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The march of technology
Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.
Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.
A couple weeks earlier I had listened to a national meeting of pediatric ethicists discuss this technology. Some proponents discussed the possibility of doing whole exome sequencing (WES) for every newborn. Alas, many ethicists can’t do math. Even if the cost goes below $1,000 per test, at 4 million babies per year in the United States, that is $4 billion per year. That sounds like a small sum, compared with the current federal deficit, but the original budget for the entire, 10-year-long Human Genome Project (HGP) was $4.5 billion. There were complaints in that era that diverting such an enormous amount of money into the HGP would cut the funding of a lot of other very good research at the National Institutes of Health. Conversely, Medicare spends $4.5 billion on hepatitis C treatment.
Viewed differently, the yearly per capita payment to general pediatricians, excluding vaccine costs, is around $1,000. Perhaps I’m biased, but I think I provide much more value than a genetic sequence.
Precision medicine has a lot of potential. So far, it is mostly potential. One colleague related that, in the past year, he has done WES on three patients, at about $4,000 charge for each, and gotten positive results in two cases. He figures soon he will be ordering it on every child with symptoms of autism, developmental delay, or failure to thrive. Is that a wise idea? That, it seems, is the area in which there is the least illuminating research.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.
Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.
Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.
A couple weeks earlier I had listened to a national meeting of pediatric ethicists discuss this technology. Some proponents discussed the possibility of doing whole exome sequencing (WES) for every newborn. Alas, many ethicists can’t do math. Even if the cost goes below $1,000 per test, at 4 million babies per year in the United States, that is $4 billion per year. That sounds like a small sum, compared with the current federal deficit, but the original budget for the entire, 10-year-long Human Genome Project (HGP) was $4.5 billion. There were complaints in that era that diverting such an enormous amount of money into the HGP would cut the funding of a lot of other very good research at the National Institutes of Health. Conversely, Medicare spends $4.5 billion on hepatitis C treatment.
Viewed differently, the yearly per capita payment to general pediatricians, excluding vaccine costs, is around $1,000. Perhaps I’m biased, but I think I provide much more value than a genetic sequence.
Precision medicine has a lot of potential. So far, it is mostly potential. One colleague related that, in the past year, he has done WES on three patients, at about $4,000 charge for each, and gotten positive results in two cases. He figures soon he will be ordering it on every child with symptoms of autism, developmental delay, or failure to thrive. Is that a wise idea? That, it seems, is the area in which there is the least illuminating research.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.
Each year the American Academy of Pediatrics National Conference and Exhibition fills a huge convention hall with the latest products that can improve health and generate practice revenue.
Some products are solutions to the minor annoyances of everyday practice. For instance, there are ear curettes equipped with their own LED light and a magnifying lens. There are countless creams to treat rashes. There are new automated devices for testing hearing, vision, and attention. And at the far extreme, there are products with the potential to revolutionize clinical care or to bankrupt it. The latest technology in that category is whole exome sequencing.
A couple weeks earlier I had listened to a national meeting of pediatric ethicists discuss this technology. Some proponents discussed the possibility of doing whole exome sequencing (WES) for every newborn. Alas, many ethicists can’t do math. Even if the cost goes below $1,000 per test, at 4 million babies per year in the United States, that is $4 billion per year. That sounds like a small sum, compared with the current federal deficit, but the original budget for the entire, 10-year-long Human Genome Project (HGP) was $4.5 billion. There were complaints in that era that diverting such an enormous amount of money into the HGP would cut the funding of a lot of other very good research at the National Institutes of Health. Conversely, Medicare spends $4.5 billion on hepatitis C treatment.
Viewed differently, the yearly per capita payment to general pediatricians, excluding vaccine costs, is around $1,000. Perhaps I’m biased, but I think I provide much more value than a genetic sequence.
Precision medicine has a lot of potential. So far, it is mostly potential. One colleague related that, in the past year, he has done WES on three patients, at about $4,000 charge for each, and gotten positive results in two cases. He figures soon he will be ordering it on every child with symptoms of autism, developmental delay, or failure to thrive. Is that a wise idea? That, it seems, is the area in which there is the least illuminating research.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis.
Clinical Challenges - November 2016
What’s your diagnosis?
Answer to “What’s your diagnosis?” on page X: Collagenous gastritis and collagenous sprue
Recent studies have also shown the importance of obtaining at least 1 biopsy from the duodenal bulb to avoid missing the diagnosis of celiac disease. In 126 patients with newly established celiac disease and 85 patients with a previous diagnosis on a gluten-free diet presenting for reevaluation, villous atrophy was limited to the duodenal bulb in 9% and 14% of cases, respectively.3
References
1. Brain, O., Rajaguru, C., Warren, B. et al. Collagenous gastritis: reports and systematic review. Eur J Gastroenterol Hepatol. 2009;21:1419-24.
2. Gopal, P., McKenna, B.J. The collagenous gastroenteritides: similarities and differences. Arch Pathol Lab Med. 2010;134:1485-9.
3. Evans, K.E., Aziz, I., Cross, S.S. et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol. 2011;106:1837-742.
Answer to “What’s your diagnosis?” on page X: Collagenous gastritis and collagenous sprue
Recent studies have also shown the importance of obtaining at least 1 biopsy from the duodenal bulb to avoid missing the diagnosis of celiac disease. In 126 patients with newly established celiac disease and 85 patients with a previous diagnosis on a gluten-free diet presenting for reevaluation, villous atrophy was limited to the duodenal bulb in 9% and 14% of cases, respectively.3
References
1. Brain, O., Rajaguru, C., Warren, B. et al. Collagenous gastritis: reports and systematic review. Eur J Gastroenterol Hepatol. 2009;21:1419-24.
2. Gopal, P., McKenna, B.J. The collagenous gastroenteritides: similarities and differences. Arch Pathol Lab Med. 2010;134:1485-9.
3. Evans, K.E., Aziz, I., Cross, S.S. et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol. 2011;106:1837-742.
Answer to “What’s your diagnosis?” on page X: Collagenous gastritis and collagenous sprue
Recent studies have also shown the importance of obtaining at least 1 biopsy from the duodenal bulb to avoid missing the diagnosis of celiac disease. In 126 patients with newly established celiac disease and 85 patients with a previous diagnosis on a gluten-free diet presenting for reevaluation, villous atrophy was limited to the duodenal bulb in 9% and 14% of cases, respectively.3
References
1. Brain, O., Rajaguru, C., Warren, B. et al. Collagenous gastritis: reports and systematic review. Eur J Gastroenterol Hepatol. 2009;21:1419-24.
2. Gopal, P., McKenna, B.J. The collagenous gastroenteritides: similarities and differences. Arch Pathol Lab Med. 2010;134:1485-9.
3. Evans, K.E., Aziz, I., Cross, S.S. et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol. 2011;106:1837-742.
What’s your diagnosis?
What’s your diagnosis?
What’s your diagnosis?
By Benjamin Kloesel, MD, Vishal S. Chandan, MD, and Glenn L. Alexander, MD. Published previously in Gastroenterology (2012;143:1439, 1692).
A 30-year-old woman with a past medical history of hypothyroidism presents for evaluation of epigastric discomfort, nausea without emesis, abdominal bloating, and watery, nonbloody diarrhea for 5 months. This was associated with a 15-pound weight loss. Complete blood count, liver function tests, thyroid-stimulating hormone, immunoglobulin (Ig) levels, and IgG/IgA tissue transglutaminase (tTG) were within normal limits. Stool studies for bacterial pathogens, Giardia, Clostridium difficile toxin, and ova/parasites were negative. 
Results puzzling for embolic protection during TAVR
The largest randomized clinical trial to assess the safety and efficacy of cerebral embolic protection systems during transcatheter aortic valve replacement yielded puzzling and somewhat contradictory results, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.
Virtually every device in this industry-sponsored study involving 363 elderly patients (mean age, 83.4 years) with severe aortic stenosis trapped particulate debris as intended, the mean volume of new lesions in the protected areas of the brain was reduced by 42%, and the number and volume of new lesions correlated with neurocognitive outcomes at 30 days.
However, the reduction in lesion volume did not achieve statistical significance, and the improvement in neurocognitive function also did not reach statistical significance.
In addition, “the sample size was clearly too low to assess clinical outcomes, and in retrospect, was also too low to evaluate follow-up MRI findings or neurocognitive outcomes.” Nevertheless, the trial “provides reassuring evidence of device safety,” said Samir R. Kapadia, MD, of the Cleveland Clinic (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.023).
In this prospective study, the investigators assessed patients at 17 medical centers in the United States and 2 in Germany. In addition to being elderly, the study patients were at high risk because of frequent comorbidities, including atrial fibrillation (31.7%) and prior stroke (5.8%).
The remaining 123 patients underwent TAVR but not MRI in a safety arm of the trial.
The protection devices were placed “without safety concerns” in most patients. The rate of major adverse events with the device was 7.3%, markedly less than the 18.3% prespecified performance goal for this outcome. Total procedure time was lengthened by only 13 minutes when the device was used, and total fluoroscopy time was increased by only 3 minutes. These findings demonstrate the overall safety of using the device, Dr. Kapadia said.
Debris including thrombus with tissue elements, artery wall particles, calcifications, valve tissue, and foreign materials was retrieved from the filters in 99% of patients.
The mean volume of new cerebral lesions in areas of the brain protected by the device was reduced by 42%, compared with that in patients who underwent TAVR without the protection device. However, this reduction was not statistically significant, so the primary efficacy endpoint of the study was not met.
Similarly, neurocognitive testing at 30 days showed that the volume of new lesions correlated with poorer outcomes. However, the difference in neurocognitive function between the intervention group and the control group did not reach statistical significance.
Several limitations likely contributed to this lack of statistical significance, Dr. Kapadia said.
First, the 5-day “window” for MRI assessment was too long. Both the number and the volume of new lesions rapidly changed over time, which led to marked variance in MRI findings depending on when the images were taken.
In addition, only one TAVR device was available at the time the trial was designed, so the study wasn’t stratified by type of valve device. But several new devices became available during the study, and the study investigators were permitted to use any of them. Both pre- and postimplantation techniques differ among these TAVR devices, but these differences could not be accounted for, given the study design.
Also, certain risk factors for stroke, especially certain findings on baseline MRI, were not understood when the trial was designed, and those factors also were not accounted for, Dr. Kapadia said.
Claret Medical funded the study. Dr. Kapadia reported having no relevant financial disclosures; his associates reported numerous ties to industry sources. The meeting was sponsored by the Cardiovascular Research Foundation.
From a logical standpoint, a device that collects cerebral embolic material in 99% of cases should prevent ischemic brain injury, yet the findings from this randomized trial don’t appear to support the routine use of such devices. But it would be inappropriate and unfair to close the book on cerebral protection after this chapter.
The authors acknowledge that an MRI “window” of 5 days creates too much heterogeneity in the data, that multiple TAVR devices requiring different implantation techniques further muddy the picture, and that in retrospect the sample size was inadequate and the study was underpowered. In addition, rigorous neurocognitive assessment can be challenging in elderly, recovering patients, and results can depend on the time of day and the patient’s alertness.
Despite the negative findings regarding both primary and secondary endpoints, the data do show the overall safety of embolic protection devices. We are dealing with a potential benefit that cannot be ignored as TAVR shifts to younger and lower-risk patients.
Azeem Latib, MD, is in the interventional cardiology unit at San Raffaele Scientific Institute in Milan. Matteo Pagnesi, MD, is in the interventional cardiology unit at EMO-GVM Centro Cuore Columbus in Milan. San Raffaele Scientific Institute has been involved in clinical studies of embolic protection devices made by Claret Medical, Innovative Cardiovascular Solutions, and Keystone Heart. Dr. Latib and Dr. Pagnesi reported having no other relevant financial disclosures. They made these remarks in an editorial accompanying Dr. Kapadia’s report (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.036).
From a logical standpoint, a device that collects cerebral embolic material in 99% of cases should prevent ischemic brain injury, yet the findings from this randomized trial don’t appear to support the routine use of such devices. But it would be inappropriate and unfair to close the book on cerebral protection after this chapter.
The authors acknowledge that an MRI “window” of 5 days creates too much heterogeneity in the data, that multiple TAVR devices requiring different implantation techniques further muddy the picture, and that in retrospect the sample size was inadequate and the study was underpowered. In addition, rigorous neurocognitive assessment can be challenging in elderly, recovering patients, and results can depend on the time of day and the patient’s alertness.
Despite the negative findings regarding both primary and secondary endpoints, the data do show the overall safety of embolic protection devices. We are dealing with a potential benefit that cannot be ignored as TAVR shifts to younger and lower-risk patients.
Azeem Latib, MD, is in the interventional cardiology unit at San Raffaele Scientific Institute in Milan. Matteo Pagnesi, MD, is in the interventional cardiology unit at EMO-GVM Centro Cuore Columbus in Milan. San Raffaele Scientific Institute has been involved in clinical studies of embolic protection devices made by Claret Medical, Innovative Cardiovascular Solutions, and Keystone Heart. Dr. Latib and Dr. Pagnesi reported having no other relevant financial disclosures. They made these remarks in an editorial accompanying Dr. Kapadia’s report (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.036).
From a logical standpoint, a device that collects cerebral embolic material in 99% of cases should prevent ischemic brain injury, yet the findings from this randomized trial don’t appear to support the routine use of such devices. But it would be inappropriate and unfair to close the book on cerebral protection after this chapter.
The authors acknowledge that an MRI “window” of 5 days creates too much heterogeneity in the data, that multiple TAVR devices requiring different implantation techniques further muddy the picture, and that in retrospect the sample size was inadequate and the study was underpowered. In addition, rigorous neurocognitive assessment can be challenging in elderly, recovering patients, and results can depend on the time of day and the patient’s alertness.
Despite the negative findings regarding both primary and secondary endpoints, the data do show the overall safety of embolic protection devices. We are dealing with a potential benefit that cannot be ignored as TAVR shifts to younger and lower-risk patients.
Azeem Latib, MD, is in the interventional cardiology unit at San Raffaele Scientific Institute in Milan. Matteo Pagnesi, MD, is in the interventional cardiology unit at EMO-GVM Centro Cuore Columbus in Milan. San Raffaele Scientific Institute has been involved in clinical studies of embolic protection devices made by Claret Medical, Innovative Cardiovascular Solutions, and Keystone Heart. Dr. Latib and Dr. Pagnesi reported having no other relevant financial disclosures. They made these remarks in an editorial accompanying Dr. Kapadia’s report (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.036).
The largest randomized clinical trial to assess the safety and efficacy of cerebral embolic protection systems during transcatheter aortic valve replacement yielded puzzling and somewhat contradictory results, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.
Virtually every device in this industry-sponsored study involving 363 elderly patients (mean age, 83.4 years) with severe aortic stenosis trapped particulate debris as intended, the mean volume of new lesions in the protected areas of the brain was reduced by 42%, and the number and volume of new lesions correlated with neurocognitive outcomes at 30 days.
However, the reduction in lesion volume did not achieve statistical significance, and the improvement in neurocognitive function also did not reach statistical significance.
In addition, “the sample size was clearly too low to assess clinical outcomes, and in retrospect, was also too low to evaluate follow-up MRI findings or neurocognitive outcomes.” Nevertheless, the trial “provides reassuring evidence of device safety,” said Samir R. Kapadia, MD, of the Cleveland Clinic (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.023).
In this prospective study, the investigators assessed patients at 17 medical centers in the United States and 2 in Germany. In addition to being elderly, the study patients were at high risk because of frequent comorbidities, including atrial fibrillation (31.7%) and prior stroke (5.8%).
The remaining 123 patients underwent TAVR but not MRI in a safety arm of the trial.
The protection devices were placed “without safety concerns” in most patients. The rate of major adverse events with the device was 7.3%, markedly less than the 18.3% prespecified performance goal for this outcome. Total procedure time was lengthened by only 13 minutes when the device was used, and total fluoroscopy time was increased by only 3 minutes. These findings demonstrate the overall safety of using the device, Dr. Kapadia said.
Debris including thrombus with tissue elements, artery wall particles, calcifications, valve tissue, and foreign materials was retrieved from the filters in 99% of patients.
The mean volume of new cerebral lesions in areas of the brain protected by the device was reduced by 42%, compared with that in patients who underwent TAVR without the protection device. However, this reduction was not statistically significant, so the primary efficacy endpoint of the study was not met.
Similarly, neurocognitive testing at 30 days showed that the volume of new lesions correlated with poorer outcomes. However, the difference in neurocognitive function between the intervention group and the control group did not reach statistical significance.
Several limitations likely contributed to this lack of statistical significance, Dr. Kapadia said.
First, the 5-day “window” for MRI assessment was too long. Both the number and the volume of new lesions rapidly changed over time, which led to marked variance in MRI findings depending on when the images were taken.
In addition, only one TAVR device was available at the time the trial was designed, so the study wasn’t stratified by type of valve device. But several new devices became available during the study, and the study investigators were permitted to use any of them. Both pre- and postimplantation techniques differ among these TAVR devices, but these differences could not be accounted for, given the study design.
Also, certain risk factors for stroke, especially certain findings on baseline MRI, were not understood when the trial was designed, and those factors also were not accounted for, Dr. Kapadia said.
Claret Medical funded the study. Dr. Kapadia reported having no relevant financial disclosures; his associates reported numerous ties to industry sources. The meeting was sponsored by the Cardiovascular Research Foundation.
The largest randomized clinical trial to assess the safety and efficacy of cerebral embolic protection systems during transcatheter aortic valve replacement yielded puzzling and somewhat contradictory results, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.
Virtually every device in this industry-sponsored study involving 363 elderly patients (mean age, 83.4 years) with severe aortic stenosis trapped particulate debris as intended, the mean volume of new lesions in the protected areas of the brain was reduced by 42%, and the number and volume of new lesions correlated with neurocognitive outcomes at 30 days.
However, the reduction in lesion volume did not achieve statistical significance, and the improvement in neurocognitive function also did not reach statistical significance.
In addition, “the sample size was clearly too low to assess clinical outcomes, and in retrospect, was also too low to evaluate follow-up MRI findings or neurocognitive outcomes.” Nevertheless, the trial “provides reassuring evidence of device safety,” said Samir R. Kapadia, MD, of the Cleveland Clinic (J Am Coll Cardiol. 2016 Nov 1. doi: 10.1016/j.jacc.2016.10.023).
In this prospective study, the investigators assessed patients at 17 medical centers in the United States and 2 in Germany. In addition to being elderly, the study patients were at high risk because of frequent comorbidities, including atrial fibrillation (31.7%) and prior stroke (5.8%).
The remaining 123 patients underwent TAVR but not MRI in a safety arm of the trial.
The protection devices were placed “without safety concerns” in most patients. The rate of major adverse events with the device was 7.3%, markedly less than the 18.3% prespecified performance goal for this outcome. Total procedure time was lengthened by only 13 minutes when the device was used, and total fluoroscopy time was increased by only 3 minutes. These findings demonstrate the overall safety of using the device, Dr. Kapadia said.
Debris including thrombus with tissue elements, artery wall particles, calcifications, valve tissue, and foreign materials was retrieved from the filters in 99% of patients.
The mean volume of new cerebral lesions in areas of the brain protected by the device was reduced by 42%, compared with that in patients who underwent TAVR without the protection device. However, this reduction was not statistically significant, so the primary efficacy endpoint of the study was not met.
Similarly, neurocognitive testing at 30 days showed that the volume of new lesions correlated with poorer outcomes. However, the difference in neurocognitive function between the intervention group and the control group did not reach statistical significance.
Several limitations likely contributed to this lack of statistical significance, Dr. Kapadia said.
First, the 5-day “window” for MRI assessment was too long. Both the number and the volume of new lesions rapidly changed over time, which led to marked variance in MRI findings depending on when the images were taken.
In addition, only one TAVR device was available at the time the trial was designed, so the study wasn’t stratified by type of valve device. But several new devices became available during the study, and the study investigators were permitted to use any of them. Both pre- and postimplantation techniques differ among these TAVR devices, but these differences could not be accounted for, given the study design.
Also, certain risk factors for stroke, especially certain findings on baseline MRI, were not understood when the trial was designed, and those factors also were not accounted for, Dr. Kapadia said.
Claret Medical funded the study. Dr. Kapadia reported having no relevant financial disclosures; his associates reported numerous ties to industry sources. The meeting was sponsored by the Cardiovascular Research Foundation.
Key clinical point: The largest randomized clinical trial to assess the safety and efficacy of cerebral embolic protection systems during TAVR yielded puzzling and contradictory results.
Major finding: Debris including thrombus with tissue elements, artery wall particles, calcifications, valve tissue, and foreign materials was retrieved from the cerebral protection filters in 99% of patients.
Data source: A prospective, international, randomized trial involving 363 elderly patients undergoing TAVR for severe aortic stenosis.
Disclosures: Claret Medical funded the study. Dr. Kapadia reported having no relevant financial disclosures; his associates reported numerous ties to industry sources.
Does Transdermal Nicotine Benefit Patients With Parkinson’s Disease?
PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.
Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease. Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative. 
The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.
The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.
Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.Adverse events occurred in more patients in the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.
—Jake Remaly
PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.
Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease. Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.
The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.
The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.
Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.Adverse events occurred in more patients in the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.
—Jake Remaly
PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.
Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease. Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.
The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.
The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.
Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.Adverse events occurred in more patients in the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.
—Jake Remaly
Hospitalizations for opioid poisoning tripled in preschool children
From 1997 to 2012, the annual number of hospitalizations for opioid poisoning rose 178% among children aged 1-19 years, according to data from over 13,000 discharge records.
In 2012, there were 2,918 hospitalizations for opioid poisoning among children aged 1-19, compared with 1,049 in 1997, reported Julie R. Gaither, PhD, MPH, RN, and her associates at Yale University in New Haven, Conn. (JAMA Pediatr. 2016 Oct 31. doi: 10.1001/jamapediatrics.2016.2154).
The greatest change occurred among the youngest children, as the number of those aged 1-4 years rose from 133 in 1997 to 421 in 2012 – an increase of 217%. For those aged 15-19 years, the annual number of hospitalizations went from 715 to 2,171 (204%) over that time period, which included a slight drop from 2009 to 2012, according to the investigators, who used data from 13,052 discharges in the Agency for Healthcare Research and Quality’s Kids’ Inpatient Database.
The increase in hospitalizations for prescription opioid poisoning in children aged 10-14 years was 58% from 1997 to 2012 (rising from 171 to 272), while estimates for 5- to 9-year-olds did not meet the criteria for statistical reliability and were not included in the analysis, Dr. Gaither and her associates said.
The study was supported by grants from the National Institute on Drug Abuse. The investigators did not report any conflicts of interest.
From 1997 to 2012, the annual number of hospitalizations for opioid poisoning rose 178% among children aged 1-19 years, according to data from over 13,000 discharge records.
In 2012, there were 2,918 hospitalizations for opioid poisoning among children aged 1-19, compared with 1,049 in 1997, reported Julie R. Gaither, PhD, MPH, RN, and her associates at Yale University in New Haven, Conn. (JAMA Pediatr. 2016 Oct 31. doi: 10.1001/jamapediatrics.2016.2154).
The greatest change occurred among the youngest children, as the number of those aged 1-4 years rose from 133 in 1997 to 421 in 2012 – an increase of 217%. For those aged 15-19 years, the annual number of hospitalizations went from 715 to 2,171 (204%) over that time period, which included a slight drop from 2009 to 2012, according to the investigators, who used data from 13,052 discharges in the Agency for Healthcare Research and Quality’s Kids’ Inpatient Database.
The increase in hospitalizations for prescription opioid poisoning in children aged 10-14 years was 58% from 1997 to 2012 (rising from 171 to 272), while estimates for 5- to 9-year-olds did not meet the criteria for statistical reliability and were not included in the analysis, Dr. Gaither and her associates said.
The study was supported by grants from the National Institute on Drug Abuse. The investigators did not report any conflicts of interest.
From 1997 to 2012, the annual number of hospitalizations for opioid poisoning rose 178% among children aged 1-19 years, according to data from over 13,000 discharge records.
In 2012, there were 2,918 hospitalizations for opioid poisoning among children aged 1-19, compared with 1,049 in 1997, reported Julie R. Gaither, PhD, MPH, RN, and her associates at Yale University in New Haven, Conn. (JAMA Pediatr. 2016 Oct 31. doi: 10.1001/jamapediatrics.2016.2154).
The greatest change occurred among the youngest children, as the number of those aged 1-4 years rose from 133 in 1997 to 421 in 2012 – an increase of 217%. For those aged 15-19 years, the annual number of hospitalizations went from 715 to 2,171 (204%) over that time period, which included a slight drop from 2009 to 2012, according to the investigators, who used data from 13,052 discharges in the Agency for Healthcare Research and Quality’s Kids’ Inpatient Database.
The increase in hospitalizations for prescription opioid poisoning in children aged 10-14 years was 58% from 1997 to 2012 (rising from 171 to 272), while estimates for 5- to 9-year-olds did not meet the criteria for statistical reliability and were not included in the analysis, Dr. Gaither and her associates said.
The study was supported by grants from the National Institute on Drug Abuse. The investigators did not report any conflicts of interest.
FROM JAMA PEDIATRICS
From 1997 to 2012, the annual number of hospitalizations for opioid poisoning rose 178% among children aged 1-19 years, according to data from over 13,000 discharge records.
ECMO patients need less sedation, pain meds than previously reported
Patients on extracorporeal membrane oxygenation (ECMO) received relatively low doses of sedatives and analgesics while at a light level of sedation in a single-center prospective study of 32 patients.
In addition, patients rarely required neuromuscular blockade, investigators reported online in the Journal of Critical Care.
This finding contrasts with current guidelines on the management of pain, agitation, and delirium in patients on ECMO. The guidelines are based upon previous research that indicated the need for significant increases in sedative and analgesic doses, as well as the need for neuromuscular blockade, wrote Jeremy R. DeGrado, PharmD, of the department of pharmacy at Brigham and Women’s Hospital, Boston, and his colleagues (J Crit Care. 2016 Aug 10;37:1-6. doi: 10.1016/j.jcrc.2016.07.020).
“Patients required significantly lower doses of opioids and sedatives than previously reported in the literature and did not demonstrate a need for increasing doses throughout the study period,” the investigators said. “Continuous infusions of opioids were utilized on most ECMO days, but continuous infusions of benzodiazepines were used on less than half of all ECMO days.”
Their 2-year, prospective, observational study assessed 32 adult intensive care unit patients on ECMO support for more than 48 hours. A total of 15 patients received VA (venoarterial) ECMO and 17 received VV (venovenous) ECMO. Patients received a median daily dose of benzodiazepines (midazolam equivalents) of 24 mg and a median daily dose of opioids (fentanyl equivalents) of 3,875 mcg.
The primary indication for VA ECMO was cardiogenic shock, while VV ECMO was mainly used as a bridge to lung transplant or in patients with severe acute respiratory distress syndrome. The researchers evaluated a total of 475 ECMO days: 110 VA ECMO and 365 VV ECMO.
On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and −1. Across all 475 ECMO days, patients were treated with continuous infusions of opioids (on 85% of ECMO days), benzodiazepines (42%), propofol (20%), dexmedetomidine (7%), and neuromuscular blocking agents (13%).
In total, patients who received VV ECMO had a higher median dose of opioids and trended toward a lower dose of benzodiazepines than those who received VA ECMO, Dr. DeGrado and his associates reported.
In total, patients in the VA arm, compared with those in the VV arm, more frequently received a continuous infusion opioid (96% vs. 82% of days) and a benzodiazepine (58% vs. 37% of days). These differences were statistically significant.
Adjunctive therapies, including antipsychotics and clonidine, were administered frequently, according to the report.
“We did not observe an increase in dose requirement over time during ECMO support, possibly due to a multi-modal pharmacologic approach. Overall, patients were not deeply sedated and rarely required neuromuscular blockade. The hypothesis that patients on ECMO require high doses of sedatives and analgesics should be further investigated,” the researchers concluded.
The authors reported that they had no disclosures.
Patients on extracorporeal membrane oxygenation (ECMO) received relatively low doses of sedatives and analgesics while at a light level of sedation in a single-center prospective study of 32 patients.
In addition, patients rarely required neuromuscular blockade, investigators reported online in the Journal of Critical Care.
This finding contrasts with current guidelines on the management of pain, agitation, and delirium in patients on ECMO. The guidelines are based upon previous research that indicated the need for significant increases in sedative and analgesic doses, as well as the need for neuromuscular blockade, wrote Jeremy R. DeGrado, PharmD, of the department of pharmacy at Brigham and Women’s Hospital, Boston, and his colleagues (J Crit Care. 2016 Aug 10;37:1-6. doi: 10.1016/j.jcrc.2016.07.020).
“Patients required significantly lower doses of opioids and sedatives than previously reported in the literature and did not demonstrate a need for increasing doses throughout the study period,” the investigators said. “Continuous infusions of opioids were utilized on most ECMO days, but continuous infusions of benzodiazepines were used on less than half of all ECMO days.”
Their 2-year, prospective, observational study assessed 32 adult intensive care unit patients on ECMO support for more than 48 hours. A total of 15 patients received VA (venoarterial) ECMO and 17 received VV (venovenous) ECMO. Patients received a median daily dose of benzodiazepines (midazolam equivalents) of 24 mg and a median daily dose of opioids (fentanyl equivalents) of 3,875 mcg.
The primary indication for VA ECMO was cardiogenic shock, while VV ECMO was mainly used as a bridge to lung transplant or in patients with severe acute respiratory distress syndrome. The researchers evaluated a total of 475 ECMO days: 110 VA ECMO and 365 VV ECMO.
On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and −1. Across all 475 ECMO days, patients were treated with continuous infusions of opioids (on 85% of ECMO days), benzodiazepines (42%), propofol (20%), dexmedetomidine (7%), and neuromuscular blocking agents (13%).
In total, patients who received VV ECMO had a higher median dose of opioids and trended toward a lower dose of benzodiazepines than those who received VA ECMO, Dr. DeGrado and his associates reported.
In total, patients in the VA arm, compared with those in the VV arm, more frequently received a continuous infusion opioid (96% vs. 82% of days) and a benzodiazepine (58% vs. 37% of days). These differences were statistically significant.
Adjunctive therapies, including antipsychotics and clonidine, were administered frequently, according to the report.
“We did not observe an increase in dose requirement over time during ECMO support, possibly due to a multi-modal pharmacologic approach. Overall, patients were not deeply sedated and rarely required neuromuscular blockade. The hypothesis that patients on ECMO require high doses of sedatives and analgesics should be further investigated,” the researchers concluded.
The authors reported that they had no disclosures.
Patients on extracorporeal membrane oxygenation (ECMO) received relatively low doses of sedatives and analgesics while at a light level of sedation in a single-center prospective study of 32 patients.
In addition, patients rarely required neuromuscular blockade, investigators reported online in the Journal of Critical Care.
This finding contrasts with current guidelines on the management of pain, agitation, and delirium in patients on ECMO. The guidelines are based upon previous research that indicated the need for significant increases in sedative and analgesic doses, as well as the need for neuromuscular blockade, wrote Jeremy R. DeGrado, PharmD, of the department of pharmacy at Brigham and Women’s Hospital, Boston, and his colleagues (J Crit Care. 2016 Aug 10;37:1-6. doi: 10.1016/j.jcrc.2016.07.020).
“Patients required significantly lower doses of opioids and sedatives than previously reported in the literature and did not demonstrate a need for increasing doses throughout the study period,” the investigators said. “Continuous infusions of opioids were utilized on most ECMO days, but continuous infusions of benzodiazepines were used on less than half of all ECMO days.”
Their 2-year, prospective, observational study assessed 32 adult intensive care unit patients on ECMO support for more than 48 hours. A total of 15 patients received VA (venoarterial) ECMO and 17 received VV (venovenous) ECMO. Patients received a median daily dose of benzodiazepines (midazolam equivalents) of 24 mg and a median daily dose of opioids (fentanyl equivalents) of 3,875 mcg.
The primary indication for VA ECMO was cardiogenic shock, while VV ECMO was mainly used as a bridge to lung transplant or in patients with severe acute respiratory distress syndrome. The researchers evaluated a total of 475 ECMO days: 110 VA ECMO and 365 VV ECMO.
On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and −1. Across all 475 ECMO days, patients were treated with continuous infusions of opioids (on 85% of ECMO days), benzodiazepines (42%), propofol (20%), dexmedetomidine (7%), and neuromuscular blocking agents (13%).
In total, patients who received VV ECMO had a higher median dose of opioids and trended toward a lower dose of benzodiazepines than those who received VA ECMO, Dr. DeGrado and his associates reported.
In total, patients in the VA arm, compared with those in the VV arm, more frequently received a continuous infusion opioid (96% vs. 82% of days) and a benzodiazepine (58% vs. 37% of days). These differences were statistically significant.
Adjunctive therapies, including antipsychotics and clonidine, were administered frequently, according to the report.
“We did not observe an increase in dose requirement over time during ECMO support, possibly due to a multi-modal pharmacologic approach. Overall, patients were not deeply sedated and rarely required neuromuscular blockade. The hypothesis that patients on ECMO require high doses of sedatives and analgesics should be further investigated,” the researchers concluded.
The authors reported that they had no disclosures.
FROM JOURNAL OF CRITICAL CARE
Key clinical point:
Major finding: Patients required lower doses of opioids and sedatives than previously reported and did not need increasing doses.
Data source: A single-institution, prospective study of 32 patients on extracorporeal membrane oxygenation.
Disclosures: Dr. DeGrado reported having no financial disclosures.
NRS awards grants for rosacea studies
The National Rosacea Society (NRS) is awarding funding to three new studies and continuing funding for two ongoing studies on topics that include the impact of epigenetics on rosacea, the society announced.
The first study, by Dr. Luis Garza at John Hopkins University, Baltimore, will examine epigenetic lesions in rosacea. Epigenetics, the study of how DNA can be modified to act in certain ways, “may be responsible for why rosacea persists even though keratinocytes … slough off and are replaced every 2 months,” the NRS said in a written statement.
The second study, by Dr. Wenqing Li of Brown University, Providence, R.I., will use data from the Nurses’ Health Study II to examine how hormone use and hormone levels during menopause and pregnancy affect the risk of developing rosacea.
The third study, by Dr. Anna Di Nardo of the University of California, San Diego, and her associates, is looking at “whether the release of cathelicidin antimicrobial peptides, key players in the body’s normal innate immune system response, is central to the connection between the nervous system and skin inflammation through the activation of mast cells in rosacea,” the NRS statement noted.
Ongoing studies that also are receiving funding include work by Dr. Gideon Smith of Massachusetts General Hospital, Boston, and his associates, who are examining the risk of vascular disorders in people with rosacea, and a study by Dr. Lori Lee Stohl of Cornell University, New York, who is researching how stress-related biochemicals can increase mast-cell count.
“Research supported by the NRS has led to important insights into the physiology of the disorder, providing an essential foundation for developing new and better treatments. In addition, our growing knowledge is now pointing toward potentially meaningful connections between rosacea and other systemic illnesses,” Dr. Martin Steinhoff, chairman of dermatology and director of the Charles Institute of Dermatology, University College, Dublin, and a member of the NRS Medical Advisory Board, said in the statement.
Find the full NRS statement on the society’s website.
The National Rosacea Society (NRS) is awarding funding to three new studies and continuing funding for two ongoing studies on topics that include the impact of epigenetics on rosacea, the society announced.
The first study, by Dr. Luis Garza at John Hopkins University, Baltimore, will examine epigenetic lesions in rosacea. Epigenetics, the study of how DNA can be modified to act in certain ways, “may be responsible for why rosacea persists even though keratinocytes … slough off and are replaced every 2 months,” the NRS said in a written statement.
The second study, by Dr. Wenqing Li of Brown University, Providence, R.I., will use data from the Nurses’ Health Study II to examine how hormone use and hormone levels during menopause and pregnancy affect the risk of developing rosacea.
The third study, by Dr. Anna Di Nardo of the University of California, San Diego, and her associates, is looking at “whether the release of cathelicidin antimicrobial peptides, key players in the body’s normal innate immune system response, is central to the connection between the nervous system and skin inflammation through the activation of mast cells in rosacea,” the NRS statement noted.
Ongoing studies that also are receiving funding include work by Dr. Gideon Smith of Massachusetts General Hospital, Boston, and his associates, who are examining the risk of vascular disorders in people with rosacea, and a study by Dr. Lori Lee Stohl of Cornell University, New York, who is researching how stress-related biochemicals can increase mast-cell count.
“Research supported by the NRS has led to important insights into the physiology of the disorder, providing an essential foundation for developing new and better treatments. In addition, our growing knowledge is now pointing toward potentially meaningful connections between rosacea and other systemic illnesses,” Dr. Martin Steinhoff, chairman of dermatology and director of the Charles Institute of Dermatology, University College, Dublin, and a member of the NRS Medical Advisory Board, said in the statement.
Find the full NRS statement on the society’s website.
The National Rosacea Society (NRS) is awarding funding to three new studies and continuing funding for two ongoing studies on topics that include the impact of epigenetics on rosacea, the society announced.
The first study, by Dr. Luis Garza at John Hopkins University, Baltimore, will examine epigenetic lesions in rosacea. Epigenetics, the study of how DNA can be modified to act in certain ways, “may be responsible for why rosacea persists even though keratinocytes … slough off and are replaced every 2 months,” the NRS said in a written statement.
The second study, by Dr. Wenqing Li of Brown University, Providence, R.I., will use data from the Nurses’ Health Study II to examine how hormone use and hormone levels during menopause and pregnancy affect the risk of developing rosacea.
The third study, by Dr. Anna Di Nardo of the University of California, San Diego, and her associates, is looking at “whether the release of cathelicidin antimicrobial peptides, key players in the body’s normal innate immune system response, is central to the connection between the nervous system and skin inflammation through the activation of mast cells in rosacea,” the NRS statement noted.
Ongoing studies that also are receiving funding include work by Dr. Gideon Smith of Massachusetts General Hospital, Boston, and his associates, who are examining the risk of vascular disorders in people with rosacea, and a study by Dr. Lori Lee Stohl of Cornell University, New York, who is researching how stress-related biochemicals can increase mast-cell count.
“Research supported by the NRS has led to important insights into the physiology of the disorder, providing an essential foundation for developing new and better treatments. In addition, our growing knowledge is now pointing toward potentially meaningful connections between rosacea and other systemic illnesses,” Dr. Martin Steinhoff, chairman of dermatology and director of the Charles Institute of Dermatology, University College, Dublin, and a member of the NRS Medical Advisory Board, said in the statement.
Find the full NRS statement on the society’s website.
Blood pressure changes and persistent hypertension elevate dementia risk
BALTIMORE – The impact of blood pressure on the risk of dementia in late life follows a U-shaped curve in which elevated mid-life and late-life blood pressure, as well as late-life decline in blood pressure, all independently raise the risk of dementia, according to findings from a longitudinal study of the Framingham Offspring cohort of the Framingham Heart Study.
The findings highlight the benefits of establishing and maintaining lower blood pressure in midlife in preventing or lowering the risk of dementia, Emer McGrath, MD, said at the annual meeting of the American Neurological Association.
The researchers explored the issue using data from the Framingham Offspring cohort of the Framingham Heart Study. The cohort comprises 5,124 children, and spouses of children, of the original Framingham cohort. They have been examined clinically at regular intervals since 1971. The present study focused on 1,440 individuals who had five consecutive examinations during a 15-year period anytime between 1983 and 2001 and who had not been diagnosed with dementia at the time of the final blood pressure determination.
The 1,440 participants had a mean age of 69 years at their fifth examination. Just over half were female, 20% had been diagnosed with cardiovascular disease, and slightly less than 20% had been diagnosed with diabetes. Half were using antihypertensive medications.
During a mean 8-year follow-up period, 107 individuals developed dementia. Dementia was independently associated with midlife hypertension (140/90 mm Hg or higher), with a stronger association for systolic hypertension (hazard ratio, 1.57; 95% confidence interval, 1.05-2.35). Persistence of hypertension into late life, particularly systolic hypertension (HR, 1.96; 95% CI, 1.25-3.09), was another independent risk factor for dementia.
Among individuals who did not have hypertension at midlife, a decline in systolic blood pressure to less than 100/70 mm Hg in the ensuing years increased the risk of dementia (HR, 1.63; 95% CI, 1.08-2.46).
According to the researchers, the findings support the hypothesis of the U-shaped relationship between blood pressure and dementia. “Our data also highlight the potential sustained cognitive benefits of lower midlife blood pressure,” Dr. McGrath said.
The study was funded by the Framingham Heart Study, the National Institute on Aging, and the National Institute for Neurological Diseases and Stroke. Dr. McGrath had no disclosures.
BALTIMORE – The impact of blood pressure on the risk of dementia in late life follows a U-shaped curve in which elevated mid-life and late-life blood pressure, as well as late-life decline in blood pressure, all independently raise the risk of dementia, according to findings from a longitudinal study of the Framingham Offspring cohort of the Framingham Heart Study.
The findings highlight the benefits of establishing and maintaining lower blood pressure in midlife in preventing or lowering the risk of dementia, Emer McGrath, MD, said at the annual meeting of the American Neurological Association.
The researchers explored the issue using data from the Framingham Offspring cohort of the Framingham Heart Study. The cohort comprises 5,124 children, and spouses of children, of the original Framingham cohort. They have been examined clinically at regular intervals since 1971. The present study focused on 1,440 individuals who had five consecutive examinations during a 15-year period anytime between 1983 and 2001 and who had not been diagnosed with dementia at the time of the final blood pressure determination.
The 1,440 participants had a mean age of 69 years at their fifth examination. Just over half were female, 20% had been diagnosed with cardiovascular disease, and slightly less than 20% had been diagnosed with diabetes. Half were using antihypertensive medications.
During a mean 8-year follow-up period, 107 individuals developed dementia. Dementia was independently associated with midlife hypertension (140/90 mm Hg or higher), with a stronger association for systolic hypertension (hazard ratio, 1.57; 95% confidence interval, 1.05-2.35). Persistence of hypertension into late life, particularly systolic hypertension (HR, 1.96; 95% CI, 1.25-3.09), was another independent risk factor for dementia.
Among individuals who did not have hypertension at midlife, a decline in systolic blood pressure to less than 100/70 mm Hg in the ensuing years increased the risk of dementia (HR, 1.63; 95% CI, 1.08-2.46).
According to the researchers, the findings support the hypothesis of the U-shaped relationship between blood pressure and dementia. “Our data also highlight the potential sustained cognitive benefits of lower midlife blood pressure,” Dr. McGrath said.
The study was funded by the Framingham Heart Study, the National Institute on Aging, and the National Institute for Neurological Diseases and Stroke. Dr. McGrath had no disclosures.
BALTIMORE – The impact of blood pressure on the risk of dementia in late life follows a U-shaped curve in which elevated mid-life and late-life blood pressure, as well as late-life decline in blood pressure, all independently raise the risk of dementia, according to findings from a longitudinal study of the Framingham Offspring cohort of the Framingham Heart Study.
The findings highlight the benefits of establishing and maintaining lower blood pressure in midlife in preventing or lowering the risk of dementia, Emer McGrath, MD, said at the annual meeting of the American Neurological Association.
The researchers explored the issue using data from the Framingham Offspring cohort of the Framingham Heart Study. The cohort comprises 5,124 children, and spouses of children, of the original Framingham cohort. They have been examined clinically at regular intervals since 1971. The present study focused on 1,440 individuals who had five consecutive examinations during a 15-year period anytime between 1983 and 2001 and who had not been diagnosed with dementia at the time of the final blood pressure determination.
The 1,440 participants had a mean age of 69 years at their fifth examination. Just over half were female, 20% had been diagnosed with cardiovascular disease, and slightly less than 20% had been diagnosed with diabetes. Half were using antihypertensive medications.
During a mean 8-year follow-up period, 107 individuals developed dementia. Dementia was independently associated with midlife hypertension (140/90 mm Hg or higher), with a stronger association for systolic hypertension (hazard ratio, 1.57; 95% confidence interval, 1.05-2.35). Persistence of hypertension into late life, particularly systolic hypertension (HR, 1.96; 95% CI, 1.25-3.09), was another independent risk factor for dementia.
Among individuals who did not have hypertension at midlife, a decline in systolic blood pressure to less than 100/70 mm Hg in the ensuing years increased the risk of dementia (HR, 1.63; 95% CI, 1.08-2.46).
According to the researchers, the findings support the hypothesis of the U-shaped relationship between blood pressure and dementia. “Our data also highlight the potential sustained cognitive benefits of lower midlife blood pressure,” Dr. McGrath said.
The study was funded by the Framingham Heart Study, the National Institute on Aging, and the National Institute for Neurological Diseases and Stroke. Dr. McGrath had no disclosures.
AT ANA 2016
Key clinical point:
Major finding: Persistence of hypertension into late life, particularly systolic hypertension (HR, 1.96; 95% CI, 1.25-3.09), was another independent risk factor for dementia.
Data source: Offspring cohort of the Framingham Heart Study.
Disclosures: The study was funded by the Framingham Heart Study, the National Institute on Aging, and the National Institute for Neurological Diseases and Stroke. Dr. McGrath had no disclosures.
Pediatric Dermatology Consult - November 2016
BY JUSLEEN AHLUWALIA, MD, AND LAWRENCE F. EICHENFIELD, MD
The presence of an initial tense bulla on the vertex scalp suggests a diagnosis of aplasia cutis congenita. Given the palpable quality of the lesion, magnetic resonance imaging and angiogram (MRI/MRA) of the head with gadolinium enhancement was performed, revealing a 1.5-cm mass underlying the scalp defect, without calvarial deformations. The mass was excised with advancement flap closure. Histologic evaluation of the excised specimen revealed polypoid tissue with unremarkable epidermis and hypocellular dermis with loose connective tissue, lacking adnexal structures. Neural and glial tissue were not identified.
Aplasia cutis congenita (ACC) is a term used to describe congenital absence or defects of the skin.
According to its developmental stage in utero, scalp ACC may present at birth as a deep ulceration, superficial erosion, or a healed, alopecic scar.2 Rarely, some defects may have a cystic or bullous component that may transform into a smooth, atrophic scar with an overlying translucent membrane. This clinical subtype has been described as the “bullous” or “membranous” variant, depending on the stage of bulla maturation.4-8 Our patient displays features demonstrative of the membranous variant. Most commonly, membranous aplasia cutis is an isolated defect and, if there is no palpable component, does not require imaging.2 These usually heal spontaneously, including those with small bone defects. Larger lesions of AC (greater than 3 cm) with large bone defects require urgent imaging.2 Papules or nodules around aplasia cutis may be associated with more significant neural tube anomalies, including congenital ectopic meningeal tissue, also termed atretic or rudimentary meningoceles.7 These may be associated with defects of the skull or tracts with intracranial connections.7 Hair collars, a collarette of coarser hair surrounding bullous or membranous variant of AC, may be indicative of defective neural tube closure.4-8 MRI of the head is recommended in cases of bullous or membranous scalp ACC with a palpable nodule to evaluate for intracranial connection and ectopic neural tissue, as performed in our patient.2 Because imaging of our patient was concerning for ectopic neural tissue within the defect, excision was recommended with histologic examination for neural or glial tissue.
Small scalp ACC lesions can heal by secondary intention with supportive wound care, whereas larger defects may require bone or skin grafting.2 Cautious monitoring of the defect will help prevent the serious sequelae rarely associated with large scalp ACC, including hemorrhage, infection, sagittal sinus thrombosis, and hydrocephalus.2 Generally, most defects heal well within months and the resultant scars become relatively unnoticeable. Those that are apparent can be surgically reconstructed.2
Although most infants with ACC are otherwise healthy, several anomalies have been noted to be associated with the presence of ACC, and thus a multisystem evaluation is recommended during the initial visit. These anomalies include limb abnormalities, epidermal nevi, epidermolysis bullosa, chromosomal abnormalities, such as trisomy 13, ectodermal dysplasias, or other malformation syndromes, including Adams-Oliver syndrome.2,8 Around 30 years ago, Frieden et al. stratified ACC into nine different groups based on the location and presence of these associations.9
Differentiation of scalp ACC from other conditions may be necessary. HSV usually appears as grouped vesicles that can evolve to appear punched out.2 Iatrogenic trauma can produce erosions at the site of scalp electrode placement or forceps use, but is less likely to occur over the vertex scalp.2 Congenital triangular alopecia usually presents as an alopecic, lancet-shaped pattern on the frontal temporal scalp without evidence of scarring. Nevus sebaceous characteristically presents as a solitary yellow-orange, mammilated plaque, but may mimic an erosion given its slightly pink appearance in the neonate.2
References
1. Developmental abnormalities, in “Neonatal and infant dermatology,” 3rd ed. (Philadelphia: Saunders, 2015).
2. Dermatol Ther. 2013 Nov-Dec;26(6):439-44.
3. Br J Plast Surg. 2002 Sep;55(6):530-2.
4. J Am Acad Dermatol. 2003 May;48(5 Suppl):S95-8.
5. J Ultrasound Med. 2009 Oct;28(10):1393-6.
6. Arch Dermatol. 1995 Dec;131(12):1427-31.
7. Pediatr Dermatol. 2015 Mar-Apr;32(2):161-70.
8. Indian J Dermatol. 2011 May;56(3):337-8.
9. J Am Acad Dermatol. 1986 Apr;14(4):646-60.
Dr. Ahluwalia is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego. Dr. Eichenfield is in the departments of dermatology and pediatrics, University of California, San Diego.
BY JUSLEEN AHLUWALIA, MD, AND LAWRENCE F. EICHENFIELD, MD
The presence of an initial tense bulla on the vertex scalp suggests a diagnosis of aplasia cutis congenita. Given the palpable quality of the lesion, magnetic resonance imaging and angiogram (MRI/MRA) of the head with gadolinium enhancement was performed, revealing a 1.5-cm mass underlying the scalp defect, without calvarial deformations. The mass was excised with advancement flap closure. Histologic evaluation of the excised specimen revealed polypoid tissue with unremarkable epidermis and hypocellular dermis with loose connective tissue, lacking adnexal structures. Neural and glial tissue were not identified.
Aplasia cutis congenita (ACC) is a term used to describe congenital absence or defects of the skin.
According to its developmental stage in utero, scalp ACC may present at birth as a deep ulceration, superficial erosion, or a healed, alopecic scar.2 Rarely, some defects may have a cystic or bullous component that may transform into a smooth, atrophic scar with an overlying translucent membrane. This clinical subtype has been described as the “bullous” or “membranous” variant, depending on the stage of bulla maturation.4-8 Our patient displays features demonstrative of the membranous variant. Most commonly, membranous aplasia cutis is an isolated defect and, if there is no palpable component, does not require imaging.2 These usually heal spontaneously, including those with small bone defects. Larger lesions of AC (greater than 3 cm) with large bone defects require urgent imaging.2 Papules or nodules around aplasia cutis may be associated with more significant neural tube anomalies, including congenital ectopic meningeal tissue, also termed atretic or rudimentary meningoceles.7 These may be associated with defects of the skull or tracts with intracranial connections.7 Hair collars, a collarette of coarser hair surrounding bullous or membranous variant of AC, may be indicative of defective neural tube closure.4-8 MRI of the head is recommended in cases of bullous or membranous scalp ACC with a palpable nodule to evaluate for intracranial connection and ectopic neural tissue, as performed in our patient.2 Because imaging of our patient was concerning for ectopic neural tissue within the defect, excision was recommended with histologic examination for neural or glial tissue.
Small scalp ACC lesions can heal by secondary intention with supportive wound care, whereas larger defects may require bone or skin grafting.2 Cautious monitoring of the defect will help prevent the serious sequelae rarely associated with large scalp ACC, including hemorrhage, infection, sagittal sinus thrombosis, and hydrocephalus.2 Generally, most defects heal well within months and the resultant scars become relatively unnoticeable. Those that are apparent can be surgically reconstructed.2
Although most infants with ACC are otherwise healthy, several anomalies have been noted to be associated with the presence of ACC, and thus a multisystem evaluation is recommended during the initial visit. These anomalies include limb abnormalities, epidermal nevi, epidermolysis bullosa, chromosomal abnormalities, such as trisomy 13, ectodermal dysplasias, or other malformation syndromes, including Adams-Oliver syndrome.2,8 Around 30 years ago, Frieden et al. stratified ACC into nine different groups based on the location and presence of these associations.9
Differentiation of scalp ACC from other conditions may be necessary. HSV usually appears as grouped vesicles that can evolve to appear punched out.2 Iatrogenic trauma can produce erosions at the site of scalp electrode placement or forceps use, but is less likely to occur over the vertex scalp.2 Congenital triangular alopecia usually presents as an alopecic, lancet-shaped pattern on the frontal temporal scalp without evidence of scarring. Nevus sebaceous characteristically presents as a solitary yellow-orange, mammilated plaque, but may mimic an erosion given its slightly pink appearance in the neonate.2
References
1. Developmental abnormalities, in “Neonatal and infant dermatology,” 3rd ed. (Philadelphia: Saunders, 2015).
2. Dermatol Ther. 2013 Nov-Dec;26(6):439-44.
3. Br J Plast Surg. 2002 Sep;55(6):530-2.
4. J Am Acad Dermatol. 2003 May;48(5 Suppl):S95-8.
5. J Ultrasound Med. 2009 Oct;28(10):1393-6.
6. Arch Dermatol. 1995 Dec;131(12):1427-31.
7. Pediatr Dermatol. 2015 Mar-Apr;32(2):161-70.
8. Indian J Dermatol. 2011 May;56(3):337-8.
9. J Am Acad Dermatol. 1986 Apr;14(4):646-60.
Dr. Ahluwalia is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego. Dr. Eichenfield is in the departments of dermatology and pediatrics, University of California, San Diego.
BY JUSLEEN AHLUWALIA, MD, AND LAWRENCE F. EICHENFIELD, MD
The presence of an initial tense bulla on the vertex scalp suggests a diagnosis of aplasia cutis congenita. Given the palpable quality of the lesion, magnetic resonance imaging and angiogram (MRI/MRA) of the head with gadolinium enhancement was performed, revealing a 1.5-cm mass underlying the scalp defect, without calvarial deformations. The mass was excised with advancement flap closure. Histologic evaluation of the excised specimen revealed polypoid tissue with unremarkable epidermis and hypocellular dermis with loose connective tissue, lacking adnexal structures. Neural and glial tissue were not identified.
Aplasia cutis congenita (ACC) is a term used to describe congenital absence or defects of the skin.
According to its developmental stage in utero, scalp ACC may present at birth as a deep ulceration, superficial erosion, or a healed, alopecic scar.2 Rarely, some defects may have a cystic or bullous component that may transform into a smooth, atrophic scar with an overlying translucent membrane. This clinical subtype has been described as the “bullous” or “membranous” variant, depending on the stage of bulla maturation.4-8 Our patient displays features demonstrative of the membranous variant. Most commonly, membranous aplasia cutis is an isolated defect and, if there is no palpable component, does not require imaging.2 These usually heal spontaneously, including those with small bone defects. Larger lesions of AC (greater than 3 cm) with large bone defects require urgent imaging.2 Papules or nodules around aplasia cutis may be associated with more significant neural tube anomalies, including congenital ectopic meningeal tissue, also termed atretic or rudimentary meningoceles.7 These may be associated with defects of the skull or tracts with intracranial connections.7 Hair collars, a collarette of coarser hair surrounding bullous or membranous variant of AC, may be indicative of defective neural tube closure.4-8 MRI of the head is recommended in cases of bullous or membranous scalp ACC with a palpable nodule to evaluate for intracranial connection and ectopic neural tissue, as performed in our patient.2 Because imaging of our patient was concerning for ectopic neural tissue within the defect, excision was recommended with histologic examination for neural or glial tissue.
Small scalp ACC lesions can heal by secondary intention with supportive wound care, whereas larger defects may require bone or skin grafting.2 Cautious monitoring of the defect will help prevent the serious sequelae rarely associated with large scalp ACC, including hemorrhage, infection, sagittal sinus thrombosis, and hydrocephalus.2 Generally, most defects heal well within months and the resultant scars become relatively unnoticeable. Those that are apparent can be surgically reconstructed.2
Although most infants with ACC are otherwise healthy, several anomalies have been noted to be associated with the presence of ACC, and thus a multisystem evaluation is recommended during the initial visit. These anomalies include limb abnormalities, epidermal nevi, epidermolysis bullosa, chromosomal abnormalities, such as trisomy 13, ectodermal dysplasias, or other malformation syndromes, including Adams-Oliver syndrome.2,8 Around 30 years ago, Frieden et al. stratified ACC into nine different groups based on the location and presence of these associations.9
Differentiation of scalp ACC from other conditions may be necessary. HSV usually appears as grouped vesicles that can evolve to appear punched out.2 Iatrogenic trauma can produce erosions at the site of scalp electrode placement or forceps use, but is less likely to occur over the vertex scalp.2 Congenital triangular alopecia usually presents as an alopecic, lancet-shaped pattern on the frontal temporal scalp without evidence of scarring. Nevus sebaceous characteristically presents as a solitary yellow-orange, mammilated plaque, but may mimic an erosion given its slightly pink appearance in the neonate.2
References
1. Developmental abnormalities, in “Neonatal and infant dermatology,” 3rd ed. (Philadelphia: Saunders, 2015).
2. Dermatol Ther. 2013 Nov-Dec;26(6):439-44.
3. Br J Plast Surg. 2002 Sep;55(6):530-2.
4. J Am Acad Dermatol. 2003 May;48(5 Suppl):S95-8.
5. J Ultrasound Med. 2009 Oct;28(10):1393-6.
6. Arch Dermatol. 1995 Dec;131(12):1427-31.
7. Pediatr Dermatol. 2015 Mar-Apr;32(2):161-70.
8. Indian J Dermatol. 2011 May;56(3):337-8.
9. J Am Acad Dermatol. 1986 Apr;14(4):646-60.
Dr. Ahluwalia is with the division of pediatric and adolescent dermatology, Rady Children’s Hospital, San Diego. Dr. Eichenfield is in the departments of dermatology and pediatrics, University of California, San Diego.
A 9-month-old previously healthy female, born at term, presents to the dermatology clinic for evaluation of a bluish nodule on the posterior vertex of the scalp (Figure 1). Initially at birth, the area was described as a hairless, tense blister that flattened over several weeks. The hairless nodule has persisted without symptoms. The family denies any history of trauma, including the use of forceps or scalp electrodes during labor. Family history was noncontributory. Review of systems was otherwise negative.
On examination, the patient is a well-developed, active female with a 2-cm, bluish nodule with an overlying atrophic, glistening membrane on the posterior parietal scalp, lateral to the midline. The lesion is surrounded by a ring of subtly coarse, terminal hair. There is no evidence of bleeding or ulceration, and no scalp defects were palpable. The lesion was unchanged with crying. The remainder of the physical examination was normal.
The 50-year quest for better pregnancy data
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).
The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.