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Opening the door to gene editing?
In early August, in Portland, Ore. The scale and success of such experimentation with human embryos is unprecedented in the United States. Given the highly experimental nature of fertility clinics in the United States and abroad, many suggest that these findings open the door to designer babies. A careful read of the report, however, indicates that the door is still quite closed, perhaps cracked open just a little.
The research team used a new method of cutting the genome, called CRISPR-Cas9. CRISPR utilizes two key components that the team combined in a test tube together: a Cas9 protein that can cut the DNA and a synthetic RNA that can guide the protein to cut a 20-letter sequence in the human genome specifically. In these experiments, the Cas9-RNA protein was designed to cut a pathogenic mutation in the MYBPC3 gene, which can cause hypertrophic cardiomyopathy. The research team could not obtain human zygotes with this mutation on both copies of the genome (a rare homozygous genotype). Such zygotes would have the most severe phenotype and be the most compelling test case for CRISPR. Instead, they focused on gene editing heterozygous human zygotes that have one normal maternal copy of the MYBPC3 gene and one pathogenic paternal copy. The heterozygous zygotes were produced by the research team via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) using sperm donated by males carrying the pathogenic mutation (Nature. 2017 Aug 2. doi: 10.1038/nature23305).
When researchers injected the Cas9-RNA protein targeting the mutation into already fertilized zygotes, they found that 67% of the resulting embryos had two normal copies of the MYBPC3 gene. Without gene editing, approximately 50% of the embryos would have two normal copies, because the male sperm donor would produce equal numbers of sperm with normal and pathogenic genotypes. Thus, editing likely corrected only about 17% of the embryos that would have otherwise had one pathogenic paternal mutation. Thirty-six percent of embryos had additional mutations from imprecise gene editing. Further, some of the gene edits and additional mutations were mosaic, meaning that the resulting embryo harbored many different genotypes.
To overcome these challenges, the research team precisely controlled the timing of CRISPR injection to coincide with fertilization. With controlled timing, gene editing was restricted to only the paternal pathogenic mutation, resulting in 72% of all injected embryos having two normal copies of the gene in all cells without any mosaicism. Whole genome sequencing revealed no additional mutations above the detection limit of the assay. Finally, preimplantation development proceeded normally to the blastocyst stage, suggesting that the edited embryos have no functional deficits from the procedure.
A surprising finding was that new sequences could not be put into the embryo. The research team had coinjected a synthetic DNA template that differed from the normal maternal copy, but never saw this sequence incorporated into any embryo. Instead, the zygote utilized the maternal copy of the gene with the normal sequence as a template for repairing the DNA cut in the paternal copy produced by CRISPR. The biology behind this repair process is poorly understood and has not been previously reported with other human cell types. These observations suggest that we cannot easily “write” our genome. Instead, our vocabulary is limited to what is already within either the maternal or paternal copy of the genome. In other words, designer babies are not around the corner. While preimplantation genetic diagnosis (PGD) is still currently the safest way to avoid passing on autosomal dominant mutations, these new findings could enable correction of such mutations within IVF embryos, resulting in a larger pool of embryos for IVF clinics to work with.
Apart from these technical challenges, the National Academies has not given a green light to implant edited human embryos. Instead, the organization calls for several requirements to be met, including “broad societal consensus” on the need for this type of intervention. While it is not clear whether or how consensus could be achieved, it is clear that scientists, clinicians, and patients will need help from the rest of society for this research to have an impact clinically.
Dr. Saha is assistant professor of biomedical engineering at the Wisconsin Institute for Discovery at the University of Wisconsin, Madison. His lab works on gene editing of human cells. He has patent filings through the Wisconsin Alumni Research Foundation on gene editing inventions.
In early August, in Portland, Ore. The scale and success of such experimentation with human embryos is unprecedented in the United States. Given the highly experimental nature of fertility clinics in the United States and abroad, many suggest that these findings open the door to designer babies. A careful read of the report, however, indicates that the door is still quite closed, perhaps cracked open just a little.
The research team used a new method of cutting the genome, called CRISPR-Cas9. CRISPR utilizes two key components that the team combined in a test tube together: a Cas9 protein that can cut the DNA and a synthetic RNA that can guide the protein to cut a 20-letter sequence in the human genome specifically. In these experiments, the Cas9-RNA protein was designed to cut a pathogenic mutation in the MYBPC3 gene, which can cause hypertrophic cardiomyopathy. The research team could not obtain human zygotes with this mutation on both copies of the genome (a rare homozygous genotype). Such zygotes would have the most severe phenotype and be the most compelling test case for CRISPR. Instead, they focused on gene editing heterozygous human zygotes that have one normal maternal copy of the MYBPC3 gene and one pathogenic paternal copy. The heterozygous zygotes were produced by the research team via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) using sperm donated by males carrying the pathogenic mutation (Nature. 2017 Aug 2. doi: 10.1038/nature23305).
When researchers injected the Cas9-RNA protein targeting the mutation into already fertilized zygotes, they found that 67% of the resulting embryos had two normal copies of the MYBPC3 gene. Without gene editing, approximately 50% of the embryos would have two normal copies, because the male sperm donor would produce equal numbers of sperm with normal and pathogenic genotypes. Thus, editing likely corrected only about 17% of the embryos that would have otherwise had one pathogenic paternal mutation. Thirty-six percent of embryos had additional mutations from imprecise gene editing. Further, some of the gene edits and additional mutations were mosaic, meaning that the resulting embryo harbored many different genotypes.
To overcome these challenges, the research team precisely controlled the timing of CRISPR injection to coincide with fertilization. With controlled timing, gene editing was restricted to only the paternal pathogenic mutation, resulting in 72% of all injected embryos having two normal copies of the gene in all cells without any mosaicism. Whole genome sequencing revealed no additional mutations above the detection limit of the assay. Finally, preimplantation development proceeded normally to the blastocyst stage, suggesting that the edited embryos have no functional deficits from the procedure.
A surprising finding was that new sequences could not be put into the embryo. The research team had coinjected a synthetic DNA template that differed from the normal maternal copy, but never saw this sequence incorporated into any embryo. Instead, the zygote utilized the maternal copy of the gene with the normal sequence as a template for repairing the DNA cut in the paternal copy produced by CRISPR. The biology behind this repair process is poorly understood and has not been previously reported with other human cell types. These observations suggest that we cannot easily “write” our genome. Instead, our vocabulary is limited to what is already within either the maternal or paternal copy of the genome. In other words, designer babies are not around the corner. While preimplantation genetic diagnosis (PGD) is still currently the safest way to avoid passing on autosomal dominant mutations, these new findings could enable correction of such mutations within IVF embryos, resulting in a larger pool of embryos for IVF clinics to work with.
Apart from these technical challenges, the National Academies has not given a green light to implant edited human embryos. Instead, the organization calls for several requirements to be met, including “broad societal consensus” on the need for this type of intervention. While it is not clear whether or how consensus could be achieved, it is clear that scientists, clinicians, and patients will need help from the rest of society for this research to have an impact clinically.
Dr. Saha is assistant professor of biomedical engineering at the Wisconsin Institute for Discovery at the University of Wisconsin, Madison. His lab works on gene editing of human cells. He has patent filings through the Wisconsin Alumni Research Foundation on gene editing inventions.
In early August, in Portland, Ore. The scale and success of such experimentation with human embryos is unprecedented in the United States. Given the highly experimental nature of fertility clinics in the United States and abroad, many suggest that these findings open the door to designer babies. A careful read of the report, however, indicates that the door is still quite closed, perhaps cracked open just a little.
The research team used a new method of cutting the genome, called CRISPR-Cas9. CRISPR utilizes two key components that the team combined in a test tube together: a Cas9 protein that can cut the DNA and a synthetic RNA that can guide the protein to cut a 20-letter sequence in the human genome specifically. In these experiments, the Cas9-RNA protein was designed to cut a pathogenic mutation in the MYBPC3 gene, which can cause hypertrophic cardiomyopathy. The research team could not obtain human zygotes with this mutation on both copies of the genome (a rare homozygous genotype). Such zygotes would have the most severe phenotype and be the most compelling test case for CRISPR. Instead, they focused on gene editing heterozygous human zygotes that have one normal maternal copy of the MYBPC3 gene and one pathogenic paternal copy. The heterozygous zygotes were produced by the research team via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) using sperm donated by males carrying the pathogenic mutation (Nature. 2017 Aug 2. doi: 10.1038/nature23305).
When researchers injected the Cas9-RNA protein targeting the mutation into already fertilized zygotes, they found that 67% of the resulting embryos had two normal copies of the MYBPC3 gene. Without gene editing, approximately 50% of the embryos would have two normal copies, because the male sperm donor would produce equal numbers of sperm with normal and pathogenic genotypes. Thus, editing likely corrected only about 17% of the embryos that would have otherwise had one pathogenic paternal mutation. Thirty-six percent of embryos had additional mutations from imprecise gene editing. Further, some of the gene edits and additional mutations were mosaic, meaning that the resulting embryo harbored many different genotypes.
To overcome these challenges, the research team precisely controlled the timing of CRISPR injection to coincide with fertilization. With controlled timing, gene editing was restricted to only the paternal pathogenic mutation, resulting in 72% of all injected embryos having two normal copies of the gene in all cells without any mosaicism. Whole genome sequencing revealed no additional mutations above the detection limit of the assay. Finally, preimplantation development proceeded normally to the blastocyst stage, suggesting that the edited embryos have no functional deficits from the procedure.
A surprising finding was that new sequences could not be put into the embryo. The research team had coinjected a synthetic DNA template that differed from the normal maternal copy, but never saw this sequence incorporated into any embryo. Instead, the zygote utilized the maternal copy of the gene with the normal sequence as a template for repairing the DNA cut in the paternal copy produced by CRISPR. The biology behind this repair process is poorly understood and has not been previously reported with other human cell types. These observations suggest that we cannot easily “write” our genome. Instead, our vocabulary is limited to what is already within either the maternal or paternal copy of the genome. In other words, designer babies are not around the corner. While preimplantation genetic diagnosis (PGD) is still currently the safest way to avoid passing on autosomal dominant mutations, these new findings could enable correction of such mutations within IVF embryos, resulting in a larger pool of embryos for IVF clinics to work with.
Apart from these technical challenges, the National Academies has not given a green light to implant edited human embryos. Instead, the organization calls for several requirements to be met, including “broad societal consensus” on the need for this type of intervention. While it is not clear whether or how consensus could be achieved, it is clear that scientists, clinicians, and patients will need help from the rest of society for this research to have an impact clinically.
Dr. Saha is assistant professor of biomedical engineering at the Wisconsin Institute for Discovery at the University of Wisconsin, Madison. His lab works on gene editing of human cells. He has patent filings through the Wisconsin Alumni Research Foundation on gene editing inventions.
Researchers identify ‘congenital NAD deficiency disorders’
Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.
The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).
Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”
Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.
This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.
“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.
“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”
The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.
Shi et al. report that a deficiency of nicotinamide adenine dinucleotide (NAD) causes congenital malformations, suggesting that interventions to raise NAD levels during fetal and early postnatal development might further reduce the incidence of congenital anomalies.
Regardless of how NAD depletion leads to congenital malformations (whether by compromising the detection of DNA damage by PARP proteins, reducing the supply of nucleotides, or both), dietary supplementation with NAD precursors merits further study. At high doses, niacin can cause flushing and gastrointestinal symptoms, but it has few side effects at lower doses.
Nicotinamide mononucleotide, nicotinamide riboside, and nicotinamide itself are better tolerated than niacin and are generally considered to be safe as dietary supplements, but the doses of NAD precursors required to reduce the risk of congenital malformations in humans are not known. Also unknown is the extent to which raising dietary levels of NAD would limit cognitive impairment in infants with congenital malformations.
Matthew G. Vander Heiden, MD, PhD, is with the Massachusetts Institute of Technology, Cambridge, Mass., and the Dana Farber Cancer Center, Boston. He reported receiving personal fees from Agios Pharmaceuticals and Aeglea Biotherapeutics outside the submitted work. These comments are adapted from an editorial (N Engl J Med. 2007;377:509-11).
Shi et al. report that a deficiency of nicotinamide adenine dinucleotide (NAD) causes congenital malformations, suggesting that interventions to raise NAD levels during fetal and early postnatal development might further reduce the incidence of congenital anomalies.
Regardless of how NAD depletion leads to congenital malformations (whether by compromising the detection of DNA damage by PARP proteins, reducing the supply of nucleotides, or both), dietary supplementation with NAD precursors merits further study. At high doses, niacin can cause flushing and gastrointestinal symptoms, but it has few side effects at lower doses.
Nicotinamide mononucleotide, nicotinamide riboside, and nicotinamide itself are better tolerated than niacin and are generally considered to be safe as dietary supplements, but the doses of NAD precursors required to reduce the risk of congenital malformations in humans are not known. Also unknown is the extent to which raising dietary levels of NAD would limit cognitive impairment in infants with congenital malformations.
Matthew G. Vander Heiden, MD, PhD, is with the Massachusetts Institute of Technology, Cambridge, Mass., and the Dana Farber Cancer Center, Boston. He reported receiving personal fees from Agios Pharmaceuticals and Aeglea Biotherapeutics outside the submitted work. These comments are adapted from an editorial (N Engl J Med. 2007;377:509-11).
Shi et al. report that a deficiency of nicotinamide adenine dinucleotide (NAD) causes congenital malformations, suggesting that interventions to raise NAD levels during fetal and early postnatal development might further reduce the incidence of congenital anomalies.
Regardless of how NAD depletion leads to congenital malformations (whether by compromising the detection of DNA damage by PARP proteins, reducing the supply of nucleotides, or both), dietary supplementation with NAD precursors merits further study. At high doses, niacin can cause flushing and gastrointestinal symptoms, but it has few side effects at lower doses.
Nicotinamide mononucleotide, nicotinamide riboside, and nicotinamide itself are better tolerated than niacin and are generally considered to be safe as dietary supplements, but the doses of NAD precursors required to reduce the risk of congenital malformations in humans are not known. Also unknown is the extent to which raising dietary levels of NAD would limit cognitive impairment in infants with congenital malformations.
Matthew G. Vander Heiden, MD, PhD, is with the Massachusetts Institute of Technology, Cambridge, Mass., and the Dana Farber Cancer Center, Boston. He reported receiving personal fees from Agios Pharmaceuticals and Aeglea Biotherapeutics outside the submitted work. These comments are adapted from an editorial (N Engl J Med. 2007;377:509-11).
Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.
The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).
Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”
Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.
This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.
“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.
“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”
The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.
Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.
The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).
Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”
Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.
This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.
“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.
“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”
The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Major congenital defects affecting unrelated families were associated with variants in genes encoding 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU).
Data source: Genomic sequencing of four unrelated families in which a person was born with multiple congenital malformations, plus in vitro measurements of enzyme activity and plasma metabolites and studies of mouse models created with the CRISPR–Cas9 system.
Disclosures: The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.
Mobile messages support safe sleep practices
Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.
Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).
A total of 1,263 mothers completed the study, and mothers who received the mobile messages about safe sleep were significantly more likely than those who received the control messages to engage in safe sleep practices, including placing babies on their backs (89% vs. 80%), sharing a room without cosleeping (83% vs. 70%), avoiding the use of soft bedding (79% vs. 68%), and use of pacifiers (69% vs. 60%). The initial nursing quality intervention alone had no significant impact on any of the safe sleep practices, the researchers noted.
The results were limited by several factors, including the 21% lost to follow up and lack of data on adverse events and clinical outcomes, the researchers said. However, the results suggest that mobile messages could be cost effective and easily implemented by hospitals.
“Furthermore, because the rates of opening and viewing messages in this study were consistently higher than 50%, and almost all adults now have cell phones or email access, it is likely that this type of intervention would be feasible and well received by parents,” Dr. Moon and her associates added. “Whether widespread implementation is feasible or if it reduces sudden and unexpected infant death rates remains to be studied.”
“The messages and videos were timed to address challenges and questions that arise at specific time points; therefore, providing this additional information to parents at critical times may have been important in assuaging concerns about adherence to recommended practices. Furthermore, receiving frequent videos and email or text messages may have served as a virtual support system for mothers, reinforcing safe parental practices,” Dr. Moon and her associates noted.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Institute of Child Health and Human Development and by the CJ Foundation for SIDS.
In this study by Dr. Moon and her associates, new mothers who received both the nursing educational intervention and mobile intervention for safe sleep reported the highest percentages for adhering to safe sleep practices, and moms who received the safe sleep mobile intervention alone had the second-highest percentages.
However, the study was underpowered and too short termed to determine whether this intervention actually will reduce the occurrence of SIDS.
Limitations of this study include that the mothers who did not respond at follow-up were more likely to be younger, black, single, and less educated – all risk factors for SIDS. The study also was restricted to healthy term infants, and preterm babies are another high-risk SIDS group.
Nonetheless, the fact that this study chose to use multifaceted approaches was promising, combining “health messaging, education of health care professionals, and interventions aimed at reducing barriers to safe sleep practices for infant caregivers.” Whatever interventions are tried, they “need to be adapted for implementation among the highest-risk groups such as non-Hispanic black, American Indian, and Alaskan Native mothers and families because these are the populations with the highest rates of SIDS and sleep-related infant death.”
Carrie K. Shapiro-Mendoza, PhD, MPH is affiliated with the division of reproductive health at the Centers for Disease Control and Prevention in Atlanta, Georgia. She commented in an editorial accompanying the report by Moon et al. (JAMA. 2017;318:336-8). Dr. Shapiro-Mendoza had no financial conflicts to disclose.
In this study by Dr. Moon and her associates, new mothers who received both the nursing educational intervention and mobile intervention for safe sleep reported the highest percentages for adhering to safe sleep practices, and moms who received the safe sleep mobile intervention alone had the second-highest percentages.
However, the study was underpowered and too short termed to determine whether this intervention actually will reduce the occurrence of SIDS.
Limitations of this study include that the mothers who did not respond at follow-up were more likely to be younger, black, single, and less educated – all risk factors for SIDS. The study also was restricted to healthy term infants, and preterm babies are another high-risk SIDS group.
Nonetheless, the fact that this study chose to use multifaceted approaches was promising, combining “health messaging, education of health care professionals, and interventions aimed at reducing barriers to safe sleep practices for infant caregivers.” Whatever interventions are tried, they “need to be adapted for implementation among the highest-risk groups such as non-Hispanic black, American Indian, and Alaskan Native mothers and families because these are the populations with the highest rates of SIDS and sleep-related infant death.”
Carrie K. Shapiro-Mendoza, PhD, MPH is affiliated with the division of reproductive health at the Centers for Disease Control and Prevention in Atlanta, Georgia. She commented in an editorial accompanying the report by Moon et al. (JAMA. 2017;318:336-8). Dr. Shapiro-Mendoza had no financial conflicts to disclose.
In this study by Dr. Moon and her associates, new mothers who received both the nursing educational intervention and mobile intervention for safe sleep reported the highest percentages for adhering to safe sleep practices, and moms who received the safe sleep mobile intervention alone had the second-highest percentages.
However, the study was underpowered and too short termed to determine whether this intervention actually will reduce the occurrence of SIDS.
Limitations of this study include that the mothers who did not respond at follow-up were more likely to be younger, black, single, and less educated – all risk factors for SIDS. The study also was restricted to healthy term infants, and preterm babies are another high-risk SIDS group.
Nonetheless, the fact that this study chose to use multifaceted approaches was promising, combining “health messaging, education of health care professionals, and interventions aimed at reducing barriers to safe sleep practices for infant caregivers.” Whatever interventions are tried, they “need to be adapted for implementation among the highest-risk groups such as non-Hispanic black, American Indian, and Alaskan Native mothers and families because these are the populations with the highest rates of SIDS and sleep-related infant death.”
Carrie K. Shapiro-Mendoza, PhD, MPH is affiliated with the division of reproductive health at the Centers for Disease Control and Prevention in Atlanta, Georgia. She commented in an editorial accompanying the report by Moon et al. (JAMA. 2017;318:336-8). Dr. Shapiro-Mendoza had no financial conflicts to disclose.
Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.
Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).
A total of 1,263 mothers completed the study, and mothers who received the mobile messages about safe sleep were significantly more likely than those who received the control messages to engage in safe sleep practices, including placing babies on their backs (89% vs. 80%), sharing a room without cosleeping (83% vs. 70%), avoiding the use of soft bedding (79% vs. 68%), and use of pacifiers (69% vs. 60%). The initial nursing quality intervention alone had no significant impact on any of the safe sleep practices, the researchers noted.
The results were limited by several factors, including the 21% lost to follow up and lack of data on adverse events and clinical outcomes, the researchers said. However, the results suggest that mobile messages could be cost effective and easily implemented by hospitals.
“Furthermore, because the rates of opening and viewing messages in this study were consistently higher than 50%, and almost all adults now have cell phones or email access, it is likely that this type of intervention would be feasible and well received by parents,” Dr. Moon and her associates added. “Whether widespread implementation is feasible or if it reduces sudden and unexpected infant death rates remains to be studied.”
“The messages and videos were timed to address challenges and questions that arise at specific time points; therefore, providing this additional information to parents at critical times may have been important in assuaging concerns about adherence to recommended practices. Furthermore, receiving frequent videos and email or text messages may have served as a virtual support system for mothers, reinforcing safe parental practices,” Dr. Moon and her associates noted.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Institute of Child Health and Human Development and by the CJ Foundation for SIDS.
Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.
Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).
A total of 1,263 mothers completed the study, and mothers who received the mobile messages about safe sleep were significantly more likely than those who received the control messages to engage in safe sleep practices, including placing babies on their backs (89% vs. 80%), sharing a room without cosleeping (83% vs. 70%), avoiding the use of soft bedding (79% vs. 68%), and use of pacifiers (69% vs. 60%). The initial nursing quality intervention alone had no significant impact on any of the safe sleep practices, the researchers noted.
The results were limited by several factors, including the 21% lost to follow up and lack of data on adverse events and clinical outcomes, the researchers said. However, the results suggest that mobile messages could be cost effective and easily implemented by hospitals.
“Furthermore, because the rates of opening and viewing messages in this study were consistently higher than 50%, and almost all adults now have cell phones or email access, it is likely that this type of intervention would be feasible and well received by parents,” Dr. Moon and her associates added. “Whether widespread implementation is feasible or if it reduces sudden and unexpected infant death rates remains to be studied.”
“The messages and videos were timed to address challenges and questions that arise at specific time points; therefore, providing this additional information to parents at critical times may have been important in assuaging concerns about adherence to recommended practices. Furthermore, receiving frequent videos and email or text messages may have served as a virtual support system for mothers, reinforcing safe parental practices,” Dr. Moon and her associates noted.
The researchers had no financial conflicts to disclose. The study was supported in part by the National Institute of Child Health and Human Development and by the CJ Foundation for SIDS.
FROM JAMA
Key clinical point: Email and text messages effectively communicated safe infant sleep practices to mothers.
Major finding: Overall,
Data source: The data come from a randomized trial of 1,600 mothers with healthy newborns.
Disclosures: The researchers had no financial conflicts to disclose. The study was supported in part by the National Institute of Child Health and Human Development and by the CJ Foundation for SIDS.
Extreme caffeine use in early pregnancy risks offspring behavioral disorders
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
, Susanne Hvolgaard Mikkelsen, PhD, of Aarhus (Denmark) University and her associates said.
“Caffeine metabolism is delayed during pregnancy, allowing longer opportunities for absorption. Caffeine increases dopamine levels by slowing down the rate of dopamine reabsorption, and this dysfunction of the dopaminergic system is thought to explain part of the association between caffeine consumption and offspring behavioral disorders,” the investigators said.
From 1996 to 2002, Danish physicians recruited women during their first pregnancy visit to participate in a study evaluating daily coffee and tea consumption during pregnancy, with follow-up of the children at age 11 years using the Danish National Birth Cohort. A follow-up questionnaire, including the Strength and Difficulties Questionnaire, was completed by the children, their parents, and their teachers; the results were paired with data on coffee and tea consumption by the mothers of 47,491 children. At 15 weeks’ gestation, 12% of the women had consumed more than three cups/day of coffee, and 3% ingested eight or more cups/day of coffee; 19% of the women drank more than three cups/day of tea, and 4% drank eight or more cups/day of tea. The amount of coffee and tea consumed at 30 weeks’ gestation was only slightly less.
The percentage of children predicted to have “possible/probable” ADHD was 5%, conduct-oppositional disorders was 7%, anxiety-depressive disorders was 7%, and any psychiatric disorder was 14%.
A statistically significant association was found between maternal consumption of eight or more cups of coffee at 15 weeks’ gestation and greater risk of ADHD (a risk ratio [RR] of 1.47), conduct-oppositional disorder (RR, 1.22), and any psychiatric disorder (RR, 1.23). A statistically significant link was found between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and greater risk of conduct-oppositional disorder (RR, 1.21). There was a statistically significant association between maternal consumption of eight or more cups of tea at 15 weeks’ gestation and a higher risk of anxiety-depressive disorder (RR, 1.28), but not for coffee. These significant relationships were not found again at 30 weeks’ gestation.
“The period of greatest prenatal brain development is 10-26 weeks after conception,which may explain our results suggesting the fetus to be more vulnerable to caffeine in first and second trimester, compared with the third trimester,” the researchers said.
There was no information available about caffeine consumption by chocolate, energy drinks, or medication; the measure of cola consumption also was not taken into account. Confounding by genetics or socioeconomic factors may affect these findings, Dr. Mikkelsen and her associates said.
Read more at (J Pediatr. 2017 Jul 18. doi: 10.1016/j.jpeds.2017.06.051).
FROM THE JOURNAL OF PEDIATRICS
Procalcitonin-guided decision making found best in neonatal suspected sepsis
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
Dr. Stocker, Dr. Herk, and their coauthors “are to be commended for conducting this pragmatic and international, multicenter trial.” When withholding antibiotics, especially from neonates who are susceptible to infection, safety is key. In this “landmark study done in neonates,” the authors determined that procalcitonin can be safely used to guide decision making in neonates at low risk of sepsis. Using procalcitonin in a clinical algorithm also was effective, reducing the duration of antibiotic therapy by around 20% and the length of hospital stay by around 5%.
Although the biomarker is the most accurate diagnostic tool currently available, it should be used with caution. On its own, it is not enough to determine if a neonate is in need of continued antibiotic therapy. It should be used in conjunction with clinical examination and reasoning on the part of the physician. In addition, the cutoffs that have been determined for adults are too low for neonates. “Nevertheless, if the cutoff is adapted accordingly and embedded in a reasonable clinical algorithm – as done in the NeoPInS study – procalcitonin can and should be used to improve antibiotic stewardship.
“Procalcitonin-guided antibiotic de-escalation therapy is evidence based and state of the art for antibiotic therapy for suspected and proven bacterial infection in different clinical settings and different acuity of infections.”
Philipp Schuetz, MD, and Beat Mueller, MD, are of the University of Basel, Aarau, Switzerland. Dr. Schuetz received support from BRAHMS/Thermofisher and bioMérieux to attend meetings, fulfill speaking engagements, and for unrestricted research grants related to procalcitonin. Dr. Mueller has received research support, as well as consulting fees and speakers’ honoraria, from BRAHMS/Thermofisher and bioMérieux, related to procalcitonin. They made these remarks in a commentary accompanying Dr. Stocker’s and Dr. van Herk’s report (Lancet. 2017 Jul 12. doi: 10.1016/S0140-6736[17]31628-8).
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
, according to an investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study.
In the Neonatal Procalcitonin Intervention Study (NeoPInS) study aimed to reduce the duration of antibiotic treatment, 1,710 neonates who were already receiving antibiotic therapy were enrolled in 18 hospitals in Canada, the Czech Republic, the Netherlands, and Switzerland, and randomized to procalcitonin-guided decision making or standard care. Some patients were excluded from the larger initial population because of congenital malformation, surgery in the first week of life, or a lack of parental consent, among other reasons.
The intention-to-treat population included 866 neonates in the procalcitonin group whose median treatment duration was 55 hours (95% confidence interval [CI], 50.5-60.0) and 844 in the standard group whose median treatment duration was 65 hours (95% CI, 63.0-69.0; P less than .0001), with a median difference of –9.9. The per-protocol population saw an even greater median difference of –12.2, with a treatment duration of 52 hours in 745 neonates assigned to procalcitonin-guided decision making (95% CI, 48.2-56.0) and a duration of 64 hours in 663 neonates assigned to standard care (95% CI, 61.0-68.1; P less than .0001).
Length of hospital stay also was significantly shorter in both procalcitonin groups, according to the researchers.
One neonate in the standard group died from the consequences of severe perinatal asphyxia. In each procalcitonin group, five (0.6% and 0.7%, respectively) had a suspected reinfection, compared with three in each of the standard groups (0.5% and 0.6%, respectively). None of the neonates suspected of reinfection had a culture-proven bacteria infection.
“In this era of globally increasing antibiotic resistance rates ... every dose of antimicrobial therapy counts in the emergence of antimicrobial resistance and in changing the human microbiome,” the investigators wrote, “and other evidence suggests that changes in the microbiome in early life are particularly important in shaping the individual’s immune system and future health.”
The primary outcomes of the study were duration of treatment and reinfection or death in the first month of life, with a secondary outcome of length of hospital stay. Noninferiority for reinfection and death could not be shown because there were too few of these events.
“Procalcitonin-guided decision making led to a significant reduction in duration of empirical antibiotic therapy and hospital stay in term and near-term neonates with suspected early-onset sepsis, with a low rate of reinfections and with no study-related mortality. Combining serial procalcitonin measurements with initial assessment based on perinatal risk factors, the neonate’s clinical signs and symptoms, and conventional laboratory variables support antimicrobial stewardship and help physicians to decide to discontinue antibiotic treatment sooner in neonates classified as having low or moderate risk of infection,” Dr. Stocker, Dr. van Herk, and their associates said.
A limitation was that results cannot be extrapolated to other populations. The neonates in this study all had easy and low-threshold access to care, so the results may not apply to low-income or low-access areas, they said.
Length of hospital stay results may be affected by other conditions developed by the neonates. “It would be interesting to analyze duration of hospital stay separately for neonates with or without other reasons for hospital admission, but this was not possible in our study design,” the investigators said.
The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
FROM THE LANCET
Key clinical point: Procalcitonin-guided decision making had a significant impact on duration of antibiotic treatment and hospital stay in pediatric patients with suspected early-onset sepsis.
Major finding: The median differences in antibiotic treatment duration between procalcitonin groups and standard care groups were –9.9 and –12.1 hours in intention-to-treat and per protocol study populations.
Data source: An investigator-initiated, superiority and noninferiority, multicenter, randomized controlled intervention study (NeoPInS) of 1,710 neonates with suspected early-stage sepsis.
Disclosures: The authors reported no relevant financial disclosures. The Thrasher Foundation, the NutsOhra Foundation, and the Sophia Foundation for Scientific Research funded the study.
Early neuroimaging essential for Zika-exposed neonates
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Maternal protection against measles steadily declines prior to vaccination
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
, and for coxsackievirus (CoxA16), for which there currently is no vaccine.
EV71 and CoxA16 are enteroviruses that are common agents of hand-foot-and-mouth disease. Some patients infected with EV71 or CoxA16 develop neurological and systemic complications that can kill them. An EV71 vaccine, which is initially administered at 6 months, has been licensed in China since December 2015.
In a longitudinally designed study conducted by Chuanxi Fu and Jichuan Shen of Guangzhou (China) Center for Disease Control and Prevention, and their associates, sera was collected from 717 infants ages 0, 3, and 6 months, and examined for levels of measles IgG antibodies, and neutralizing antibodies for EV71 and CoxA16. Measles IgG antibody concentration from 717, 233, and 75 sera were assessed in infants of 0 month, 3 months, and 6 months, and 225, 217, and 72 sera were assessed for EV71 and CoxA16 at these time periods.
This study provides evidence of the rapid declining of measles antibodies in infants prior to vaccination under the Expanded Program on Immunization schedule in China, and confirms the rapid decrease of measles antibody levels suggested by prior cross-sectional studies in China. “Further modifications of vaccination strategies for measles, earlier vaccination for EV71 infection, and development and provision of a CoxA16 vaccine should be investigated and considered in the future,” concluded the researchers.
FROM VACCINE
Pneumococcal conjugate vaccines modestly reduce complex acute otitis media
Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.
The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.
Incidence of Streptococcus pneumoniae cases decreased from 38% in the prevaccine era to 31% in the PCV-7 era and decreased even more to 16% in the PCV-13 era. The incidence of the second most frequently isolated bacteria, group A streptococcus (GAS), fell from 17% in the prevaccine era to 16% in the PCV-13 era, becoming equal to S. pneumoniae. The “no growth” results rose from 12% in the prevaccine era to 38% and 44% in the PCV-7 and PCV-13 eras, respectively (Int J Pediatr Otorhinolaryngol. 2017 Jul 4. doi: 10.1016/j.ijporl.2017.07.002) .
In the M+AM group, S. pneumoniae–positive cases fell to 10% in the PCV-13 era, compared with 44% in the prevaccine era and 41% in the PCV-7 era. A rise in GAS-positive cultures was seen in the M+AM group, from 15% in the prevaccine era to 30% in the PCV-13 era. The “no growth” group rose in incidence from 13% of cases in the prevaccine era to 26% in the PCV-7 era and 33% in the PCV-13 era.
“This microbiological shift is worrisome, because GAS may cause very serious infections due to its invasive nature,” Dr. Laursen and associates wrote. “An increase in GAS as described in this study has not been demonstrated elsewhere so far. In contrast to our findings, the most common species to ‘take over’ in the United States was Haemophilus influenzae.
“As [S. pneumoniae] and GAS are potentially invasive pathogens causing more severe clinical signs and symptoms, such cases are more likely to be admitted compared to cases caused by non-typable Haemophilus influenzae that gives rise to more subtle middle ear infections and clinical pictures,” the researchers noted.
Considering how many patients received antibiotics prior to admission in the hAOM group, there was a slight increase from 45% in the prevaccine era to 54% in the PCV-13 era, but a “more pronounced increase was found in the M+AM group, from 27% in the prevaccine era to 46% in the PCV-13 era,” they said.
The investigators called for continued surveillance of the microbiology associated with complex AOM.
No study funding or investigator disclosure information was provided.
Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.
The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.
Incidence of Streptococcus pneumoniae cases decreased from 38% in the prevaccine era to 31% in the PCV-7 era and decreased even more to 16% in the PCV-13 era. The incidence of the second most frequently isolated bacteria, group A streptococcus (GAS), fell from 17% in the prevaccine era to 16% in the PCV-13 era, becoming equal to S. pneumoniae. The “no growth” results rose from 12% in the prevaccine era to 38% and 44% in the PCV-7 and PCV-13 eras, respectively (Int J Pediatr Otorhinolaryngol. 2017 Jul 4. doi: 10.1016/j.ijporl.2017.07.002) .
In the M+AM group, S. pneumoniae–positive cases fell to 10% in the PCV-13 era, compared with 44% in the prevaccine era and 41% in the PCV-7 era. A rise in GAS-positive cultures was seen in the M+AM group, from 15% in the prevaccine era to 30% in the PCV-13 era. The “no growth” group rose in incidence from 13% of cases in the prevaccine era to 26% in the PCV-7 era and 33% in the PCV-13 era.
“This microbiological shift is worrisome, because GAS may cause very serious infections due to its invasive nature,” Dr. Laursen and associates wrote. “An increase in GAS as described in this study has not been demonstrated elsewhere so far. In contrast to our findings, the most common species to ‘take over’ in the United States was Haemophilus influenzae.
“As [S. pneumoniae] and GAS are potentially invasive pathogens causing more severe clinical signs and symptoms, such cases are more likely to be admitted compared to cases caused by non-typable Haemophilus influenzae that gives rise to more subtle middle ear infections and clinical pictures,” the researchers noted.
Considering how many patients received antibiotics prior to admission in the hAOM group, there was a slight increase from 45% in the prevaccine era to 54% in the PCV-13 era, but a “more pronounced increase was found in the M+AM group, from 27% in the prevaccine era to 46% in the PCV-13 era,” they said.
The investigators called for continued surveillance of the microbiology associated with complex AOM.
No study funding or investigator disclosure information was provided.
Incidence rate ratios of children hospitalized with acute otitis media (hAOM) or more advanced stages, such as mastoidismus and acute mastoiditis (M+AM) declined by 10% and 20%, respectively, after introduction of pneumococcal conjugate vaccines (PCV) in the central region of Denmark, reported Bjarke B. Laursen of Aarhus University in Denmark, and associates.
The use of antibiotics for AOM prior to hospitalization increased markedly during the study period, and that may have impacted the modest reduction in hAOM and M+AM, the researchers said.
Incidence of Streptococcus pneumoniae cases decreased from 38% in the prevaccine era to 31% in the PCV-7 era and decreased even more to 16% in the PCV-13 era. The incidence of the second most frequently isolated bacteria, group A streptococcus (GAS), fell from 17% in the prevaccine era to 16% in the PCV-13 era, becoming equal to S. pneumoniae. The “no growth” results rose from 12% in the prevaccine era to 38% and 44% in the PCV-7 and PCV-13 eras, respectively (Int J Pediatr Otorhinolaryngol. 2017 Jul 4. doi: 10.1016/j.ijporl.2017.07.002) .
In the M+AM group, S. pneumoniae–positive cases fell to 10% in the PCV-13 era, compared with 44% in the prevaccine era and 41% in the PCV-7 era. A rise in GAS-positive cultures was seen in the M+AM group, from 15% in the prevaccine era to 30% in the PCV-13 era. The “no growth” group rose in incidence from 13% of cases in the prevaccine era to 26% in the PCV-7 era and 33% in the PCV-13 era.
“This microbiological shift is worrisome, because GAS may cause very serious infections due to its invasive nature,” Dr. Laursen and associates wrote. “An increase in GAS as described in this study has not been demonstrated elsewhere so far. In contrast to our findings, the most common species to ‘take over’ in the United States was Haemophilus influenzae.
“As [S. pneumoniae] and GAS are potentially invasive pathogens causing more severe clinical signs and symptoms, such cases are more likely to be admitted compared to cases caused by non-typable Haemophilus influenzae that gives rise to more subtle middle ear infections and clinical pictures,” the researchers noted.
Considering how many patients received antibiotics prior to admission in the hAOM group, there was a slight increase from 45% in the prevaccine era to 54% in the PCV-13 era, but a “more pronounced increase was found in the M+AM group, from 27% in the prevaccine era to 46% in the PCV-13 era,” they said.
The investigators called for continued surveillance of the microbiology associated with complex AOM.
No study funding or investigator disclosure information was provided.
FROM THE INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY
Key clinical point:
Major finding: Overall incidence in hAOM decreased numerically from 6.45/100,000 annually in the prevaccine era to 2.43/100,000 in the PCV-7 era, and to 5.88/100,000 annually in the PCV-13 era.
Data source: A retrospective study of 246 cases of children hospitalized with acute otitis media.
Disclosures: No study funding or investigator disclosure information was provided.
Prenatal methadone maintenance linked to poorer child neurodevelopment
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
AT PAS 17
Key clinical point:
Major finding: Three-fourths of methadone-exposed infants showed psychomotor delays at 6 months, and 50% showed cognitive delays and/or psychomotor delays at 18-24 months.
Data source: A retrospective analysis of neurodevelopment scores of children born to 61 mothers in Geneva who received methadone maintenance therapy during pregnancy.
Disclosures: The researchers did not report having any external funding or relevant financial disclosures.
FDA has the resources to answer questions about medicines and pregnancy
There are about 6 million pregnancies in the United States each year, and it’s estimated that 50% of pregnant women take at least one medicine. Physicians play an important role in helping their pregnant patients make informed health choices, especially when it comes to the safe use of medications.
- Emphasize that patients should always talk to their health care provider before taking any medicines, herbs, or vitamins. The website provides tips on how to start the conversation with patients about what medicines, herbs, or vitamins to avoid when pregnant.
- Encourage patients to check the drug label and other information that comes with their medicine to learn about possible risks for women who are pregnant or breastfeeding.
- Assist pregnant patients with changing medications as needed.
- Advise pregnant patients if they need to take more or less of their medicines.
- Advise patients about medicines that can and cannot be used when they start breastfeeding.
- Encourage patients to talk about any problems they have with their medicine.
- Report any serious problems your pregnant patients have had after taking a medicine to the FDA. It falls to physicians to report to the FDA any cases of serious side effects, problems with product quality, and product-use errors or with any of the following products: human drugs, medical devices, blood products and other biologics (except vaccines), and/or medical foods.
- Encourage patients to enroll in a Pregnancy Exposure Registry, if applicable at the FDA website, which collects information on pregnancy outcomes in women who already are taking medications. Observational studies of the patients that physicians help enroll in a pregnancy exposure registry can improve drug safety information for medicines used during pregnancy and can be used to update drug labeling. The observational studies included with the registries can also help physicians make medicine recommendations for use during pregnancy. The list includes contact information for each registry. Physicians can check online to see if there is a registry for their patients’ medicine.
The FDA website also provides information about the Pregnancy and Lactation Labeling Final Rule, which requires changes to the content and format for information presented in prescription drug labeling. The changes are implemented to help health care providers assess risk versus benefit and in subsequent counseling of pregnant women and nursing mothers.
The FDA offers free medicine safety and pregnancy resources for pregnant women, including downloadable infographics; a Medicines Record Keeper brochure in English, Spanish 
Pregnancy is an exciting time for women, but they may have questions and concerns about how medicines they take will affect their babies. Our pregnancy website can help make a woman’s pregnancy happier and healthier.
Dr. Yao is the director of the division of pediatrics and maternal health, Office of Drug Evaluation IV, Center for Drug Evaluation and Research at the FDA, in Silver Spring, Md.
There are about 6 million pregnancies in the United States each year, and it’s estimated that 50% of pregnant women take at least one medicine. Physicians play an important role in helping their pregnant patients make informed health choices, especially when it comes to the safe use of medications.
- Emphasize that patients should always talk to their health care provider before taking any medicines, herbs, or vitamins. The website provides tips on how to start the conversation with patients about what medicines, herbs, or vitamins to avoid when pregnant.
- Encourage patients to check the drug label and other information that comes with their medicine to learn about possible risks for women who are pregnant or breastfeeding.
- Assist pregnant patients with changing medications as needed.
- Advise pregnant patients if they need to take more or less of their medicines.
- Advise patients about medicines that can and cannot be used when they start breastfeeding.
- Encourage patients to talk about any problems they have with their medicine.
- Report any serious problems your pregnant patients have had after taking a medicine to the FDA. It falls to physicians to report to the FDA any cases of serious side effects, problems with product quality, and product-use errors or with any of the following products: human drugs, medical devices, blood products and other biologics (except vaccines), and/or medical foods.
- Encourage patients to enroll in a Pregnancy Exposure Registry, if applicable at the FDA website, which collects information on pregnancy outcomes in women who already are taking medications. Observational studies of the patients that physicians help enroll in a pregnancy exposure registry can improve drug safety information for medicines used during pregnancy and can be used to update drug labeling. The observational studies included with the registries can also help physicians make medicine recommendations for use during pregnancy. The list includes contact information for each registry. Physicians can check online to see if there is a registry for their patients’ medicine.
The FDA website also provides information about the Pregnancy and Lactation Labeling Final Rule, which requires changes to the content and format for information presented in prescription drug labeling. The changes are implemented to help health care providers assess risk versus benefit and in subsequent counseling of pregnant women and nursing mothers.
The FDA offers free medicine safety and pregnancy resources for pregnant women, including downloadable infographics; a Medicines Record Keeper brochure in English, Spanish
Pregnancy is an exciting time for women, but they may have questions and concerns about how medicines they take will affect their babies. Our pregnancy website can help make a woman’s pregnancy happier and healthier.
Dr. Yao is the director of the division of pediatrics and maternal health, Office of Drug Evaluation IV, Center for Drug Evaluation and Research at the FDA, in Silver Spring, Md.
There are about 6 million pregnancies in the United States each year, and it’s estimated that 50% of pregnant women take at least one medicine. Physicians play an important role in helping their pregnant patients make informed health choices, especially when it comes to the safe use of medications.
- Emphasize that patients should always talk to their health care provider before taking any medicines, herbs, or vitamins. The website provides tips on how to start the conversation with patients about what medicines, herbs, or vitamins to avoid when pregnant.
- Encourage patients to check the drug label and other information that comes with their medicine to learn about possible risks for women who are pregnant or breastfeeding.
- Assist pregnant patients with changing medications as needed.
- Advise pregnant patients if they need to take more or less of their medicines.
- Advise patients about medicines that can and cannot be used when they start breastfeeding.
- Encourage patients to talk about any problems they have with their medicine.
- Report any serious problems your pregnant patients have had after taking a medicine to the FDA. It falls to physicians to report to the FDA any cases of serious side effects, problems with product quality, and product-use errors or with any of the following products: human drugs, medical devices, blood products and other biologics (except vaccines), and/or medical foods.
- Encourage patients to enroll in a Pregnancy Exposure Registry, if applicable at the FDA website, which collects information on pregnancy outcomes in women who already are taking medications. Observational studies of the patients that physicians help enroll in a pregnancy exposure registry can improve drug safety information for medicines used during pregnancy and can be used to update drug labeling. The observational studies included with the registries can also help physicians make medicine recommendations for use during pregnancy. The list includes contact information for each registry. Physicians can check online to see if there is a registry for their patients’ medicine.
The FDA website also provides information about the Pregnancy and Lactation Labeling Final Rule, which requires changes to the content and format for information presented in prescription drug labeling. The changes are implemented to help health care providers assess risk versus benefit and in subsequent counseling of pregnant women and nursing mothers.
The FDA offers free medicine safety and pregnancy resources for pregnant women, including downloadable infographics; a Medicines Record Keeper brochure in English, Spanish
Pregnancy is an exciting time for women, but they may have questions and concerns about how medicines they take will affect their babies. Our pregnancy website can help make a woman’s pregnancy happier and healthier.
Dr. Yao is the director of the division of pediatrics and maternal health, Office of Drug Evaluation IV, Center for Drug Evaluation and Research at the FDA, in Silver Spring, Md.