User login
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.
ENDEAR Study Demonstrates Efficacy of Nusinersen in Infants With Spinal Muscular Atrophy
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA. 
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
Buprenorphine is an alternative to morphine in treating NAS
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
AT PAS 17
Key clinical point:
Major finding: Buprenorphine reduced median length of treatment (15 vs. 28 days, P less than .001) and median length of stay (21 vs. 34.5 days, P less than .001), compared with morphine.
Data source: Double-blind, double-dummy, single-site, randomized clinical trial (NCT01452789).
Disclosures: Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
Tips for Living With ADHD
Click here to download the PDF. 
Click here to download the PDF.
Click here to download the PDF.
Smoking During Pregnancy May Damage Offspring’s Retinal Nerve Fiber Layer
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Toddlers’ neurodevelopmental deficits linked with maternal diabetes
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
Key clinical point:
Major finding: The Bayley motor scale score averaged 88 in children from insulin-resistant mothers and 98 when no insulin resistance existed.
Data source: Prospective, single-center observational study with 75 pregnant women.
Disclosures: Dr. Cahill had no disclosures.
Recognizing Congenital Zika Syndrome
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.” 
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.”
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.”
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
Combined Erythropoietin and Hypothermia May Provide Neuroprotection in Neonates With Hypoxic-Ischemic Encephalopathy
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco. 
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
Neonatal Sleep Measures Predict Neurodevelopmental Outcomes
VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.
Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues. 
To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.
Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.
Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.
In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.
In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.
“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”
—Jake Remaly
Suggested Reading
Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.
Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.
VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.
Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues.
To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.
Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.
Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.
In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.
In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.
“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”
—Jake Remaly
Suggested Reading
Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.
Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.
VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.
Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues.
To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.
Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.
Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.
In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.
In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.
“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”
—Jake Remaly
Suggested Reading
Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.
Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.
Follow-Up of Infants With Zika Virus Identifies Several Neurologic Impairments
A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.
“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.
Follow-Up of 11 Neonates
Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.
Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.
Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.
“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.
Formulating a Plan of Action
“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”
But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”
—Glenn S. Williams
Suggested Reading
Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].
Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].
A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.
“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.
Follow-Up of 11 Neonates
Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.
Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.
Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.
“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.
Formulating a Plan of Action
“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”
But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”
—Glenn S. Williams
Suggested Reading
Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].
Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].
A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.
“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.
Follow-Up of 11 Neonates
Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.
Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.
Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.
“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.
Formulating a Plan of Action
“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”
But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”
—Glenn S. Williams
Suggested Reading
Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].
Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].