Pediatrics

 

BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.

Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.

patrisyu/Thinkstock

“On the other hand, we did not find an association between age at ART start and length of therapy with a longer time to rebound. However, we should interpret these results with some caution, obviously because the range of ages at ART start was quite small, from 6-12 weeks, so we didn’t really have enough spread in the data to enable us to draw solid conclusions,” she said at the annual Conference on Retroviruses & Opportunistic Infections.

The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).

In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.

They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.

Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.

 

The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.

In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)

In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.

Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.

 

The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.

SOURCE: Violari A et al. CROI 2018, Abstract 137

 

BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.

Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.

patrisyu/Thinkstock

“On the other hand, we did not find an association between age at ART start and length of therapy with a longer time to rebound. However, we should interpret these results with some caution, obviously because the range of ages at ART start was quite small, from 6-12 weeks, so we didn’t really have enough spread in the data to enable us to draw solid conclusions,” she said at the annual Conference on Retroviruses & Opportunistic Infections.

The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).

In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.

They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.

Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.

 

The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.

In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)

In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.

Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.

 

The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.

SOURCE: Violari A et al. CROI 2018, Abstract 137

 

BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.

Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.

patrisyu/Thinkstock

“On the other hand, we did not find an association between age at ART start and length of therapy with a longer time to rebound. However, we should interpret these results with some caution, obviously because the range of ages at ART start was quite small, from 6-12 weeks, so we didn’t really have enough spread in the data to enable us to draw solid conclusions,” she said at the annual Conference on Retroviruses & Opportunistic Infections.

The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).

In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.

They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.

Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.

 

The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.

In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)

In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.

Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.

 

The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.

SOURCE: Violari A et al. CROI 2018, Abstract 137

 

The resurgence of whooping cough in the United States could be the result of waning pertussis immunity combined with incomplete historical coverage, researchers said.

In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.

copyright CDC

The three modes of vaccine failure modeled in the study were primary vaccine failure in a fraction of the population; waning of vaccine-induced protection over time; and failure in the degree of protection offered by the vaccine, perhaps caused by antigenic evolution in the pertussis bacteria.

Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.

This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.

“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.

The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.

 

“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.

The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.

This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.

“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”

 

Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.

SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.

 

The resurgence of whooping cough in the United States could be the result of waning pertussis immunity combined with incomplete historical coverage, researchers said.

In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.

copyright CDC

The three modes of vaccine failure modeled in the study were primary vaccine failure in a fraction of the population; waning of vaccine-induced protection over time; and failure in the degree of protection offered by the vaccine, perhaps caused by antigenic evolution in the pertussis bacteria.

Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.

This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.

“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.

The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.

 

“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.

The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.

This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.

“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”

 

Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.

SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.

 

The resurgence of whooping cough in the United States could be the result of waning pertussis immunity combined with incomplete historical coverage, researchers said.

In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.

copyright CDC

The three modes of vaccine failure modeled in the study were primary vaccine failure in a fraction of the population; waning of vaccine-induced protection over time; and failure in the degree of protection offered by the vaccine, perhaps caused by antigenic evolution in the pertussis bacteria.

Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.

This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.

“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.

The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.

 

“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.

The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.

This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.

“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”

 

Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.

SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.

 

Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’¹

Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.

tab1962/Thinkstock

Katie is a 14-year-old girl diagnosed with morbid obesity, hypertension, ADHD, and binge-eating disorder. She is taking lisinopril, methylphenidate ER, and diphenhydramine. She has been in residential treatment to address overeating, and her parents report that, since she has returned home, they are very anxious about her eating behavior. Katie, however, presents less concern about eating, but rather identifies sleep difficulties, school performance, and family tension as priorities.

In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.²Given the general prevalence of mental health conditions, a psychiatric screening interview is prudent in any patient presenting with sleep difficulties.

Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).

After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?

For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.³ CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.

 

In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.⁴ Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.

Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.

In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.

Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.

 

Returning to Katie’s story, careful assessment revealed no evidence for active ADHD or binge eating, but instead, a significant predisposition to anxiety and high levels of intrafamilial hostility. In keeping with Katie’s own goals, we discussed ways to improve sleep and maintain school performance, while looking for opportunities to decrease family discord. Her methylphenidate ER was tapered to reduce early insomnia. The possibility of tolerance to diphenhydramine and its side effects, including increased appetite, led to a plan to taper this medication while titrating citalopram, one of the more soporific SSRIs, to reduce worry thoughts that might disrupt sleep onset. Education was provided about the circadian shift in adolescence that leads to later bedtimes and rising times with an ongoing need for about 8 hours of sleep nightly. Her behavior plan addressed increased daytime exercise, meditation as part of a pre-bedtime routine, and meeting with a nutritionist to regulate dietary variety and portion sizes without a focus on weight loss. Individual and family therapy were recommended, and Katie seemed to benefit from support and learning to talk back to her anxious automatic thoughts.

The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.

Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.

 

References

1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).

2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000

3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.

4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.

 

Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’¹

Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.

tab1962/Thinkstock

Katie is a 14-year-old girl diagnosed with morbid obesity, hypertension, ADHD, and binge-eating disorder. She is taking lisinopril, methylphenidate ER, and diphenhydramine. She has been in residential treatment to address overeating, and her parents report that, since she has returned home, they are very anxious about her eating behavior. Katie, however, presents less concern about eating, but rather identifies sleep difficulties, school performance, and family tension as priorities.

In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.²Given the general prevalence of mental health conditions, a psychiatric screening interview is prudent in any patient presenting with sleep difficulties.

Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).

After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?

For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.³ CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.

 

In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.⁴ Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.

Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.

In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.

Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.

 

Returning to Katie’s story, careful assessment revealed no evidence for active ADHD or binge eating, but instead, a significant predisposition to anxiety and high levels of intrafamilial hostility. In keeping with Katie’s own goals, we discussed ways to improve sleep and maintain school performance, while looking for opportunities to decrease family discord. Her methylphenidate ER was tapered to reduce early insomnia. The possibility of tolerance to diphenhydramine and its side effects, including increased appetite, led to a plan to taper this medication while titrating citalopram, one of the more soporific SSRIs, to reduce worry thoughts that might disrupt sleep onset. Education was provided about the circadian shift in adolescence that leads to later bedtimes and rising times with an ongoing need for about 8 hours of sleep nightly. Her behavior plan addressed increased daytime exercise, meditation as part of a pre-bedtime routine, and meeting with a nutritionist to regulate dietary variety and portion sizes without a focus on weight loss. Individual and family therapy were recommended, and Katie seemed to benefit from support and learning to talk back to her anxious automatic thoughts.

The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.

Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.

 

References

1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).

2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000

3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.

4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.

 

Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’¹

Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.

tab1962/Thinkstock

Katie is a 14-year-old girl diagnosed with morbid obesity, hypertension, ADHD, and binge-eating disorder. She is taking lisinopril, methylphenidate ER, and diphenhydramine. She has been in residential treatment to address overeating, and her parents report that, since she has returned home, they are very anxious about her eating behavior. Katie, however, presents less concern about eating, but rather identifies sleep difficulties, school performance, and family tension as priorities.

In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.²Given the general prevalence of mental health conditions, a psychiatric screening interview is prudent in any patient presenting with sleep difficulties.

Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).

After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?

For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.³ CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.

 

In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.⁴ Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.

Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.

In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.

Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.

 

Returning to Katie’s story, careful assessment revealed no evidence for active ADHD or binge eating, but instead, a significant predisposition to anxiety and high levels of intrafamilial hostility. In keeping with Katie’s own goals, we discussed ways to improve sleep and maintain school performance, while looking for opportunities to decrease family discord. Her methylphenidate ER was tapered to reduce early insomnia. The possibility of tolerance to diphenhydramine and its side effects, including increased appetite, led to a plan to taper this medication while titrating citalopram, one of the more soporific SSRIs, to reduce worry thoughts that might disrupt sleep onset. Education was provided about the circadian shift in adolescence that leads to later bedtimes and rising times with an ongoing need for about 8 hours of sleep nightly. Her behavior plan addressed increased daytime exercise, meditation as part of a pre-bedtime routine, and meeting with a nutritionist to regulate dietary variety and portion sizes without a focus on weight loss. Individual and family therapy were recommended, and Katie seemed to benefit from support and learning to talk back to her anxious automatic thoughts.

The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.

Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.

 

References

1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).

2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000

3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.

4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.

 

Children who are particularly irritable, depressive, and anxious might be at greater risk of suicidality in adolescence, according to a population-based cohort study.

Researchers enrolled 1,430 participants from the Québec Longitudinal Study of Child Development, aged 6-12 years, and performed yearly or biyearly assessments over a follow-up of 5 months to 17 years, according to a study published online March 28 in JAMA Psychiatry (doi: 10.1001/jamapsychiatry.2018.0174).

They found that girls who rated highly for irritability and for the depressive/anxious mood profile on the Behavior Questionnaire, a measure created for Canada’s National Longitudinal Study of Children and Youth, had a threefold higher risk of suicidality (odds ratio, 3.07; 95% confidence interval, 1.54-6.12). Meanwhile, boys had a twofold higher risk (OR, 2.13; 95% CI, 0.95-4.78), compared with children with low irritability and depressive/anxious mood.

“Exploratory analyses by sex indicated that this association was more important for girls than boys, as indicated by the need to prevent the exposure among 5 girls to avoid 1 case of suicidality,” wrote Massimiliano Orri, PhD, and his associates.

The rates of suicidality in children with high irritability and high depressive/anxious mood were 16.4%, compared with 11% in the group with the lowest symptom levels.

Even in children with only moderate irritability and low depressive/anxious mood, a significant increase was found in the odds of showing suicidality, compared with the reference group (OR, 1.51; 95% CI, 1.02-2.25).

“Although previous studies reported associations between irritability during childhood and adolescence and later depression, anxiety, and suicidality, we found that even moderate levels of irritability may contribute to suicidal risk,” wrote Dr. Orri of Bordeaux Population Health Research Centre, at the Institut National de la Santé et de la Recherche Medicale in France. “Such results indicate that children presenting with only irritability symptoms may benefit from an assessment for suicidal behaviors.”

 

Children with a high depressive/anxious mood profile showed the same odds of suicidality as those of the reference group.

The authors noted that there was considerably stability in developmental profiles, so children who showed the highest levels of symptoms at age 6 were likely to exhibit those same high levels at age 12.

They also commented on their study’s use of an “innovative, person-centered approach” to describe the joint course of these moods over the time course of the study.

The investigators cited several limitations. One is that the assessment of childhood symptoms were based on teachers only, so depressive/anxious mood might have been underrated compared with irritability “because internalizing symptoms may be more difficult to observe in a school setting than externalized symptoms.”

Dr. Orri and two associates reported receiving support from the Canadian Institutes of Health Research. The other researchers cited funding from the National Alliance for Research on Schizophrenia and Depression and the Fonds de Recherche du Québec. No other financial disclosures were reported. The Québec Longitudinal Study of Child Development was supported by several entities, including the Québec Government’s Ministry of Health, Ministry of Education, and Ministry of Family Affairs.

cpnews@mdedge.com

SOURCE: Orri M et al. JAMA Psychiatry. 2018 Mar 28. doi: 10.1001/jamapsychiatry.2018.0174.

 

Children who are particularly irritable, depressive, and anxious might be at greater risk of suicidality in adolescence, according to a population-based cohort study.

Researchers enrolled 1,430 participants from the Québec Longitudinal Study of Child Development, aged 6-12 years, and performed yearly or biyearly assessments over a follow-up of 5 months to 17 years, according to a study published online March 28 in JAMA Psychiatry (doi: 10.1001/jamapsychiatry.2018.0174).

They found that girls who rated highly for irritability and for the depressive/anxious mood profile on the Behavior Questionnaire, a measure created for Canada’s National Longitudinal Study of Children and Youth, had a threefold higher risk of suicidality (odds ratio, 3.07; 95% confidence interval, 1.54-6.12). Meanwhile, boys had a twofold higher risk (OR, 2.13; 95% CI, 0.95-4.78), compared with children with low irritability and depressive/anxious mood.

“Exploratory analyses by sex indicated that this association was more important for girls than boys, as indicated by the need to prevent the exposure among 5 girls to avoid 1 case of suicidality,” wrote Massimiliano Orri, PhD, and his associates.

The rates of suicidality in children with high irritability and high depressive/anxious mood were 16.4%, compared with 11% in the group with the lowest symptom levels.

Even in children with only moderate irritability and low depressive/anxious mood, a significant increase was found in the odds of showing suicidality, compared with the reference group (OR, 1.51; 95% CI, 1.02-2.25).

“Although previous studies reported associations between irritability during childhood and adolescence and later depression, anxiety, and suicidality, we found that even moderate levels of irritability may contribute to suicidal risk,” wrote Dr. Orri of Bordeaux Population Health Research Centre, at the Institut National de la Santé et de la Recherche Medicale in France. “Such results indicate that children presenting with only irritability symptoms may benefit from an assessment for suicidal behaviors.”

 

Children with a high depressive/anxious mood profile showed the same odds of suicidality as those of the reference group.

The authors noted that there was considerably stability in developmental profiles, so children who showed the highest levels of symptoms at age 6 were likely to exhibit those same high levels at age 12.

They also commented on their study’s use of an “innovative, person-centered approach” to describe the joint course of these moods over the time course of the study.

The investigators cited several limitations. One is that the assessment of childhood symptoms were based on teachers only, so depressive/anxious mood might have been underrated compared with irritability “because internalizing symptoms may be more difficult to observe in a school setting than externalized symptoms.”

Dr. Orri and two associates reported receiving support from the Canadian Institutes of Health Research. The other researchers cited funding from the National Alliance for Research on Schizophrenia and Depression and the Fonds de Recherche du Québec. No other financial disclosures were reported. The Québec Longitudinal Study of Child Development was supported by several entities, including the Québec Government’s Ministry of Health, Ministry of Education, and Ministry of Family Affairs.

cpnews@mdedge.com

SOURCE: Orri M et al. JAMA Psychiatry. 2018 Mar 28. doi: 10.1001/jamapsychiatry.2018.0174.

 

Children who are particularly irritable, depressive, and anxious might be at greater risk of suicidality in adolescence, according to a population-based cohort study.

Researchers enrolled 1,430 participants from the Québec Longitudinal Study of Child Development, aged 6-12 years, and performed yearly or biyearly assessments over a follow-up of 5 months to 17 years, according to a study published online March 28 in JAMA Psychiatry (doi: 10.1001/jamapsychiatry.2018.0174).

They found that girls who rated highly for irritability and for the depressive/anxious mood profile on the Behavior Questionnaire, a measure created for Canada’s National Longitudinal Study of Children and Youth, had a threefold higher risk of suicidality (odds ratio, 3.07; 95% confidence interval, 1.54-6.12). Meanwhile, boys had a twofold higher risk (OR, 2.13; 95% CI, 0.95-4.78), compared with children with low irritability and depressive/anxious mood.

“Exploratory analyses by sex indicated that this association was more important for girls than boys, as indicated by the need to prevent the exposure among 5 girls to avoid 1 case of suicidality,” wrote Massimiliano Orri, PhD, and his associates.

The rates of suicidality in children with high irritability and high depressive/anxious mood were 16.4%, compared with 11% in the group with the lowest symptom levels.

Even in children with only moderate irritability and low depressive/anxious mood, a significant increase was found in the odds of showing suicidality, compared with the reference group (OR, 1.51; 95% CI, 1.02-2.25).

“Although previous studies reported associations between irritability during childhood and adolescence and later depression, anxiety, and suicidality, we found that even moderate levels of irritability may contribute to suicidal risk,” wrote Dr. Orri of Bordeaux Population Health Research Centre, at the Institut National de la Santé et de la Recherche Medicale in France. “Such results indicate that children presenting with only irritability symptoms may benefit from an assessment for suicidal behaviors.”

 

Children with a high depressive/anxious mood profile showed the same odds of suicidality as those of the reference group.

The authors noted that there was considerably stability in developmental profiles, so children who showed the highest levels of symptoms at age 6 were likely to exhibit those same high levels at age 12.

They also commented on their study’s use of an “innovative, person-centered approach” to describe the joint course of these moods over the time course of the study.

The investigators cited several limitations. One is that the assessment of childhood symptoms were based on teachers only, so depressive/anxious mood might have been underrated compared with irritability “because internalizing symptoms may be more difficult to observe in a school setting than externalized symptoms.”

Dr. Orri and two associates reported receiving support from the Canadian Institutes of Health Research. The other researchers cited funding from the National Alliance for Research on Schizophrenia and Depression and the Fonds de Recherche du Québec. No other financial disclosures were reported. The Québec Longitudinal Study of Child Development was supported by several entities, including the Québec Government’s Ministry of Health, Ministry of Education, and Ministry of Family Affairs.

cpnews@mdedge.com

SOURCE: Orri M et al. JAMA Psychiatry. 2018 Mar 28. doi: 10.1001/jamapsychiatry.2018.0174.

Photo courtesy of GOSH

LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.

Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.

Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.

In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.

Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.

However, 2 patients died of progression, and 1 died of transplant-related complications.

Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).

The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.

Prior experience

Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.

Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).

When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.

Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.

Phase 1 patients and treatment

Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).

All patients had morphological disease or an MRD level of at least 1 x 10^-3 (via flow cytometry and/or qPCR) at baseline.

One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.

Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.

Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).

The patients received UCART19 at doses of 2 x 10⁷ total cells or 1.1 to 2.3 x 10⁶ cells/kg.

Toxicity

All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.

Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.

Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.

One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.

One patient had grade 1 acute cutaneous graft-versus-host disease.

Efficacy

All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.

The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.

 

Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.

A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.

The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.

*Data in the abstract were updated in the presentation.

Photo courtesy of GOSH

LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.

Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.

Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.

In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.

Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.

However, 2 patients died of progression, and 1 died of transplant-related complications.

Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).

The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.

Prior experience

Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.

Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).

When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.

Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.

Phase 1 patients and treatment

Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).

All patients had morphological disease or an MRD level of at least 1 x 10^-3 (via flow cytometry and/or qPCR) at baseline.

One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.

Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.

Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).

The patients received UCART19 at doses of 2 x 10⁷ total cells or 1.1 to 2.3 x 10⁶ cells/kg.

Toxicity

All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.

Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.

Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.

One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.

One patient had grade 1 acute cutaneous graft-versus-host disease.

Efficacy

All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.

The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.

 

Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.

A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.

The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.

*Data in the abstract were updated in the presentation.

Photo courtesy of GOSH

LISBON—Early results from a phase 1, pediatric trial of UCART19 expand upon results observed in children who received the therapy via a compassionate use program.

Two patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) received UCART19, a “universal,” donor-derived chimeric antigen receptor (CAR) T-cell therapy, via the program.

Both achieved remission and were still alive at last follow-up, more than 2 years after proceeding to transplant.

In the phase 1 trial, 5 of 6 B-ALL patients have achieved remission and gone on to transplant.

Three of the patients are still alive, and 2 are still negative for minimal residual disease (MRD) at 10 months and 11 months after UCART19 infusion.

However, 2 patients died of progression, and 1 died of transplant-related complications.

Paul Veys, MBBS, of Great Ormond Street Hospital (GOSH) in London, UK, presented these results, from the PALL trial, at the 44th Annual Meeting of the EBMT (abstract OS18-5*).

The trial is sponsored by Servier. In 2015, Servier acquired exclusive rights from Cellectis for UCART19, which is being co-developed by Servier and Pfizer.

Prior experience

Researchers previously reported results with UCART19 in 2 infants with relapsed/refractory B-ALL who had exhausted all other treatment options and received UCART19 via a compassionate use program.

Both patients achieved remission after UCART19 and proceeded to allogeneic hematopoietic stem cell transplant (allo-HSCT).

When these results were published, in January 2017, both patients were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19 infusion.

Dr Veys provided an update, noting that these patients were still alive and in remission at 24 months and 30 months after allo-HSCT.

Phase 1 patients and treatment

Thus far, the phase 1 trial has enrolled and treated 6 patients with relapsed B-ALL. They had a median age of 3.75 (range, 0.8-16.4).

All patients had morphological disease or an MRD level of at least 1 x 10^-3 (via flow cytometry and/or qPCR) at baseline.

One patient had received 1 prior therapy, 2 had 3 prior therapies, and 3 had 4 or more prior therapies. Two patients had prior inotuzumab ozogamicin, and 2 had prior allo-HSCT. Both had relapsed within 6 months of allo-HSCT.

Five patients had less than 10% bone marrow blasts prior to lymphodepletion, and 1 had greater than 50% blasts.

Patients underwent lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (n=5) or fludarabine and cyclophosphamide (n=1).

The patients received UCART19 at doses of 2 x 10⁷ total cells or 1.1 to 2.3 x 10⁶ cells/kg.

Toxicity

All 6 patients developed cytokine release syndrome (CRS), including grade 1 (n=1), grade 2 (n=4), and grade 3 (n-1) CRS. However, all 6 cases resolved completely.

Three patients had neurotoxic events, 2 grade 1 and 1 grade 2. One patient had grade 3 febrile neutropenia.

Three patients had grade 4 prolonged cytopenia. This was defined as persistent neutropenia and/or thrombocytopenia beyond day 42 after UCART19 infusion, except if the patient had >5% bone marrow blasts.

One patient had grade 1 adenovirus infection, 1 had grade 3 cytomegalovirus infection, 2 had grade 3 BK virus hemorrhagic cystitis, and 1 had grade 4 metapneumovirus infection.

One patient had grade 1 acute cutaneous graft-versus-host disease.

Efficacy

All 6 patients achieved a complete response at day 28 to 42 after UCART19 infusion. Five patients achieved MRD negativity according to flow cytometry, and 3 were MRD-negative according to PCR.

The 5 flow-MRD-negative patients went on to receive an allo-HSCT between 49 days and 62 days after UCART19 infusion. Conditioning consisted of total body irradiation and fludarabine, with or without cyclophosphamide and antithymocyte globulin. All of these patients received a dose of rituximab as well, which was intended to target any remaining UCART19 cells.

 

Two patients relapsed 3 months after transplant and died at 7 months and 8 months after UCART19 infusion. One of these patients was CD19-, and 1 was CD19+, but both were MRD-positive by PCR prior to receiving their transplant.

A third patient died 2.5 months after allo-HSCT from transplant-related complications, including thrombotic microangiopathy, BK hemorrhagic cystitis, and nephritis.

The remaining 3 patients are still alive at 1.5 months, 10 months, and 11 months after UCART19 infusion. Two are still MRD-negative, and 1 is MRD-positive. The MRD-positive patient has not undergone allo-HSCT.

*Data in the abstract were updated in the presentation.

Giant congenital nevus was diagnosed in this patient. Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis. Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), or giant (>40 cm).

Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi, which are rare, are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair. CMN can cover any part of the body and occur independent of skin color and other ethnic factors.

CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations are part of the differential diagnosis for CMN and have individual location and color characteristics that set them apart clinically.

Patients with CMN are at increased risk for neurocutaneous melanosis (NCM; a melanocyte proliferation in the central nervous system) and melanoma. Magnetic resonance imaging (MRI) is helpful to exclude NCM. Treatment options for patients with large and giant CMN include early curettage, local excision, dermabrasion, and laser therapy. (There is, however, considerable debate about the value of surgery.) The newborn in the case underwent an MRI and the results were normal. At 4 months of age, he hadn’t developed any neurologic symptoms. The child’s nevi continue to grow and he sees his family physician for routine well-child visits and a dermatologist annually to monitor the nevi.

‌

Adapted from: Karnes J, Griffin C. Large plaques on a baby boy. J Fam Pract. 2016;65:407-409.

Giant congenital nevus was diagnosed in this patient. Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis. Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), or giant (>40 cm).

Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi, which are rare, are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair. CMN can cover any part of the body and occur independent of skin color and other ethnic factors.

CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations are part of the differential diagnosis for CMN and have individual location and color characteristics that set them apart clinically.

Patients with CMN are at increased risk for neurocutaneous melanosis (NCM; a melanocyte proliferation in the central nervous system) and melanoma. Magnetic resonance imaging (MRI) is helpful to exclude NCM. Treatment options for patients with large and giant CMN include early curettage, local excision, dermabrasion, and laser therapy. (There is, however, considerable debate about the value of surgery.) The newborn in the case underwent an MRI and the results were normal. At 4 months of age, he hadn’t developed any neurologic symptoms. The child’s nevi continue to grow and he sees his family physician for routine well-child visits and a dermatologist annually to monitor the nevi.

‌

Adapted from: Karnes J, Griffin C. Large plaques on a baby boy. J Fam Pract. 2016;65:407-409.

Giant congenital nevus was diagnosed in this patient. Congenital melanocytic nevi (CMN) are pigmented lesions that are present at birth and created by the abnormal migration of neural crest cells during embryogenesis. Nevi are categorized by size as small (<1.5 cm), medium (1.5-20 cm), large (>20 cm), or giant (>40 cm).

Congenital nevi tend to start out flat, with uniform pigmentation, but can become more variegated in texture and color as normal growth and development continue. Giant congenital nevi, which are rare, are likely to thicken, darken, and enlarge as the patient grows. Some nevi may develop very coarse or dark hair. CMN can cover any part of the body and occur independent of skin color and other ethnic factors.

CMN may present in almost any location and may be brown, black, pink, or purple in color. Café au lait macules, blue-gray spots, nevus of Ota, nevus spilus, and vascular malformations are part of the differential diagnosis for CMN and have individual location and color characteristics that set them apart clinically.

Patients with CMN are at increased risk for neurocutaneous melanosis (NCM; a melanocyte proliferation in the central nervous system) and melanoma. Magnetic resonance imaging (MRI) is helpful to exclude NCM. Treatment options for patients with large and giant CMN include early curettage, local excision, dermabrasion, and laser therapy. (There is, however, considerable debate about the value of surgery.) The newborn in the case underwent an MRI and the results were normal. At 4 months of age, he hadn’t developed any neurologic symptoms. The child’s nevi continue to grow and he sees his family physician for routine well-child visits and a dermatologist annually to monitor the nevi.

‌

Adapted from: Karnes J, Griffin C. Large plaques on a baby boy. J Fam Pract. 2016;65:407-409.

 

While every day seems to bring extraordinary new advances in science – robotic surgery, individually targeted medications, and even gene therapy – there are many people who currently approach the science of medicine with skepticism.

While it is the right of legally competent adults in a free society to chose how best to care for their own health, to explore holistic or alternative therapies, or avoid medicine altogether, it is more complex when they are skeptical of accepted medical practice in managing the health of their children. For those parents who trust you enough to bring their children to you for care but remain skeptical of vaccines or other treatments, you have an opportunity to work with that trust and engage in a discussion so that they might reconsider their position on valuable and even life-saving treatments for their children.

Wavebreakmedia/Thinkstock

The first and possibly most important step in engaging parents who are skeptical of accepted medical practice is to be respectfully curious about what is contributing to their skepticism. A different cultural, religious, or racial background may be playing a role in that many cultures have different traditions around treating specific problems. Some parents may have had experiences with health care providers that went poorly and left them harmed and feeling betrayed. There may be disagreement between spouses or intergenerational conflict between parents and grandparents, particularly over treatments that are new or controversial. Treatments such as stimulants for ADHD, avoiding antibiotics for what is likely to be a viral illness, or the human papillomavirus vaccine often are treated as controversial interventions in the popular press, so it would not be surprising if they were generating disagreement in a family. Finally, there are some people who, because of temperament or experience, tend to become oppositional or even hostile when dealing with authority figures offering “official” recommendations.

In each of these cases, launching into an enthusiastic explanation of the advanced statistics that underpin your recommendation is unlikely to bridge the gap. Instead, you want to start with these parents by being curious. Resist the urge to tell, and listen instead. When a parent expresses skepticism, respectfully learn more, and prioritize their dignity. What is their understanding of the problem you are treating or preventing? What have they heard or read about the treatment or test in question? What do they most fear is going to happen to their child if they do or do not accept your recommendation? Are there specific events (with their child or with the health care system) that have informed this fear?

Respectfully listening to their experiences, thoughts, and feelings goes a long way toward building a trusting alliance. It can help overcome feelings of distrust or defensiveness around authority figures. And it models the thoughtful, respectful give and take that are essential to a healthy collaboration between pediatrician and parents.

Once you have heard something about their understanding, opinions, and worries, resist the urge to then explain how they are mistaken! Instead, find out where their trusted information comes from. When you are making important decisions for your family, whose guidance do you seek? Whose support is important to you when managing a challenge with your family? It can be helpful to ask whether there have been other times when they went their own way in raising their child, perhaps at school. How did that go? Was there a lot of conflict or involvement of authorities, such as the Department of Children and Families? Or was it more collaborative? If they go their own way, what markers do they watch to be sure they are on track? Put another way, how would they know if it was time to give another approach a try?

Once you have information about what they think and some about how they think and make decisions, you then can offer your perspective. “You are the expert on your child, what I bring to this equation is experience with (this problem) and with assessing the scientific evidence that guides treatments in medicine. It is true that treatments often change as we learn more, but here is what the evidence currently supports.”

 

After learning something about how they think, you might offer more data or more warm acknowledgment of how difficult it can be to make medical decisions for your children with imperfect information. Be humble while also being accurate about your level of confidence in a recommendation. Humility is important because it is easy for parents to feel insecure and condescended to. You understand their greatest fear, now let them know what your greatest worry is for their child should they forgo a recommended treatment. Explaining all of this with humility and warmth makes it more likely that the parents will take in the facts you are trying to share with them and not be derailed by suspicion, defensiveness, or insecurity.

Make building an alliance with the parents your top priority. This does not mean that you do not offer your best recommendation for their child. Rather, it means that, if they still decline recommended treatment, you treat them with respect and invest your time in explaining what they should be watching or monitoring their child for without recommended treatment. Building trust is a long game. If you patiently stick with parents even when it’s not easy, they may be ready to trust you with a subsequent decision when the stakes are even higher.

Of course, there may come a time when a parent’s refusal to accept recommended treatment constitutes medical neglect. The decision to file with your state’s Department of Children and Families (or equivalent) should be guided by the severity of the potential consequences to the child, and it will help if you are confident that the parents understood your recommendations and associated risks and benefits. Where there is imminent risk, the law gives you no choice about the decision to file. If you have invested in a strong alliance with the parents, it will be easier to explain filing and its consequences to them. It may even be that they will want to continue with your practice in the aftermath, as they trust in your honesty, your dedication to their child’s health and safety, and your capacity to treat them with respect even in disagreement.

Of course, all this thoughtful communication takes a lot of time! You may learn to block off more time for certain families. It also can be helpful to have these conversations as a team. If you and your nurse or social worker can meet with parents together, then some of the listening and learning can be done by the nurse or social worker alone, so that everyone’s time might be managed more efficiently. And managing skeptical parents as a team also can help to prevent frustration or burnout. It will not always succeed, but in some cases, your investment will pay off in a trusting alliance, mutual respect, and healthy patients.
 

 

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics at Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

 

While every day seems to bring extraordinary new advances in science – robotic surgery, individually targeted medications, and even gene therapy – there are many people who currently approach the science of medicine with skepticism.

While it is the right of legally competent adults in a free society to chose how best to care for their own health, to explore holistic or alternative therapies, or avoid medicine altogether, it is more complex when they are skeptical of accepted medical practice in managing the health of their children. For those parents who trust you enough to bring their children to you for care but remain skeptical of vaccines or other treatments, you have an opportunity to work with that trust and engage in a discussion so that they might reconsider their position on valuable and even life-saving treatments for their children.

Wavebreakmedia/Thinkstock

The first and possibly most important step in engaging parents who are skeptical of accepted medical practice is to be respectfully curious about what is contributing to their skepticism. A different cultural, religious, or racial background may be playing a role in that many cultures have different traditions around treating specific problems. Some parents may have had experiences with health care providers that went poorly and left them harmed and feeling betrayed. There may be disagreement between spouses or intergenerational conflict between parents and grandparents, particularly over treatments that are new or controversial. Treatments such as stimulants for ADHD, avoiding antibiotics for what is likely to be a viral illness, or the human papillomavirus vaccine often are treated as controversial interventions in the popular press, so it would not be surprising if they were generating disagreement in a family. Finally, there are some people who, because of temperament or experience, tend to become oppositional or even hostile when dealing with authority figures offering “official” recommendations.

In each of these cases, launching into an enthusiastic explanation of the advanced statistics that underpin your recommendation is unlikely to bridge the gap. Instead, you want to start with these parents by being curious. Resist the urge to tell, and listen instead. When a parent expresses skepticism, respectfully learn more, and prioritize their dignity. What is their understanding of the problem you are treating or preventing? What have they heard or read about the treatment or test in question? What do they most fear is going to happen to their child if they do or do not accept your recommendation? Are there specific events (with their child or with the health care system) that have informed this fear?

Respectfully listening to their experiences, thoughts, and feelings goes a long way toward building a trusting alliance. It can help overcome feelings of distrust or defensiveness around authority figures. And it models the thoughtful, respectful give and take that are essential to a healthy collaboration between pediatrician and parents.

Once you have heard something about their understanding, opinions, and worries, resist the urge to then explain how they are mistaken! Instead, find out where their trusted information comes from. When you are making important decisions for your family, whose guidance do you seek? Whose support is important to you when managing a challenge with your family? It can be helpful to ask whether there have been other times when they went their own way in raising their child, perhaps at school. How did that go? Was there a lot of conflict or involvement of authorities, such as the Department of Children and Families? Or was it more collaborative? If they go their own way, what markers do they watch to be sure they are on track? Put another way, how would they know if it was time to give another approach a try?

Once you have information about what they think and some about how they think and make decisions, you then can offer your perspective. “You are the expert on your child, what I bring to this equation is experience with (this problem) and with assessing the scientific evidence that guides treatments in medicine. It is true that treatments often change as we learn more, but here is what the evidence currently supports.”

 

After learning something about how they think, you might offer more data or more warm acknowledgment of how difficult it can be to make medical decisions for your children with imperfect information. Be humble while also being accurate about your level of confidence in a recommendation. Humility is important because it is easy for parents to feel insecure and condescended to. You understand their greatest fear, now let them know what your greatest worry is for their child should they forgo a recommended treatment. Explaining all of this with humility and warmth makes it more likely that the parents will take in the facts you are trying to share with them and not be derailed by suspicion, defensiveness, or insecurity.

Make building an alliance with the parents your top priority. This does not mean that you do not offer your best recommendation for their child. Rather, it means that, if they still decline recommended treatment, you treat them with respect and invest your time in explaining what they should be watching or monitoring their child for without recommended treatment. Building trust is a long game. If you patiently stick with parents even when it’s not easy, they may be ready to trust you with a subsequent decision when the stakes are even higher.

Of course, there may come a time when a parent’s refusal to accept recommended treatment constitutes medical neglect. The decision to file with your state’s Department of Children and Families (or equivalent) should be guided by the severity of the potential consequences to the child, and it will help if you are confident that the parents understood your recommendations and associated risks and benefits. Where there is imminent risk, the law gives you no choice about the decision to file. If you have invested in a strong alliance with the parents, it will be easier to explain filing and its consequences to them. It may even be that they will want to continue with your practice in the aftermath, as they trust in your honesty, your dedication to their child’s health and safety, and your capacity to treat them with respect even in disagreement.

Of course, all this thoughtful communication takes a lot of time! You may learn to block off more time for certain families. It also can be helpful to have these conversations as a team. If you and your nurse or social worker can meet with parents together, then some of the listening and learning can be done by the nurse or social worker alone, so that everyone’s time might be managed more efficiently. And managing skeptical parents as a team also can help to prevent frustration or burnout. It will not always succeed, but in some cases, your investment will pay off in a trusting alliance, mutual respect, and healthy patients.
 

 

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics at Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

 

While every day seems to bring extraordinary new advances in science – robotic surgery, individually targeted medications, and even gene therapy – there are many people who currently approach the science of medicine with skepticism.

While it is the right of legally competent adults in a free society to chose how best to care for their own health, to explore holistic or alternative therapies, or avoid medicine altogether, it is more complex when they are skeptical of accepted medical practice in managing the health of their children. For those parents who trust you enough to bring their children to you for care but remain skeptical of vaccines or other treatments, you have an opportunity to work with that trust and engage in a discussion so that they might reconsider their position on valuable and even life-saving treatments for their children.

Wavebreakmedia/Thinkstock

The first and possibly most important step in engaging parents who are skeptical of accepted medical practice is to be respectfully curious about what is contributing to their skepticism. A different cultural, religious, or racial background may be playing a role in that many cultures have different traditions around treating specific problems. Some parents may have had experiences with health care providers that went poorly and left them harmed and feeling betrayed. There may be disagreement between spouses or intergenerational conflict between parents and grandparents, particularly over treatments that are new or controversial. Treatments such as stimulants for ADHD, avoiding antibiotics for what is likely to be a viral illness, or the human papillomavirus vaccine often are treated as controversial interventions in the popular press, so it would not be surprising if they were generating disagreement in a family. Finally, there are some people who, because of temperament or experience, tend to become oppositional or even hostile when dealing with authority figures offering “official” recommendations.

In each of these cases, launching into an enthusiastic explanation of the advanced statistics that underpin your recommendation is unlikely to bridge the gap. Instead, you want to start with these parents by being curious. Resist the urge to tell, and listen instead. When a parent expresses skepticism, respectfully learn more, and prioritize their dignity. What is their understanding of the problem you are treating or preventing? What have they heard or read about the treatment or test in question? What do they most fear is going to happen to their child if they do or do not accept your recommendation? Are there specific events (with their child or with the health care system) that have informed this fear?

Respectfully listening to their experiences, thoughts, and feelings goes a long way toward building a trusting alliance. It can help overcome feelings of distrust or defensiveness around authority figures. And it models the thoughtful, respectful give and take that are essential to a healthy collaboration between pediatrician and parents.

Once you have heard something about their understanding, opinions, and worries, resist the urge to then explain how they are mistaken! Instead, find out where their trusted information comes from. When you are making important decisions for your family, whose guidance do you seek? Whose support is important to you when managing a challenge with your family? It can be helpful to ask whether there have been other times when they went their own way in raising their child, perhaps at school. How did that go? Was there a lot of conflict or involvement of authorities, such as the Department of Children and Families? Or was it more collaborative? If they go their own way, what markers do they watch to be sure they are on track? Put another way, how would they know if it was time to give another approach a try?

Once you have information about what they think and some about how they think and make decisions, you then can offer your perspective. “You are the expert on your child, what I bring to this equation is experience with (this problem) and with assessing the scientific evidence that guides treatments in medicine. It is true that treatments often change as we learn more, but here is what the evidence currently supports.”

 

After learning something about how they think, you might offer more data or more warm acknowledgment of how difficult it can be to make medical decisions for your children with imperfect information. Be humble while also being accurate about your level of confidence in a recommendation. Humility is important because it is easy for parents to feel insecure and condescended to. You understand their greatest fear, now let them know what your greatest worry is for their child should they forgo a recommended treatment. Explaining all of this with humility and warmth makes it more likely that the parents will take in the facts you are trying to share with them and not be derailed by suspicion, defensiveness, or insecurity.

Make building an alliance with the parents your top priority. This does not mean that you do not offer your best recommendation for their child. Rather, it means that, if they still decline recommended treatment, you treat them with respect and invest your time in explaining what they should be watching or monitoring their child for without recommended treatment. Building trust is a long game. If you patiently stick with parents even when it’s not easy, they may be ready to trust you with a subsequent decision when the stakes are even higher.

Of course, there may come a time when a parent’s refusal to accept recommended treatment constitutes medical neglect. The decision to file with your state’s Department of Children and Families (or equivalent) should be guided by the severity of the potential consequences to the child, and it will help if you are confident that the parents understood your recommendations and associated risks and benefits. Where there is imminent risk, the law gives you no choice about the decision to file. If you have invested in a strong alliance with the parents, it will be easier to explain filing and its consequences to them. It may even be that they will want to continue with your practice in the aftermath, as they trust in your honesty, your dedication to their child’s health and safety, and your capacity to treat them with respect even in disagreement.

Of course, all this thoughtful communication takes a lot of time! You may learn to block off more time for certain families. It also can be helpful to have these conversations as a team. If you and your nurse or social worker can meet with parents together, then some of the listening and learning can be done by the nurse or social worker alone, so that everyone’s time might be managed more efficiently. And managing skeptical parents as a team also can help to prevent frustration or burnout. It will not always succeed, but in some cases, your investment will pay off in a trusting alliance, mutual respect, and healthy patients.
 

 

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton Wellesley Hospital, also in Boston. Dr. Jellinek is professor emeritus of psychiatry and pediatrics at Harvard Medical School, Boston. Email them at pdnews@mdedge.com.

 

You may not realize it, but as you navigated through this morning’s hospital rounds and your busy office schedule, some of what you did and how you did it was the result of the pioneering work of Boston-based pediatrician T. Berry Brazelton, MD, who died March 13, 2018, at the age of 99.

You probably found the newborn you needed to examine in his mother’s hospital room. The 3-year-old in the croup tent was sharing his room with his father, who was sleeping on a cot at his crib side, and three out of the first four patients you saw in your office had been breastfed. These scenarios would have been unheard of 50 years ago. But Dr. Brazelton’s voice was the most widely heard, yet gentlest and persuasive in support of rooming-in and breastfeeding.

Although I was fortunate to have had dinner with Benjamin Spock’s widow, I never met Dr. Spock himself. However, I did interact on several occasions with the man who inherited his mantle as the most well-recognized pediatrician in America. Dr. T. Berry Brazelton and his fellows played an active role in the pediatric training of those of us who rotated through Boston Children’s Hospital as medical students and house officers.

Watching Dr. Brazelton examine a newborn for the first time was a unique experience and a critical turning point in my training. My fellow house officers and I had been accustomed to picking up infants to assess their tone. However, when Dr. Brazelton picked up a newborn, it was more like a conversation, an interview, and in a sense, it was a meeting of the minds.

It wasn’t that we had been rejecting the notion that a newborn could have a personality. It is just that we hadn’t been taught to look for it or to take it seriously. Dr. Brazelton taught us how to examine the person inside that little body and understand the importance of her temperament. By sharing what we learned from doing a Brazelton-style exam, we hoped to encourage the child’s parents to adopt more realistic expectations, and as a consequence, make parenting less mysterious and stressful.

When I first met Dr. Brazelton, he was in his mid-40s and just beginning on his trajectory toward national prominence. When we were assigned to take care of his hospitalized patients, it was obvious that his patient skills with sick children had taken a back seat to his interest in newborn temperament. He was more than willing to let us make the management decisions. In retrospect, that experience was a warning that I, like many other pediatricians, would face the similar challenge of maintaining my clinical skills in the face of a patient mix that was steadily acquiring a more behavioral and developmental flavor.

It is impossible to quantify the degree to which Dr. Brazelton’s ubiquity contributed to the popularity of a more child-centered parenting style. However, I think it would be unfair to blame him for the unfortunate phenomenon known as “helicopter parenting.”

 

He has been quoted as saying, “I would like to look at what can be done to get parents to relax and not to take [parenthood] too seriously.” (“T. Berry Brazelton, doctor who challenged parents to read babies’ cues, dies,” Washington Post, March 14, 2018). And for the most part with his calm and gentle demeanor, he achieved his goal. Unfortunately, not every parent who tried to follow Dr. Brazelton’s advice about reading their baby’s cues was successful. With his passing, it is up to us as pediatricians to continue comforting those parents who are struggling and echo his reassuring message.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

 

You may not realize it, but as you navigated through this morning’s hospital rounds and your busy office schedule, some of what you did and how you did it was the result of the pioneering work of Boston-based pediatrician T. Berry Brazelton, MD, who died March 13, 2018, at the age of 99.

You probably found the newborn you needed to examine in his mother’s hospital room. The 3-year-old in the croup tent was sharing his room with his father, who was sleeping on a cot at his crib side, and three out of the first four patients you saw in your office had been breastfed. These scenarios would have been unheard of 50 years ago. But Dr. Brazelton’s voice was the most widely heard, yet gentlest and persuasive in support of rooming-in and breastfeeding.

Although I was fortunate to have had dinner with Benjamin Spock’s widow, I never met Dr. Spock himself. However, I did interact on several occasions with the man who inherited his mantle as the most well-recognized pediatrician in America. Dr. T. Berry Brazelton and his fellows played an active role in the pediatric training of those of us who rotated through Boston Children’s Hospital as medical students and house officers.

Watching Dr. Brazelton examine a newborn for the first time was a unique experience and a critical turning point in my training. My fellow house officers and I had been accustomed to picking up infants to assess their tone. However, when Dr. Brazelton picked up a newborn, it was more like a conversation, an interview, and in a sense, it was a meeting of the minds.

It wasn’t that we had been rejecting the notion that a newborn could have a personality. It is just that we hadn’t been taught to look for it or to take it seriously. Dr. Brazelton taught us how to examine the person inside that little body and understand the importance of her temperament. By sharing what we learned from doing a Brazelton-style exam, we hoped to encourage the child’s parents to adopt more realistic expectations, and as a consequence, make parenting less mysterious and stressful.

When I first met Dr. Brazelton, he was in his mid-40s and just beginning on his trajectory toward national prominence. When we were assigned to take care of his hospitalized patients, it was obvious that his patient skills with sick children had taken a back seat to his interest in newborn temperament. He was more than willing to let us make the management decisions. In retrospect, that experience was a warning that I, like many other pediatricians, would face the similar challenge of maintaining my clinical skills in the face of a patient mix that was steadily acquiring a more behavioral and developmental flavor.

It is impossible to quantify the degree to which Dr. Brazelton’s ubiquity contributed to the popularity of a more child-centered parenting style. However, I think it would be unfair to blame him for the unfortunate phenomenon known as “helicopter parenting.”

 

He has been quoted as saying, “I would like to look at what can be done to get parents to relax and not to take [parenthood] too seriously.” (“T. Berry Brazelton, doctor who challenged parents to read babies’ cues, dies,” Washington Post, March 14, 2018). And for the most part with his calm and gentle demeanor, he achieved his goal. Unfortunately, not every parent who tried to follow Dr. Brazelton’s advice about reading their baby’s cues was successful. With his passing, it is up to us as pediatricians to continue comforting those parents who are struggling and echo his reassuring message.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

 

You may not realize it, but as you navigated through this morning’s hospital rounds and your busy office schedule, some of what you did and how you did it was the result of the pioneering work of Boston-based pediatrician T. Berry Brazelton, MD, who died March 13, 2018, at the age of 99.

You probably found the newborn you needed to examine in his mother’s hospital room. The 3-year-old in the croup tent was sharing his room with his father, who was sleeping on a cot at his crib side, and three out of the first four patients you saw in your office had been breastfed. These scenarios would have been unheard of 50 years ago. But Dr. Brazelton’s voice was the most widely heard, yet gentlest and persuasive in support of rooming-in and breastfeeding.

Although I was fortunate to have had dinner with Benjamin Spock’s widow, I never met Dr. Spock himself. However, I did interact on several occasions with the man who inherited his mantle as the most well-recognized pediatrician in America. Dr. T. Berry Brazelton and his fellows played an active role in the pediatric training of those of us who rotated through Boston Children’s Hospital as medical students and house officers.

Watching Dr. Brazelton examine a newborn for the first time was a unique experience and a critical turning point in my training. My fellow house officers and I had been accustomed to picking up infants to assess their tone. However, when Dr. Brazelton picked up a newborn, it was more like a conversation, an interview, and in a sense, it was a meeting of the minds.

It wasn’t that we had been rejecting the notion that a newborn could have a personality. It is just that we hadn’t been taught to look for it or to take it seriously. Dr. Brazelton taught us how to examine the person inside that little body and understand the importance of her temperament. By sharing what we learned from doing a Brazelton-style exam, we hoped to encourage the child’s parents to adopt more realistic expectations, and as a consequence, make parenting less mysterious and stressful.

When I first met Dr. Brazelton, he was in his mid-40s and just beginning on his trajectory toward national prominence. When we were assigned to take care of his hospitalized patients, it was obvious that his patient skills with sick children had taken a back seat to his interest in newborn temperament. He was more than willing to let us make the management decisions. In retrospect, that experience was a warning that I, like many other pediatricians, would face the similar challenge of maintaining my clinical skills in the face of a patient mix that was steadily acquiring a more behavioral and developmental flavor.

It is impossible to quantify the degree to which Dr. Brazelton’s ubiquity contributed to the popularity of a more child-centered parenting style. However, I think it would be unfair to blame him for the unfortunate phenomenon known as “helicopter parenting.”

 

He has been quoted as saying, “I would like to look at what can be done to get parents to relax and not to take [parenthood] too seriously.” (“T. Berry Brazelton, doctor who challenged parents to read babies’ cues, dies,” Washington Post, March 14, 2018). And for the most part with his calm and gentle demeanor, he achieved his goal. Unfortunately, not every parent who tried to follow Dr. Brazelton’s advice about reading their baby’s cues was successful. With his passing, it is up to us as pediatricians to continue comforting those parents who are struggling and echo his reassuring message.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@frontlinemedcom.com.

This past year has seen an incredible transformation in our awareness and understanding of the extent of sexual harassment and assault in our society. The #metoo campaign and the brave women throughout the country who have come out and told us their stories have truly made a difference.

For years, I, and many other pediatricians like me, have counseled teenage girls on how to stay safe as they prepare to enter college and universities. So many times, I have mentioned the shocking statistics on rape and sexual assault in college. I have cautioned these young women on how to stay safe, to stay close to their girlfriends, to not accept drinks from other people, and if drinking, not to drink so much that they don’t know what is going on around them … and so on and so forth with many dos and don’ts.

But here is something I only recently noticed: In the last 18 years of practice, my counsel to the boys was limited to how to stay safe, protect themselves against sexually transmitted infections, and how to avoid pregnancy. It did not cross my mind to counsel the teenage boys on their respective dos and don’ts, especially when it comes to their behavior with women. For example, stern advice on how to respect women, that only yes means yes, and frankly how to make sure they don’t become sexual harassers or worse.

I have questioned myself since then, wondering if I was alone with this oversight. I asked several other pediatricians as well to see if they had spoken about sexual harassment and assault in this context with their teenage male patients. The vast majority had the same experience as I did. They had all counseled the girls on how to protect themselves from becoming victims, but somehow not the boys (or girls for that matter) on how to help them not become the aggressors.

 

It has occurred to me that our focus as physicians has largely been limited to what the victims can do to not become victims. Primary care providers were never really trained, or reminded, to talk to the potential aggressors before they would or could act.

As pediatricians, we counsel parents on how to keep their children safe, and how to protect them. It is our obligation to help, to guide, and to teach parents. We teach parents about discipline, limit setting, sleeping, feeding, and so many other things. We need to teach them how to talk to their boys and girls about appropriate behavior with whomever they may be interested in, about sexual harassment, and assault, and how not to become part of the problem.

Courtesy Bilal Zuberi

It is our turn to do more, and we need to start right now. We must help our boys and girls understand that not only does no mean no, but only yes means yes, that nothing should happen without verbal consent, that if you cannot get verbal consent then the answer is no, that sex under the influence is not okay, and so much more. These are important conversations to have. Pediatricians should be trained how to best have such conversations, and it should become part of standard of care. We must develop best practices that would include talking to the young men (or women) in our exam rooms with information and advice that would prevent them from crossing the lines in the first place.

It is our obligation as pediatricians to teach the children we see growing up in front of us how to behave in an adult, sexual world. We can make a bigger difference than we might think. As physicians, we promised to do no harm when we took our oath. It is now our turn also to take proactive steps to stop the harm caused by others.

Dr. Rimawi is a pediatrician in private practice in Atherton, Calif. Email her at pdnews@mdedge.com.

This past year has seen an incredible transformation in our awareness and understanding of the extent of sexual harassment and assault in our society. The #metoo campaign and the brave women throughout the country who have come out and told us their stories have truly made a difference.

For years, I, and many other pediatricians like me, have counseled teenage girls on how to stay safe as they prepare to enter college and universities. So many times, I have mentioned the shocking statistics on rape and sexual assault in college. I have cautioned these young women on how to stay safe, to stay close to their girlfriends, to not accept drinks from other people, and if drinking, not to drink so much that they don’t know what is going on around them … and so on and so forth with many dos and don’ts.

But here is something I only recently noticed: In the last 18 years of practice, my counsel to the boys was limited to how to stay safe, protect themselves against sexually transmitted infections, and how to avoid pregnancy. It did not cross my mind to counsel the teenage boys on their respective dos and don’ts, especially when it comes to their behavior with women. For example, stern advice on how to respect women, that only yes means yes, and frankly how to make sure they don’t become sexual harassers or worse.

I have questioned myself since then, wondering if I was alone with this oversight. I asked several other pediatricians as well to see if they had spoken about sexual harassment and assault in this context with their teenage male patients. The vast majority had the same experience as I did. They had all counseled the girls on how to protect themselves from becoming victims, but somehow not the boys (or girls for that matter) on how to help them not become the aggressors.

 

It has occurred to me that our focus as physicians has largely been limited to what the victims can do to not become victims. Primary care providers were never really trained, or reminded, to talk to the potential aggressors before they would or could act.

As pediatricians, we counsel parents on how to keep their children safe, and how to protect them. It is our obligation to help, to guide, and to teach parents. We teach parents about discipline, limit setting, sleeping, feeding, and so many other things. We need to teach them how to talk to their boys and girls about appropriate behavior with whomever they may be interested in, about sexual harassment, and assault, and how not to become part of the problem.

Courtesy Bilal Zuberi

It is our turn to do more, and we need to start right now. We must help our boys and girls understand that not only does no mean no, but only yes means yes, that nothing should happen without verbal consent, that if you cannot get verbal consent then the answer is no, that sex under the influence is not okay, and so much more. These are important conversations to have. Pediatricians should be trained how to best have such conversations, and it should become part of standard of care. We must develop best practices that would include talking to the young men (or women) in our exam rooms with information and advice that would prevent them from crossing the lines in the first place.

It is our obligation as pediatricians to teach the children we see growing up in front of us how to behave in an adult, sexual world. We can make a bigger difference than we might think. As physicians, we promised to do no harm when we took our oath. It is now our turn also to take proactive steps to stop the harm caused by others.

Dr. Rimawi is a pediatrician in private practice in Atherton, Calif. Email her at pdnews@mdedge.com.

This past year has seen an incredible transformation in our awareness and understanding of the extent of sexual harassment and assault in our society. The #metoo campaign and the brave women throughout the country who have come out and told us their stories have truly made a difference.

For years, I, and many other pediatricians like me, have counseled teenage girls on how to stay safe as they prepare to enter college and universities. So many times, I have mentioned the shocking statistics on rape and sexual assault in college. I have cautioned these young women on how to stay safe, to stay close to their girlfriends, to not accept drinks from other people, and if drinking, not to drink so much that they don’t know what is going on around them … and so on and so forth with many dos and don’ts.

But here is something I only recently noticed: In the last 18 years of practice, my counsel to the boys was limited to how to stay safe, protect themselves against sexually transmitted infections, and how to avoid pregnancy. It did not cross my mind to counsel the teenage boys on their respective dos and don’ts, especially when it comes to their behavior with women. For example, stern advice on how to respect women, that only yes means yes, and frankly how to make sure they don’t become sexual harassers or worse.

I have questioned myself since then, wondering if I was alone with this oversight. I asked several other pediatricians as well to see if they had spoken about sexual harassment and assault in this context with their teenage male patients. The vast majority had the same experience as I did. They had all counseled the girls on how to protect themselves from becoming victims, but somehow not the boys (or girls for that matter) on how to help them not become the aggressors.

 

It has occurred to me that our focus as physicians has largely been limited to what the victims can do to not become victims. Primary care providers were never really trained, or reminded, to talk to the potential aggressors before they would or could act.

As pediatricians, we counsel parents on how to keep their children safe, and how to protect them. It is our obligation to help, to guide, and to teach parents. We teach parents about discipline, limit setting, sleeping, feeding, and so many other things. We need to teach them how to talk to their boys and girls about appropriate behavior with whomever they may be interested in, about sexual harassment, and assault, and how not to become part of the problem.

Courtesy Bilal Zuberi

It is our turn to do more, and we need to start right now. We must help our boys and girls understand that not only does no mean no, but only yes means yes, that nothing should happen without verbal consent, that if you cannot get verbal consent then the answer is no, that sex under the influence is not okay, and so much more. These are important conversations to have. Pediatricians should be trained how to best have such conversations, and it should become part of standard of care. We must develop best practices that would include talking to the young men (or women) in our exam rooms with information and advice that would prevent them from crossing the lines in the first place.

It is our obligation as pediatricians to teach the children we see growing up in front of us how to behave in an adult, sexual world. We can make a bigger difference than we might think. As physicians, we promised to do no harm when we took our oath. It is now our turn also to take proactive steps to stop the harm caused by others.

Dr. Rimawi is a pediatrician in private practice in Atherton, Calif. Email her at pdnews@mdedge.com.

 

High-dose oral ibuprofen may be most likely to result in closure of hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, compared with other pharmacological treatments, according to results of a recent systematic review and meta-analysis.

However, using placebo or no treatment at all did not increase the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage in the study, published in JAMA.

herjua/Thinkstock

“This raises the question whether active pharmacological closure of hemodynamically significant PDA necessarily improves clinical outcomes,” wrote Souvik Mitra, MD, of Dalhousie University, Halifax, N.S., and his coauthors.

PDA is a common cardiovascular issue among prematurely born infants. According to Dr. Mitra and his coauthors, it’s thought that a large proportion of PDAs spontaneously close in a few days and have minimal effect on clinical outcomes.

As a result, treatment is often targeted to PDAs deemed hemodynamically significant based on clinical and echocardiographic parameters, the authors wrote, although there is little guidance on what, if any, treatment to use in this situation.

“The dilemma is whether to use pharmacotherapy at all, and if a decision is made to treat the PDA medically, what should be the ideal choice of pharmacotherapy,” they wrote.

Dr. Mitra and colleagues conducted a systematic review and meta-analysis of 68 randomized clinical trials including 4,802 infants with clinically or echocardiographically diagnosed, hemodynamically significant PDA.

 

They found that closure of hemodynamically significant PDA was significantly more likely with high-dose oral ibuprofen, compared with the two of the most widely used treatments, namely standard-dose intravenous ibuprofen (odds ratio, 3.59) and standard-dose intravenous indomethacin (odds ratio, 2.35).

Despite that finding, there was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage for use of placebo or no treatment, compared with any of the treatment modalities, the investigators added.

“With increasing emphasis on conservative management of PDA, these results may encourage researchers to revisit placebo-controlled trials against newer pharmacotherapeutic options,” they said.

Study authors reported no relevant potential conflicts of interest.

SOURCE: Mitra S et al. JAMA. 2018;319(12):1221-38.

 

High-dose oral ibuprofen may be most likely to result in closure of hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, compared with other pharmacological treatments, according to results of a recent systematic review and meta-analysis.

However, using placebo or no treatment at all did not increase the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage in the study, published in JAMA.

herjua/Thinkstock

“This raises the question whether active pharmacological closure of hemodynamically significant PDA necessarily improves clinical outcomes,” wrote Souvik Mitra, MD, of Dalhousie University, Halifax, N.S., and his coauthors.

PDA is a common cardiovascular issue among prematurely born infants. According to Dr. Mitra and his coauthors, it’s thought that a large proportion of PDAs spontaneously close in a few days and have minimal effect on clinical outcomes.

As a result, treatment is often targeted to PDAs deemed hemodynamically significant based on clinical and echocardiographic parameters, the authors wrote, although there is little guidance on what, if any, treatment to use in this situation.

“The dilemma is whether to use pharmacotherapy at all, and if a decision is made to treat the PDA medically, what should be the ideal choice of pharmacotherapy,” they wrote.

Dr. Mitra and colleagues conducted a systematic review and meta-analysis of 68 randomized clinical trials including 4,802 infants with clinically or echocardiographically diagnosed, hemodynamically significant PDA.

 

They found that closure of hemodynamically significant PDA was significantly more likely with high-dose oral ibuprofen, compared with the two of the most widely used treatments, namely standard-dose intravenous ibuprofen (odds ratio, 3.59) and standard-dose intravenous indomethacin (odds ratio, 2.35).

Despite that finding, there was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage for use of placebo or no treatment, compared with any of the treatment modalities, the investigators added.

“With increasing emphasis on conservative management of PDA, these results may encourage researchers to revisit placebo-controlled trials against newer pharmacotherapeutic options,” they said.

Study authors reported no relevant potential conflicts of interest.

SOURCE: Mitra S et al. JAMA. 2018;319(12):1221-38.

 

High-dose oral ibuprofen may be most likely to result in closure of hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, compared with other pharmacological treatments, according to results of a recent systematic review and meta-analysis.

However, using placebo or no treatment at all did not increase the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage in the study, published in JAMA.

herjua/Thinkstock

“This raises the question whether active pharmacological closure of hemodynamically significant PDA necessarily improves clinical outcomes,” wrote Souvik Mitra, MD, of Dalhousie University, Halifax, N.S., and his coauthors.

PDA is a common cardiovascular issue among prematurely born infants. According to Dr. Mitra and his coauthors, it’s thought that a large proportion of PDAs spontaneously close in a few days and have minimal effect on clinical outcomes.

As a result, treatment is often targeted to PDAs deemed hemodynamically significant based on clinical and echocardiographic parameters, the authors wrote, although there is little guidance on what, if any, treatment to use in this situation.

“The dilemma is whether to use pharmacotherapy at all, and if a decision is made to treat the PDA medically, what should be the ideal choice of pharmacotherapy,” they wrote.

Dr. Mitra and colleagues conducted a systematic review and meta-analysis of 68 randomized clinical trials including 4,802 infants with clinically or echocardiographically diagnosed, hemodynamically significant PDA.

 

They found that closure of hemodynamically significant PDA was significantly more likely with high-dose oral ibuprofen, compared with the two of the most widely used treatments, namely standard-dose intravenous ibuprofen (odds ratio, 3.59) and standard-dose intravenous indomethacin (odds ratio, 2.35).

Despite that finding, there was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage for use of placebo or no treatment, compared with any of the treatment modalities, the investigators added.

“With increasing emphasis on conservative management of PDA, these results may encourage researchers to revisit placebo-controlled trials against newer pharmacotherapeutic options,” they said.

Study authors reported no relevant potential conflicts of interest.

SOURCE: Mitra S et al. JAMA. 2018;319(12):1221-38.