but have a recommendation for one.¹

But what about a fourth dose?  There is a possibility that some patients should be receiving one.  For those who require a three-dose series due to a condition that makes them immunocompromised, they should receive their booster vaccination six months after completion of the three-dose series.  This distinction  may cause confusion for some, but is important for those immunocompromised.

Boosters in women who are pregnant

The recommendations also include specific comments about individuals who are pregnant. Although initial studies did not include pregnant individuals, there has been increasing real world data that vaccination against COVID, including booster vaccinations, is safe and recommended. As pregnancy increases the risk of severe disease if infected by COVID-19, both the CDC and the American College of Obstetricians and Gynecologists,² along with other specialty organizations, such as the Royal College of Obstetricians and Gynaecologists, recommend vaccinations for pregnant individuals.

The CDC goes on to describe that there is no evidence of vaccination increasing the risk of infertility. The vaccine protects the pregnant individual and also provides protection to the baby once born. The same is true of breastfeeding individuals.³

I hope that this information allows physicians to feel comfortable recommending vaccinations and boosters to those who are pregnant and breast feeding.
 

Expanded recommendations for those aged 16-17 years

Recently, the CDC also expanded booster recommendations to include those aged 16-17 years, 6 months after completing their vaccine series.

Those under 18 are currently only able to receive the Pfizer-BioNtech vaccine. This new guidance has left some parents wondering if there will also be approval for booster vaccinations soon for those aged 12-16 who are approaching or have reached six months past the initial vaccine.¹

Booster brand for those over 18 years?

Although the recommendation has been simplified for all over age 18 years, there is still a decision to be made about which vaccine to use as the booster.

The recommendations allow individuals to decide which brand of vaccine they would like to have as a booster. They may choose to be vaccinated with the same vaccine they originally received or with a different vaccine. This vaccine flexibility may cause confusion, but ultimately is a good thing as it allows individuals to receive whatever vaccine is available and most convenient. This also allows individuals who have been vaccinated outside of the United States by a different brand of vaccine to also receive a booster vaccination with one of the options available here.
 

Take home message

Overall, the expansion of booster recommendations will help everyone avoid severe disease from COVID-19 infections. Physicians now have more clarity on who should be receiving these vaccines. Along with testing, masking, and appropriate distancing, these recommendations should help prevent severe disease and death from COVID-19.

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program, also in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

References

1. COVID-19 Vaccine Booster Shots. Centers for Disease Control and Prevention. 2021 Dec 9.

2. COVID-19 Vaccines and Pregnancy: Conversation Guide. American College of Obstetricians and Gynecologists. 2021 November.

3. COVID-19 Vaccines While Pregnant or Breastfeeding. Centers for Disease Control and Prevention. 2021 Dec 6.

The Food and Drug Administration has authorized booster doses of Pfizer’s COVID-19 vaccine, clearing the way for millions of teenagers to get a third dose of vaccine starting 6 months after their second dose.

The FDA said it was basing its emergency authorization of boosters for 16- and 17-year-olds on data from 200 individuals who were 18-55 years of age when they received a booster dose. They are requiring Pfizer to collect data on safety in postauthorization studies.

“The FDA has determined that the benefits of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine or Comirnaty outweigh the risks of myocarditis and pericarditis in individuals 16 and 17 years of age to provide continued protection against COVID-19 and the associated serious consequences that can occur including hospitalization and death,” the agency said in a news release.

Israel has been giving booster doses of Pfizer’s vaccine to everyone 12 and up since late August. Data from that country show that myocarditis cases continue to be very rare, even in younger age groups, and are mild and temporary.

The authorization comes as the effectiveness of the current vaccines against the new Omicron variant has become a point of intense scientific inquiry.

Early studies suggest that booster doses may be necessary to keep Omicron at bay, at least until new variant-specific vaccines are ready next spring.

Current evidence suggests that the protection of the vaccines is holding up well against severe disease and death, at least with Delta and early iterations of the virus.

How well they will do against Omicron, and how severe Omicron infections may be for different age groups, remain open questions.

On Dec. 8, the World Health Organization urged countries not to wait for all the science to come in, but to act now to contain any potential threat.

The first pieces of evidence on Omicron suggest that it is highly contagious, perhaps even more than Delta, though early reports suggest symptoms caused by this version of the new coronavirus may be less severe than in previous waves. Experts have cautioned that the true severity of Omicron infections isn’t yet known, since the first cases have been detected in younger people, who tend to have milder COVID-19 symptoms than those of adults and seniors.

“Vaccination and getting a booster when eligible, along with other preventive measures like masking and avoiding large crowds and poorly ventilated spaces, remain our most effective methods for fighting COVID-19,” Acting FDA Commissioner Janet Woodcock, MD, said in a news release. “As people gather indoors with family and friends for the holidays, we can’t let up on all the preventive public health measures that we have been taking during the pandemic. With both the Delta and Omicron variants continuing to spread, vaccination remains the best protection against COVID-19.”

In mid-November, the FDA authorized boosters of the Pfizer vaccine for all individuals 18 and older, but the agency held off on expanding the use of boosters for younger age groups, partly because they have the highest risk of myocarditis, a very rare side effect.

Myocarditis cases seem to be temporary, with patients making a full recovery, though they need to be monitored in the hospital. The risk of myocarditis with a COVID-19 infection is many times higher than it is from a vaccine.

There have been little data to support the need for boosters in this age group, because children and teens tend to experience milder COVID-19 disease, though they are still at risk for post–COVID-19 complications such as long COVID and a delayed reaction to the virus called Post Acute Sequelae of SARS-CoV2 Infection among Children, or PAS-C.

All that changed with the arrival of Omicron.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has authorized booster doses of Pfizer’s COVID-19 vaccine, clearing the way for millions of teenagers to get a third dose of vaccine starting 6 months after their second dose.

The FDA said it was basing its emergency authorization of boosters for 16- and 17-year-olds on data from 200 individuals who were 18-55 years of age when they received a booster dose. They are requiring Pfizer to collect data on safety in postauthorization studies.

“The FDA has determined that the benefits of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine or Comirnaty outweigh the risks of myocarditis and pericarditis in individuals 16 and 17 years of age to provide continued protection against COVID-19 and the associated serious consequences that can occur including hospitalization and death,” the agency said in a news release.

Israel has been giving booster doses of Pfizer’s vaccine to everyone 12 and up since late August. Data from that country show that myocarditis cases continue to be very rare, even in younger age groups, and are mild and temporary.

The authorization comes as the effectiveness of the current vaccines against the new Omicron variant has become a point of intense scientific inquiry.

Early studies suggest that booster doses may be necessary to keep Omicron at bay, at least until new variant-specific vaccines are ready next spring.

Current evidence suggests that the protection of the vaccines is holding up well against severe disease and death, at least with Delta and early iterations of the virus.

How well they will do against Omicron, and how severe Omicron infections may be for different age groups, remain open questions.

On Dec. 8, the World Health Organization urged countries not to wait for all the science to come in, but to act now to contain any potential threat.

The first pieces of evidence on Omicron suggest that it is highly contagious, perhaps even more than Delta, though early reports suggest symptoms caused by this version of the new coronavirus may be less severe than in previous waves. Experts have cautioned that the true severity of Omicron infections isn’t yet known, since the first cases have been detected in younger people, who tend to have milder COVID-19 symptoms than those of adults and seniors.

“Vaccination and getting a booster when eligible, along with other preventive measures like masking and avoiding large crowds and poorly ventilated spaces, remain our most effective methods for fighting COVID-19,” Acting FDA Commissioner Janet Woodcock, MD, said in a news release. “As people gather indoors with family and friends for the holidays, we can’t let up on all the preventive public health measures that we have been taking during the pandemic. With both the Delta and Omicron variants continuing to spread, vaccination remains the best protection against COVID-19.”

In mid-November, the FDA authorized boosters of the Pfizer vaccine for all individuals 18 and older, but the agency held off on expanding the use of boosters for younger age groups, partly because they have the highest risk of myocarditis, a very rare side effect.

Myocarditis cases seem to be temporary, with patients making a full recovery, though they need to be monitored in the hospital. The risk of myocarditis with a COVID-19 infection is many times higher than it is from a vaccine.

There have been little data to support the need for boosters in this age group, because children and teens tend to experience milder COVID-19 disease, though they are still at risk for post–COVID-19 complications such as long COVID and a delayed reaction to the virus called Post Acute Sequelae of SARS-CoV2 Infection among Children, or PAS-C.

All that changed with the arrival of Omicron.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration has authorized booster doses of Pfizer’s COVID-19 vaccine, clearing the way for millions of teenagers to get a third dose of vaccine starting 6 months after their second dose.

The FDA said it was basing its emergency authorization of boosters for 16- and 17-year-olds on data from 200 individuals who were 18-55 years of age when they received a booster dose. They are requiring Pfizer to collect data on safety in postauthorization studies.

“The FDA has determined that the benefits of a single booster dose of the Pfizer-BioNTech COVID-19 Vaccine or Comirnaty outweigh the risks of myocarditis and pericarditis in individuals 16 and 17 years of age to provide continued protection against COVID-19 and the associated serious consequences that can occur including hospitalization and death,” the agency said in a news release.

Israel has been giving booster doses of Pfizer’s vaccine to everyone 12 and up since late August. Data from that country show that myocarditis cases continue to be very rare, even in younger age groups, and are mild and temporary.

The authorization comes as the effectiveness of the current vaccines against the new Omicron variant has become a point of intense scientific inquiry.

Early studies suggest that booster doses may be necessary to keep Omicron at bay, at least until new variant-specific vaccines are ready next spring.

Current evidence suggests that the protection of the vaccines is holding up well against severe disease and death, at least with Delta and early iterations of the virus.

How well they will do against Omicron, and how severe Omicron infections may be for different age groups, remain open questions.

On Dec. 8, the World Health Organization urged countries not to wait for all the science to come in, but to act now to contain any potential threat.

The first pieces of evidence on Omicron suggest that it is highly contagious, perhaps even more than Delta, though early reports suggest symptoms caused by this version of the new coronavirus may be less severe than in previous waves. Experts have cautioned that the true severity of Omicron infections isn’t yet known, since the first cases have been detected in younger people, who tend to have milder COVID-19 symptoms than those of adults and seniors.

“Vaccination and getting a booster when eligible, along with other preventive measures like masking and avoiding large crowds and poorly ventilated spaces, remain our most effective methods for fighting COVID-19,” Acting FDA Commissioner Janet Woodcock, MD, said in a news release. “As people gather indoors with family and friends for the holidays, we can’t let up on all the preventive public health measures that we have been taking during the pandemic. With both the Delta and Omicron variants continuing to spread, vaccination remains the best protection against COVID-19.”

In mid-November, the FDA authorized boosters of the Pfizer vaccine for all individuals 18 and older, but the agency held off on expanding the use of boosters for younger age groups, partly because they have the highest risk of myocarditis, a very rare side effect.

Myocarditis cases seem to be temporary, with patients making a full recovery, though they need to be monitored in the hospital. The risk of myocarditis with a COVID-19 infection is many times higher than it is from a vaccine.

There have been little data to support the need for boosters in this age group, because children and teens tend to experience milder COVID-19 disease, though they are still at risk for post–COVID-19 complications such as long COVID and a delayed reaction to the virus called Post Acute Sequelae of SARS-CoV2 Infection among Children, or PAS-C.

All that changed with the arrival of Omicron.

A version of this article first appeared on WebMD.com.

The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.

Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.

In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.

Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.

Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.

Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.

The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.

The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.

However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.

“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.

Nationwide action needed to fight underinsurance

The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.

“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.

Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.

In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.

Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.

Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.

Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.

The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.

The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.

However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.

“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.

Nationwide action needed to fight underinsurance

The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.

“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.

The proportion of U.S. children who are underinsured for health care increased by 3.4% from 2016 to 2019, reflecting approximately 2.4 million underinsured children, based on data from the National Survey of Children’s Health.

Children with inconsistent or inadequate medical coverage are more likely to forgo medical care, including preventive well-child visits, and to have unmet medical needs such as prescription medications, Justin Yu, MD, of the Children’s Hospital of Pittsburgh, and colleagues wrote. Although the American Academy of Pediatrics and the Healthy People 2030 guidelines have endorsed increasing the proportion of children with adequate coverage, recent studies suggest that advances in insuring children in the wake of the Affordable Care Act have stalled, and trends in child insurance have not been well described, the researchers said.

In a study published in Pediatrics, the researchers reviewed data from the combined 2016-2019 datasets of the National Survey of Children’s Health, a survey funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.

Adequate insurance was defined as a composite with three questions; whether the benefits “usually” or “always” meet the child’s needs; the benefits “usually” or “always” allow the child to see needed providers; and whether out-of-pocket expenses are either absent or “usually” or “always” reasonable.

Overall, the proportion of children with underinsurance increased from 30.6% in 2016 to 34.0% in 2019.

Underinsurance was significantly associated with increased health complexity and private insurance, with adjusted odds ratios of 1.9 and 3.5, respectively. In addition, underinsurance was significantly associated with child age of 6 years or older, non-Black racial identity, U.S. nonnative status, and a family income of at least 100% above the Federal Poverty Level. Notably, underinsurance grew significantly among White children living in “middle-income” families, the researchers said.

The increase in underinsurance was driven primarily by increased insurance inadequacy, which rose from 24.8% to 27.9% over the study period. The increase in insurance inadequacy was described primarily as unreasonable out-of-pocket medical expenses, according to the survey respondents.

The study findings were limited by several factors including the inability to show causality or to describe changes in outcomes for individual children, the researchers noted. Other limitations include the reliance on parent reports and the lack of a definitive definition of underinsurance.

However, the results highlight the ongoing problem of underinsurance in children, and the need to address the factors that contribute to inadequate insurance for children, the researchers said.

“Our data, demonstrating a shift from public to private insurance that is more likely to be inadequate, in conjunction with existing literature linking Medicaid/CHIP [Children’s Health Insurance Program] coverage with improved access to medical care as well as improved long-term outcomes in adulthood, should give policy makers and payers pause as they contemplate strategies to improve child health,” they concluded.

Nationwide action needed to fight underinsurance

The authors should be commended for highlighting the disturbing trend in underinsurance among children in the United States, Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, said in an interview.

“With the passage of the Affordable Care Act, the population of uninsured and underinsured had shrunk quite a bit, but in the past few years, the numbers are growing again. This population has often been called the working poor; the vast majority are legal residents who make too much to qualify for Medicaid/CHIP programs, and whose employers don’t offer affordable robust health care coverage,” Dr. Joos said.

“These families have to make the risky decisions of how much of the family budget to spend on insurance plans, often to the detriment of their own and their children’s health,” he explained. “If you believe the old adage about ‘an ounce of prevention,’ then the money we spend on preserving the health of our children will more than pay for itself in benefits of increased productivity and health care savings in the 1-2 decades later when they reach adulthood. It is time for us as a nation to come up with a more comprehensive baseline coverage for all pediatric patients and take away any barriers for families to access basic health care for children.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.