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Domperidone appears safe galactagogue for mothers and infants
Denver – Prescribing domperidone to support breastfeeding effectively reduced the use of infant formula without significant adverse effects in mothers and infants in a large retrospective study, Mitko Madjunkov, MD, reported at the annual meeting of the Teratology Society.
His study included 985 mothers who began taking domperidone to initiate and support breastfeeding after a visit to the International Breastfeeding Centre in Toronto. Collectively, the women had 1,005 infants.
The study was undertaken because few data exist on the dosing and safety of domperidone during lactation. Additionally, the Food and Drug Administration issued a warning in 2004 regarding the use of domperidone as a galactagogue in response to reports of cardiac arrhythmias and sudden deaths when the drug was prescribed as an antiemetic, explained Dr. Madjunkov of the Hospital for Sick Children in Toronto.
The FDA has not approved domperidone for any indication in the United States, though it is available in Canada and other countries.
Domperidone was used by the Toronto women for a median of 20 days. The maximum daily dose was 107 mg. The infants were an average of 38 days old at the time of the visit when domperidone was prescribed and 72 days of age at their last follow-up visit related to the study.
The drug was effective as a galactagogue: 63% of women were using infant formula before going on domperidone; after using the drug, 41% were still using formula, for an absolute 22% reduction. The drug was similarly effective in promoting breastfeeding in infants with or without tongue-tie/lip-tie defects.
In total, 18% of mothers reported minor side effects. Headaches were the most common, reported by 9.2% of domperidone users. Dose reduction was employed in just 0.6% of women in the study; 0.4% of participants discontinued treatment. Rapid heart rate and other minor cardiac side effects were reported by 0.7% of women, uniformly in conjunction with trigger factors such as anxiety or caffeine use, but none of these women discontinued treatment. No treatment-associated adverse effects occurred in the infants.
Dr. Madjunkov reported having no financial conflicts related to his study.
Denver – Prescribing domperidone to support breastfeeding effectively reduced the use of infant formula without significant adverse effects in mothers and infants in a large retrospective study, Mitko Madjunkov, MD, reported at the annual meeting of the Teratology Society.
His study included 985 mothers who began taking domperidone to initiate and support breastfeeding after a visit to the International Breastfeeding Centre in Toronto. Collectively, the women had 1,005 infants.
The study was undertaken because few data exist on the dosing and safety of domperidone during lactation. Additionally, the Food and Drug Administration issued a warning in 2004 regarding the use of domperidone as a galactagogue in response to reports of cardiac arrhythmias and sudden deaths when the drug was prescribed as an antiemetic, explained Dr. Madjunkov of the Hospital for Sick Children in Toronto.
The FDA has not approved domperidone for any indication in the United States, though it is available in Canada and other countries.
Domperidone was used by the Toronto women for a median of 20 days. The maximum daily dose was 107 mg. The infants were an average of 38 days old at the time of the visit when domperidone was prescribed and 72 days of age at their last follow-up visit related to the study.
The drug was effective as a galactagogue: 63% of women were using infant formula before going on domperidone; after using the drug, 41% were still using formula, for an absolute 22% reduction. The drug was similarly effective in promoting breastfeeding in infants with or without tongue-tie/lip-tie defects.
In total, 18% of mothers reported minor side effects. Headaches were the most common, reported by 9.2% of domperidone users. Dose reduction was employed in just 0.6% of women in the study; 0.4% of participants discontinued treatment. Rapid heart rate and other minor cardiac side effects were reported by 0.7% of women, uniformly in conjunction with trigger factors such as anxiety or caffeine use, but none of these women discontinued treatment. No treatment-associated adverse effects occurred in the infants.
Dr. Madjunkov reported having no financial conflicts related to his study.
Denver – Prescribing domperidone to support breastfeeding effectively reduced the use of infant formula without significant adverse effects in mothers and infants in a large retrospective study, Mitko Madjunkov, MD, reported at the annual meeting of the Teratology Society.
His study included 985 mothers who began taking domperidone to initiate and support breastfeeding after a visit to the International Breastfeeding Centre in Toronto. Collectively, the women had 1,005 infants.
The study was undertaken because few data exist on the dosing and safety of domperidone during lactation. Additionally, the Food and Drug Administration issued a warning in 2004 regarding the use of domperidone as a galactagogue in response to reports of cardiac arrhythmias and sudden deaths when the drug was prescribed as an antiemetic, explained Dr. Madjunkov of the Hospital for Sick Children in Toronto.
The FDA has not approved domperidone for any indication in the United States, though it is available in Canada and other countries.
Domperidone was used by the Toronto women for a median of 20 days. The maximum daily dose was 107 mg. The infants were an average of 38 days old at the time of the visit when domperidone was prescribed and 72 days of age at their last follow-up visit related to the study.
The drug was effective as a galactagogue: 63% of women were using infant formula before going on domperidone; after using the drug, 41% were still using formula, for an absolute 22% reduction. The drug was similarly effective in promoting breastfeeding in infants with or without tongue-tie/lip-tie defects.
In total, 18% of mothers reported minor side effects. Headaches were the most common, reported by 9.2% of domperidone users. Dose reduction was employed in just 0.6% of women in the study; 0.4% of participants discontinued treatment. Rapid heart rate and other minor cardiac side effects were reported by 0.7% of women, uniformly in conjunction with trigger factors such as anxiety or caffeine use, but none of these women discontinued treatment. No treatment-associated adverse effects occurred in the infants.
Dr. Madjunkov reported having no financial conflicts related to his study.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Key clinical point:
Major finding: The use of the domperidone reduced the proportion of women using infant formula by an absolute 22%.
Data source: A retrospective study of 985 women who were prescribed domperidone as a galactagogue at the International Breastfeeding Centre in Toronto.
Disclosures: Dr. Madjunkov reported having no financial conflicts of interest related to the study.
Lessons on using cannabinoids for pediatric epilepsy
DENVER – holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.
Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.
The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).
Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.
“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”
Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
- Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
- Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
- Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
- Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
- Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.
Breaking down the evidence
Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.
The knowns
Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).
The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.
In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
The unknowns
What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.
What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.
What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.
What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
Long-term effects
The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.
Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
DENVER – holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.
Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.
The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).
Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.
“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”
Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
- Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
- Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
- Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
- Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
- Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.
Breaking down the evidence
Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.
The knowns
Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).
The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.
In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
The unknowns
What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.
What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.
What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.
What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
Long-term effects
The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.
Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
DENVER – holds useful lessons for physicians in states where legal marijuana is a far more recent development, Amy R. Brooks-Kayal, MD, said at the annual meeting of the Teratology Society.
Medical marijuana has been legal in Colorado for nearly 20 years. But the drug’s potential role in treating intractable pediatric epilepsy started getting a lot more attention in 2013 when a CNN report by Sanjay Gupta, MD, chronicled a child’s remarkable turnaround in response to medical marijuana. The story triggered a migration to the state by what has been termed “marijuana refugees”: desperate families with children who had the most severe, complex, treatment-refractory seizure disorders, said Dr. Brooks-Kayal, professor of pediatrics and neurology and chief of pediatric neurology at the University of Colorado at Denver, Aurora.
The situation, fortunately, has improved. There is now phase 3 randomized, double-blind, placebo-controlled clinical trial evidence of efficacy for an investigational proprietary cannabidiol oral solution known as Epidiolex for children and young adults with Dravet syndrome and drug-resistant seizures, as well as documentation of multiple adverse effects (N Engl J Med. 2017 May 25;376[21]:2011-20).
Dr. Brooks-Kayal, a past president of the American Epilepsy Society, said she believes this medication is potentially approvable by the Food and Drug Administration.
“In the world of new seizure medications, what is usually required by the FDA is a 50% reduction in seizures, which this agent gets close to reaching. But it does have a higher adverse event rate than many of our medications. However, this is a tough crowd. These are very, very difficult-to-treat children. So I think any addition to our armamentarium for these kids is going to be beneficial,” she said. “Unfortunately, though, it’s not going to be the panacea that I think some of our families are looking for.”
Based upon the Colorado experience, Dr. Brooks-Kayal offered the following suggestions for colleagues around the country as they begin fielding questions from families about medical marijuana for pediatric epilepsy:
- Provide families with the current data, discuss what’s known and still unknown, and encourage families to disclose the use of cannabinoids so the child can be monitored.
- Have the family keep a seizure diary. Get a baseline EEG and another at about 12 weeks. Do routine laboratory monitoring every 4 weeks, including liver function tests. “We think CBDs [cannabinoids] have the potential to worsen liver function,” she said.
- Stress the importance of leaving other seizure medications unchanged. “When this first started, the medical marijuana providers were recommending patients stop their other medications. The providers don’t do that anymore, fortunately,” Dr. Brooks-Kayal said. “Every week we were putting a child in a medically induced coma because they had status epilepticus, and it was the only way to stop their seizures. They started using marijuana products, they were sure it was going to be the cure, they stopped all their other medications, and they developed status epilepticus.”
- Establish policies with the hospital administration and pharmacy about how to handle marijuana products when a child is in the hospital. The Children’s Hospital Colorado pharmacy cannot store or dispense marijuana products because of federal regulations. And again, it’s unsafe to stop seizure medications abruptly, including marijuana products. Informed consent procedures need to be developed for when patients on cannabinoids are hospitalized.
- Encourage families to participate in one of the six Food and Drug Administration–approved double-blind, placebo-controlled trials of Epidiolex for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and infantile spasms sponsored by GW Pharmaceuticals.
Breaking down the evidence
Here’s what’s known and what is still unknown about the safety and efficacy of cannabinoids for the treatment of refractory pediatric epilepsy, according to Dr. Brooks-Kayal.
The knowns
Cannabinoids show activity against seizures in animal models. Moreover, initial clinical data suggest they may decrease seizures in some children with refractory epilepsy. This evidence includes a retrospective study from Children’s Hospital Colorado reliant upon parental reports of improvement (Epilepsy Behav. 2015 Apr;45:49-52), an Israeli retrospective study (Seizure. 2016 Feb;35:41-4), a positive open-label trial of an investigational oral oil-based solution of a pharmaceutical-grade cannabidiol known as Epidiolex (Lancet Neurol. 2016 Mar;15[3]:270-8), and evidence from a Food and Drug Administration–authorized phase 3, randomized clinical trial of Epidiolex (N Engl J Med. 2017 May 25;376[21]:2011-20).
The incidence of short-term adverse events associated with cannabinoids is substantial. The rate seems to be higher with Epidiolex than with many other medical marijuana products, although the potency is greater, too. These include somnolence, fatigue, and convulsions.
In addition, gastrointestinal side effects are common with Epidiolex. “Some are probably due to the oil base; some [are] probably due to the cannabidiol itself,” said Dr. Brooks-Kayal.
The unknowns
What types of seizures does it work for? This is under study in a series of FDA-authorized phase 3 randomized trials.
What is the placebo-subtracted response rate to cannabidiol? In the randomized trial published in the New England Journal of Medicine, the median monthly frequency of seizures decreased from 12.4 to 5.9 with cannabidiol, compared with a reduction from 14.9 to 14.1 with placebo. This needs confirmation in additional trials.
What’s the optimal dose? The randomized trial tested just one dose – 20 mg/kg per day.
What are the drug interactions and their possible impact on cannabidiol efficacy? Outcomes appear to be better in patients on concomitant clobazam (Onfi), perhaps because of the significantly higher blood levels of clobazam’s major metabolite in children on cannabidiol.
Long-term effects
The jury is still out on the long-term adverse effects. “These medical marijuana products are being given by families to 2- and 3-month-olds. It will be years before we know about potential long-term cognitive and behavioral effects,” Dr. Brooks-Kayal said.
Dr. Brooks-Kayal reported having no financial conflicts of interest regarding her presentation.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Folic acid fortification prevents millions of cases of anemia
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
DENVER – Mandatory food fortification with folic acid not only prevents neural tube defects, it also prevents an estimated 10 million cases of folate-deficiency anemia annually in the United States, James L. Mills, MD, reported at the annual meeting of the Teratology Society.
“We should have people be thinking about the fact that we’re preventing millions of cases of folate-deficiency anemia, not just thousands of cases of neural tube defects. That point does not seem to have reached the public health community. We need to correct the erroneous assumption that a small group are the only ones benefiting by exposing the entire population to folic acid,” said Dr. Mills, senior investigator at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md.
Extrapolating from the nationally representative survey to the full U.S. population, Dr. Mills estimated that translates to roughly 10 million cases of folate-deficiency anemia prevented per year as a result of the mandatory fortification of grain introduced in 1998. That represents an enormous financial savings in avoided costs of diagnosis and treatment of this disorder.
The Food Fortification Initiative reports that 86 countries have embraced mandatory food fortification of wheat, maize, and/or rice. More than two dozen reports from around the world describe 40%-60% reductions in neural tube defect rates as a consequence. However, some of the world’s most populous nations are not on board. These include China, India, Russia, and the entire European Union.
Among the arguments raised by opponents of mandatory food fortification is the notion that it exposes the entire population to folic acid while benefiting only a small group of individuals who are spared having a neural tube defect. But the findings regarding prevention of folate-deficiency anemia demonstrate that argument is incorrect, Dr. Mills said.
Increased risks of asthma, cancer, and twinning as a consequence of mandatory food fortification have been proposed but are not supported by evidence. The only well-established adverse event is masking of vitamin B12 deficiency by correction of the anemia. But most reported cases have occurred after exposure to folic acid in milligram per day amounts, whereas the average U.S. exposure in women of childbearing age is just 163 mcg per day, less than half the recommended daily intake for that group. Also, no increase in cases of newly diagnosed vitamin B12 deficiency without anemia occurred in the U.S. after mandatory fortification was introduced, according to Dr. Mills.
Audience member Godfrey P. Oakley Jr., MD, noted that there is randomized trial evidence to indicate that folic acid supplementation has another important benefit: primary prevention of stroke in hypertensive adults. He cited the randomized, double-blind China Stroke Primary Prevention Trial, in which almost 21,000 hypertensive Chinese adults without a history of myocardial infarction or stroke were randomized to a single-pill combination of 10 mg of enalapril and 0.8 mg of folic acid daily or to a tablet containing 10 mg of enalapril alone.
During a median 4.5 years of follow-up, the enalapril/folic acid group had a 24% reduction in the risk of ischemic stroke and a 20% reduction in the composite of cardiovascular death, MI, and stroke (JAMA. 2015 Apr 7;313[13]:1325-35).
This is a potential game-changing finding which cries out for a confirmatory trial, he said. “There’s a lot going for that paper. I don’t know of a research agenda item that’s more important than trying to find out the relationship between folic acid fortification and stroke. I wish somebody would put some money into it,” said Dr. Oakley, research professor of epidemiology at Emory University in Atlanta.
Dr. Mills responded that he has reservations about the quality of the Chinese study, particularly in light of a Chinese government analysis that concluded that 80% of Chinese clinical trials were fraudulent (BMJ. 2016 Oct 5;355:i5396).
“That makes me want to see more data from a source I have a little bit more confidence in,” he added.
Another possible benefit of folic acid supplementation worthy of investigation is its theoretic potential for cancer prevention. “Folic acid provides one-carbon atoms for DNA repair,” Dr. Mills noted.
Dr. Mills reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
How to counsel women about marijuana in pregnancy
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
DENVER – , Torri D. Metz, MD, observed at the annual meeting of the Teratology Society.
This is of particular concern because the increasing legalization of recreational marijuana across the United States means growing use, possibly including use by pregnant women. National surveys indicate a high percentage of pregnant women believe there is slight or no harm in using marijuana once or twice per week, said Dr. Metz, an ob.gyn. at the University of Colorado, Denver, who is researching the effects of marijuana in pregnancy.
Here’s how she likes to handle that situation: She starts out by freely admitting that that’s true. The available evidence is limited, mixed, and often flawed.
“I say, ‘I can’t give you data that says absolutely it’s not safe, but I also absolutely cannot give you data saying it is safe.’ I would favor saying, ‘I can’t tell you it’s safe. And if there’s any possible risk, let’s talk about things we know are safe we can use as alternatives for whatever you’re using cannabis for,’ ” she explained.
A Colorado survey of more than 1,700 mothers in the WIC (Women, Infants, and Children) nutrition program shed light on the reasons women use marijuana while pregnant or breastfeeding. Sixty-three percent of current users cited as a perceived benefit that it helped with depression, anxiety, and/or stress. Sixty percent reported it helped with pain. Nearly half used marijuana for nausea and vomiting. Just 39% did so for recreation.
Dr. Metz’s anecdotal experience has been that many health care providers are flubbing the opportunity to counsel women about marijuana use in pregnancy. This impression was bolstered by a recent study by investigators at the University of Pittsburgh who audio-recorded 468 first prenatal visits.
In total, 19% of patients disclosed marijuana use to 47 health care providers. In nearly half of those encounters, the providers didn’t respond to the disclosure at all. And when they did respond, it typically wasn’t by providing thoughtful, informed counseling on the risks or outcomes of using marijuana in pregnancy. Instead, the response was most often punitive: for example, a warning that evidence of use at delivery would result in a call to child protective services (Obstet Gynecol. 2016 Apr;127[4]:681-7).
Because of Colorado’s lengthy experience with legalized marijuana, the state Department of Public Health and Environment has endeavored to create resources of value for health care providers and patients (www.colorado.gov/cdphe/marijuana-clinical-guidelines). The website contains a fact sheet for patients regarding marijuana in pregnancy and breastfeeding. For physicians, there is plain-language guidance on how to talk effectively about marijuana with patients, including suggested responses to selected commonly voiced misconceptions.
The website also includes the results of a 2014 marijuana-in-pregnancy literature review by a state advisory committee composed of Colorado specialists in pediatrics, ob.gyn., family medicine, public health, and addiction medicine.
The committee determined that there is moderate evidence that the use of marijuana in pregnancy is associated with increased risk of reduced fetal growth, lower IQ scores in young children, adverse effects on a child’s cognitive function and academic ability, and an increase in attention problems. There was deemed to be limited evidence of an association with stillbirth and isolated ventricular septal defects. There is also “mixed” evidence for associations with preterm delivery, reduced birth weight, and selected congenital anomalies.
Since that 2014 review, a new signal of potential harm stemming from maternal marijuana use in pregnancy has appeared: a possible increased risk of neonatal ICU admission. In one retrospective study including 361 marijuana users and 6,107 nonusers, the users had a 1.54-fold increased risk for neonatal ICU admission in an analysis adjusted for maternal demographics and tobacco use (J Perinatol. 2015 Dec;35[12]:991-5).
Moreover, investigators at the University of Arizona in Tucson performed a meta-analysis of 24 studies and concluded that infants exposed to cannabis in utero were at 2.02-fold increased likelihood of neonatal ICU admission, a 1.77-fold increased risk of low birth weight, and 1.36-fold increased odds of anemia (BMJ Open. 2016 Apr 5;6[4]:e0009986. doi: 10.1136/bmjopen-2015-009986).
“That obviously would have a big public health impact,” Dr. Metz said.
In marked contrast, however, just a few months later investigators at Washington University in St. Louis reported finding no significantly increased risk of neonatal ICU admission or any other adverse neonatal outcome after adjustment for tobacco use and other potential confounders in a meta-analysis of 31 studies (Obstet Gynecol. 2016 Oct;128[4]:713-23).
These contradictory meta-analyses underscore a key point about the existing literature on the safety of marijuana use in pregnancy: It provides few, if any, definitive answers. The studies conducted in the 1980s and 1990s are of limited generalizability because concentrations of tetrahydrocannabinol were so small, compared with today’s products. Ascertainment of exposure to marijuana in pregnancy is unreliable in the absence of confirmatory biologic sampling. Self-reported use is unreliable and is typically an underestimate. Adjustment for confounders associated with adverse neonatal outcomes is challenging.
“Biologic sampling is critical,” Dr. Metz said. “We actually don’t know who’s using, and we lack information on the timing and quantity of exposure.
“Part of the problem is the data are so mixed that you can really find whatever you want in the literature to support your bias,” she added.
Still, in light of the signals of possible harm, she urged her colleagues to advise patients not to use marijuana in pregnancy. Patients need to understand that there are no known benefits of marijuana use in pregnancy, there are possible risks, and there is no known safe amount of cannabis in pregnancy.
Dr. Metz reported having no financial conflicts related to her presentation.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
E-cigarettes: A health threat or cessation tool?
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
DENVER –
“So far, the evidence regarding e-cigarettes’ effectiveness for smoking cessation is equivocal at best,” Alison Breland, PhD, said at the annual meeting of the Teratology Society.
But Dr. Breland noted that there is significant controversy around this topic. “I can tell you that, at the conferences I go to, where there are lots of people studying nicotine and tobacco, scientists are fighting with each other over this question,” said Dr. Breland, a psychologist and project director at the Center for the Study of Tobacco Products at Virginia Commonwealth University in Richmond.
That being said, she noted that this meta-analysis has generated unusually harsh printed comments from its critics.
“We could argue about the methodology of the studies all day. If you think all the studies are garbage then you won’t believe the odds ratio, either. But I think right now the evidence shows that e-cigarettes don’t seem to help people quit,” she said. “That may change in the future with testing of different kinds of devices.”
To be useful for smoking cessation, she explained, a device would need to consistently deliver enough nicotine to enable the smoker to fend off withdrawal symptoms but not so much that the wish to quit evaporates. It’s a matter of finding the sweet spot in what is technically termed device nicotine flux.
There is a great deal of misconception about e-cigarettes, Dr. Breland said, some of it promoted through misleading product advertising. She sought to set the record straight.
How e-cigarettes work
What are e-cigarettes? They are basically nicotine delivery devices. They use electricity to power a heating element that aerosolizes a liquid containing varying concentrations of nicotine; solvents, such as propylene glycol and vegetable glycerins; and flavorants. As a class, e-cigarettes are rapidly evolving. A vast array of devices are marketed with wide differences in design, materials, construction, amount of nicotine delivered, and electrical power – which, along with puff duration, is a key factor in how much nicotine gets into a user’s blood.
“Most of the devices have a battery, but it’s important to know that some of them can be plugged directly into a USB port on a computer,” Dr. Breland said.
E-cigarettes don’t generate a vapor, as is widely believed. It’s an aerosol, and it contains toxic byproducts. On the plus side, unlike combustible cigarettes, e-cigarettes don’t deliver carbon monoxide.
A vast array of flavorant mixtures are sold, including some that are clearly designed to be attractive to children, with names like “blue cotton candy” and “Apple Jacks.”
User demographics
Who is using e-cigarettes? Primarily adolescents and young adults in prime reproductive age. National surveys indicate e-cigarettes are now the most widely used tobacco product among U.S. high school students, well ahead of combustible cigarettes.
Of particular concern, data from the Centers for Disease Control and Prevention’s National Health Interview Survey indicate that, among 18- to 24-year-olds who use e-cigarettes, about 40% also currently use conventional cigarettes, about 20% are former cigarette smokers, and about 40% are never smokers – that is, have never smoked combustible cigarettes (MMWR Morb Mortal Wkly Rep. 2016;65:1177. doi: 10.15585/mmwr.mm6542a7).
“We don’t know what’s going to happen to these never smokers who are currently using e-cigarettes. Are they starting on a lifetime of nicotine dependence via e-cigarettes, or perhaps even worse, are they going to transition to combustible cigarettes? There’s more and more evidence showing that’s happening,” Dr. Breland said.
The CDC survey also showed that 59% of adult users of e-cigarettes are what Dr. Breland called “dualies,” individuals who also smoke conventional cigarettes.
“That really diminishes any potential benefit of e-cigarettes,” she said.
Impact on pregnancy
What is known about the impact of e-cigarettes on pregnancy and birth outcomes? Almost nothing at this point. E-cigarettes deliver nicotine to the bloodstream, and nicotine is known to cause unwelcome, long-term changes in fetal brain development and in that of adolescents as well. The other aerosolized toxicants have not been well studied. A few small surveys conducted in obstetric practices indicate some pregnant women perceive e-cigarettes as posing only minor health risks and safer than combustible cigarettes. And some pregnant women are using e-cigarettes.
“I think it’s notable that we’re not finding exclusive e-cigarette users. It’s early in the study, but so far the dual users are smoking the same number of cigarettes per day as cigarette-only users, and they have the same expired carbon monoxide levels. It makes me feel concerned in particular about dual use in pregnancy,” she said.
Regulation
One audience member asked what the point of allowing e-cigarettes is since, under a best-case scenario, their effectiveness as a smoking cessation tool is similar to a nicotine patch, and smokers already have access to the patch as well as nicotine gum.
Dr. Breland replied that the patch and gum deliver nicotine very slowly, so they are not as satisfying as smoking.
“The hope with e-cigarettes is that, since they get nicotine into your blood pretty fast – similar to a cigarette – they can more effectively suppress your withdrawal,” she said. “Whether or not that’s true isn’t known yet.”
The Food and Drug Administration has the authority to regulate e-cigarettes through several different mechanisms but, in late July 2017, announced a delay in issuing new regulations that would likely have removed many of the devices and flavorings from the marketplace.
Dr. Breland’s research is supported by the National Institute on Drug Abuse and the Food and Drug Administration. She reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Thirdhand smoke shaping up as potential health hazard
DENVER – Thirdhand smoke – the persistent residue that collects on indoor surfaces where people have smoked – is “clearly” a potentially hazardous exposure, John M. Rogers, PhD, said at the annual meeting of the Teratology Society.
Everyone knows about the hazards of secondhand smoke, which have led to widespread bans on smoking in public spaces. Still, the Centers for Disease Control and Prevention estimates that 58 million nonsmokers in the United States are exposed to secondhand smoke on a regular basis. And where there is secondhand smoke, there is typically exposure to thirdhand smoke as well.
“If you walk into a hotel room you were told is a nonsmoking room and you take one breath and you know it’s not nonsmoking, that’s thirdhand smoke. Thirdhand smoke is all over the place where smokers have been,” explained Dr. Rogers, director of the toxicity assessment division at the Environmental Protection Agency in Research Triangle Park, N.C.
The main potential health risk is to young children, who ingest thirdhand smoke by the hand-to-mouth route and skin contact.
Thirdhand smoke is a much newer concept than secondhand smoke and has not yet actually been shown to pose a significant health risk. . But that is likely to change.
Thirdhand smoke has become an area of intensive research interest, with California leading the way. The Tobacco-Related Disease Research Program, a state agency funded by a tax on the sale of tobacco products, has created a research consortium on thirdhand smoke, with studies underway investigating thirdhand smoke’s precise chemical composition, cytotoxicity, genotoxicity, and true impact on public health (www.trdrp.org).
Concern regarding thirdhand smoke’s potential public health impact ramped up in response to a study in which investigators at the University of York, England, measured levels of various tobacco-specific nitrosamines, N-nitrosamines, and nicotine in house dust samples from the homes of smokers. The researchers estimated that years of early life exposure to these compounds at the levels they detected could result in one excess case of cancer per 1,000 exposed individuals (Environ Int. 2014 Oct;71:139-47).
In addition to his update on thirdhand smoke, Dr. Rogers also touched on other recent tobacco-related developments, including a determination by the Food and Drug Administration that there has been no decline in tobacco use in the last 5 years in adolescents and young adults. While cigarette smoking by young people decreased, this was offset by a large increase in the use of electronic cigarettes and a smaller rise in the use of hookah tobacco. Indeed, e-cigarette use is now about double that of cigarettes among youth.
Also of concern is evidence of a striking socioeconomic disparity in smoking prevalence: Low-education, low-income Americans have far higher tobacco use rates.
“That’s pretty alarming,” he said. “I think a lot of people in this audience probably don’t see a lot of smoking these days, but it’s still around.”
Dr. Rogers drew attention to updated evidence reviews on the reproductive and developmental effects of smoking contained in the U.S. Surgeon General’s voluminous 2014 report on the health consequences of smoking. The report concluded that there is now sufficient evidence to infer a causal relationship between maternal smoking in pregnancy, ectopic pregnancy, and orofacial clefts. The available evidence is “suggestive but not sufficient” to infer causality between maternal smoking in pregnancy and atrial septal defects, clubfoot, gastroschisis, and attention-deficit/hyperactivity disorder and other disruptive behavior disorders.
Dr. Rogers reported having no financial disclosures related to his presentation, which he noted did not necessarily reflect the views and policies of the EPA.
DENVER – Thirdhand smoke – the persistent residue that collects on indoor surfaces where people have smoked – is “clearly” a potentially hazardous exposure, John M. Rogers, PhD, said at the annual meeting of the Teratology Society.
Everyone knows about the hazards of secondhand smoke, which have led to widespread bans on smoking in public spaces. Still, the Centers for Disease Control and Prevention estimates that 58 million nonsmokers in the United States are exposed to secondhand smoke on a regular basis. And where there is secondhand smoke, there is typically exposure to thirdhand smoke as well.
“If you walk into a hotel room you were told is a nonsmoking room and you take one breath and you know it’s not nonsmoking, that’s thirdhand smoke. Thirdhand smoke is all over the place where smokers have been,” explained Dr. Rogers, director of the toxicity assessment division at the Environmental Protection Agency in Research Triangle Park, N.C.
The main potential health risk is to young children, who ingest thirdhand smoke by the hand-to-mouth route and skin contact.
Thirdhand smoke is a much newer concept than secondhand smoke and has not yet actually been shown to pose a significant health risk. . But that is likely to change.
Thirdhand smoke has become an area of intensive research interest, with California leading the way. The Tobacco-Related Disease Research Program, a state agency funded by a tax on the sale of tobacco products, has created a research consortium on thirdhand smoke, with studies underway investigating thirdhand smoke’s precise chemical composition, cytotoxicity, genotoxicity, and true impact on public health (www.trdrp.org).
Concern regarding thirdhand smoke’s potential public health impact ramped up in response to a study in which investigators at the University of York, England, measured levels of various tobacco-specific nitrosamines, N-nitrosamines, and nicotine in house dust samples from the homes of smokers. The researchers estimated that years of early life exposure to these compounds at the levels they detected could result in one excess case of cancer per 1,000 exposed individuals (Environ Int. 2014 Oct;71:139-47).
In addition to his update on thirdhand smoke, Dr. Rogers also touched on other recent tobacco-related developments, including a determination by the Food and Drug Administration that there has been no decline in tobacco use in the last 5 years in adolescents and young adults. While cigarette smoking by young people decreased, this was offset by a large increase in the use of electronic cigarettes and a smaller rise in the use of hookah tobacco. Indeed, e-cigarette use is now about double that of cigarettes among youth.
Also of concern is evidence of a striking socioeconomic disparity in smoking prevalence: Low-education, low-income Americans have far higher tobacco use rates.
“That’s pretty alarming,” he said. “I think a lot of people in this audience probably don’t see a lot of smoking these days, but it’s still around.”
Dr. Rogers drew attention to updated evidence reviews on the reproductive and developmental effects of smoking contained in the U.S. Surgeon General’s voluminous 2014 report on the health consequences of smoking. The report concluded that there is now sufficient evidence to infer a causal relationship between maternal smoking in pregnancy, ectopic pregnancy, and orofacial clefts. The available evidence is “suggestive but not sufficient” to infer causality between maternal smoking in pregnancy and atrial septal defects, clubfoot, gastroschisis, and attention-deficit/hyperactivity disorder and other disruptive behavior disorders.
Dr. Rogers reported having no financial disclosures related to his presentation, which he noted did not necessarily reflect the views and policies of the EPA.
DENVER – Thirdhand smoke – the persistent residue that collects on indoor surfaces where people have smoked – is “clearly” a potentially hazardous exposure, John M. Rogers, PhD, said at the annual meeting of the Teratology Society.
Everyone knows about the hazards of secondhand smoke, which have led to widespread bans on smoking in public spaces. Still, the Centers for Disease Control and Prevention estimates that 58 million nonsmokers in the United States are exposed to secondhand smoke on a regular basis. And where there is secondhand smoke, there is typically exposure to thirdhand smoke as well.
“If you walk into a hotel room you were told is a nonsmoking room and you take one breath and you know it’s not nonsmoking, that’s thirdhand smoke. Thirdhand smoke is all over the place where smokers have been,” explained Dr. Rogers, director of the toxicity assessment division at the Environmental Protection Agency in Research Triangle Park, N.C.
The main potential health risk is to young children, who ingest thirdhand smoke by the hand-to-mouth route and skin contact.
Thirdhand smoke is a much newer concept than secondhand smoke and has not yet actually been shown to pose a significant health risk. . But that is likely to change.
Thirdhand smoke has become an area of intensive research interest, with California leading the way. The Tobacco-Related Disease Research Program, a state agency funded by a tax on the sale of tobacco products, has created a research consortium on thirdhand smoke, with studies underway investigating thirdhand smoke’s precise chemical composition, cytotoxicity, genotoxicity, and true impact on public health (www.trdrp.org).
Concern regarding thirdhand smoke’s potential public health impact ramped up in response to a study in which investigators at the University of York, England, measured levels of various tobacco-specific nitrosamines, N-nitrosamines, and nicotine in house dust samples from the homes of smokers. The researchers estimated that years of early life exposure to these compounds at the levels they detected could result in one excess case of cancer per 1,000 exposed individuals (Environ Int. 2014 Oct;71:139-47).
In addition to his update on thirdhand smoke, Dr. Rogers also touched on other recent tobacco-related developments, including a determination by the Food and Drug Administration that there has been no decline in tobacco use in the last 5 years in adolescents and young adults. While cigarette smoking by young people decreased, this was offset by a large increase in the use of electronic cigarettes and a smaller rise in the use of hookah tobacco. Indeed, e-cigarette use is now about double that of cigarettes among youth.
Also of concern is evidence of a striking socioeconomic disparity in smoking prevalence: Low-education, low-income Americans have far higher tobacco use rates.
“That’s pretty alarming,” he said. “I think a lot of people in this audience probably don’t see a lot of smoking these days, but it’s still around.”
Dr. Rogers drew attention to updated evidence reviews on the reproductive and developmental effects of smoking contained in the U.S. Surgeon General’s voluminous 2014 report on the health consequences of smoking. The report concluded that there is now sufficient evidence to infer a causal relationship between maternal smoking in pregnancy, ectopic pregnancy, and orofacial clefts. The available evidence is “suggestive but not sufficient” to infer causality between maternal smoking in pregnancy and atrial septal defects, clubfoot, gastroschisis, and attention-deficit/hyperactivity disorder and other disruptive behavior disorders.
Dr. Rogers reported having no financial disclosures related to his presentation, which he noted did not necessarily reflect the views and policies of the EPA.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Early neuroimaging essential for Zika-exposed neonates
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
DENVER – The experience gleaned at ground zero of the Brazilian Zika virus epidemic drives home a clinical imperative: every neonate whose pregnant mother has presumed or confirmed Zika infection needs to undergo prompt neuroimaging, even if head circumference at birth is normal, Vanessa van der Linden, MD, said at the annual meeting of the Teratology Society.
Dr. van der Linden, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, has done pioneering work in characterizing the recently recognized congenital Zika syndrome. She was the lead author of the first report of infants who had laboratory evidence of congenital Zika infection and normal head circumference at birth but who developed poor head growth and microcephaly later in infancy.
Comprehensive multispecialty medical and developmental follow-up documented that 10 of 13 infants had dysphagia, 7 had epilepsy, 3 had chorioretinal abnormalities, all 13 had hypertonia, and 12 had pyramidal and extrapyramidal signs with dystonia (MMWR. 2016 Dec 2;65[47]:1343-8).
In another recent publication, Dr. van der Linden and her coinvestigators described classic congenital Zika syndrome with microcephaly at birth as simply the tip of the Zika virus iceberg. In their retrospective review of 77 infants exposed to Zika in utero, 9 had microcephaly at birth, 7 developed microcephaly postnatally, and 3 didn’t have microcephaly at all. Those with microcephaly at birth showed the traditional neuroimaging findings of congenital Zika syndrome, including reduced brain volume, ventriculomegaly, subcortical calcifications, corpus callosum abnormalities, and an enlarged extra-axial space.
Those who subsequently developed microcephaly later in infancy showed most of the same neuroimaging abnormalities. The three infants who remained normocephalic displayed calcifications in the cortico-subcortical junction, asymmetric frontal polymicrogyria, delayed myelination, and milder ventriculomegaly than in the other two groups (AJNR Am J Neuroradiol. 2017 Jul;38[7]:1427-34).
The rehabilitation center where Dr. van der Linden and her colleagues are currently following roughly 200 children with congenital Zika syndrome is in the state of Pernambuco, which was particularly hard hit by the Zika epidemic.
She reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Antiviral shows early promise for treatment of Zika infection
DENVER – An antiviral drug that is a key player in the recent revolution in the treatment of hepatitis C infection also blocks Zika virus replication both in vitro and in a mouse model, Alysson R. Muotri, PhD, said at the annual meeting of the Teratology Society.
Sofosbuvir is a promising candidate. Not only has it demonstrated efficacy in preclinical work by Dr. Muotri and other groups of investigators, but it is also already a Food and Drug Administration–approved antiviral agent with a relatively reassuring Category B rating for use in pregnancy, meaning no evidence of teratogenicity in animal studies.
Investigators at the Scripps Clinic in La Jolla, Calif., have shown that the replication machinery in the Zika virus genome is closely similar to that of another flavivirus: hepatitis C. Both viruses express an NS2B-NS3 protease essential for generation of functional viral proteins.
“That observation led us to look for drugs that would interact with that replication pocket,” Dr. Muotri said.
The researchers first established in vitro that sofosbuvir can bind to the Zika virus NS2B-NS3 protease interface in an area known as the RNA-directed RNA polymerase domain, both in Zika virus–infected human neural progenitor cells and in cerebral organoids. Next, they demonstrated that sofosbuvir inhibited Zika virus replication in mice in dose-dependent fashion (Antiviral Res. 2017 Jul;143:218-29).
Most recently – and most importantly – the researchers showed that sofosbuvir blocked vertical transmission of Zika virus infection in the mouse model. “It’s neuroprotective for the fetus. There was no PCR [polymerase chain reaction] evidence of Zika virus in the fetal head. Those animals are born normal as far as we can tell,” he said.
The researchers are also engaged in preclinical evaluation of other antiviral agents as potential treatments for Zika infection. Some show even more potent anti-Zika activity than did sofosbuvir. But they have the disadvantage of being nonapproved investigational drugs and hence are far earlier in the developmental pipeline.
Dr. Muotri, whose research is supported by the National Institutes of Health, reported having no relevant financial disclosures.
DENVER – An antiviral drug that is a key player in the recent revolution in the treatment of hepatitis C infection also blocks Zika virus replication both in vitro and in a mouse model, Alysson R. Muotri, PhD, said at the annual meeting of the Teratology Society.
Sofosbuvir is a promising candidate. Not only has it demonstrated efficacy in preclinical work by Dr. Muotri and other groups of investigators, but it is also already a Food and Drug Administration–approved antiviral agent with a relatively reassuring Category B rating for use in pregnancy, meaning no evidence of teratogenicity in animal studies.
Investigators at the Scripps Clinic in La Jolla, Calif., have shown that the replication machinery in the Zika virus genome is closely similar to that of another flavivirus: hepatitis C. Both viruses express an NS2B-NS3 protease essential for generation of functional viral proteins.
“That observation led us to look for drugs that would interact with that replication pocket,” Dr. Muotri said.
The researchers first established in vitro that sofosbuvir can bind to the Zika virus NS2B-NS3 protease interface in an area known as the RNA-directed RNA polymerase domain, both in Zika virus–infected human neural progenitor cells and in cerebral organoids. Next, they demonstrated that sofosbuvir inhibited Zika virus replication in mice in dose-dependent fashion (Antiviral Res. 2017 Jul;143:218-29).
Most recently – and most importantly – the researchers showed that sofosbuvir blocked vertical transmission of Zika virus infection in the mouse model. “It’s neuroprotective for the fetus. There was no PCR [polymerase chain reaction] evidence of Zika virus in the fetal head. Those animals are born normal as far as we can tell,” he said.
The researchers are also engaged in preclinical evaluation of other antiviral agents as potential treatments for Zika infection. Some show even more potent anti-Zika activity than did sofosbuvir. But they have the disadvantage of being nonapproved investigational drugs and hence are far earlier in the developmental pipeline.
Dr. Muotri, whose research is supported by the National Institutes of Health, reported having no relevant financial disclosures.
DENVER – An antiviral drug that is a key player in the recent revolution in the treatment of hepatitis C infection also blocks Zika virus replication both in vitro and in a mouse model, Alysson R. Muotri, PhD, said at the annual meeting of the Teratology Society.
Sofosbuvir is a promising candidate. Not only has it demonstrated efficacy in preclinical work by Dr. Muotri and other groups of investigators, but it is also already a Food and Drug Administration–approved antiviral agent with a relatively reassuring Category B rating for use in pregnancy, meaning no evidence of teratogenicity in animal studies.
Investigators at the Scripps Clinic in La Jolla, Calif., have shown that the replication machinery in the Zika virus genome is closely similar to that of another flavivirus: hepatitis C. Both viruses express an NS2B-NS3 protease essential for generation of functional viral proteins.
“That observation led us to look for drugs that would interact with that replication pocket,” Dr. Muotri said.
The researchers first established in vitro that sofosbuvir can bind to the Zika virus NS2B-NS3 protease interface in an area known as the RNA-directed RNA polymerase domain, both in Zika virus–infected human neural progenitor cells and in cerebral organoids. Next, they demonstrated that sofosbuvir inhibited Zika virus replication in mice in dose-dependent fashion (Antiviral Res. 2017 Jul;143:218-29).
Most recently – and most importantly – the researchers showed that sofosbuvir blocked vertical transmission of Zika virus infection in the mouse model. “It’s neuroprotective for the fetus. There was no PCR [polymerase chain reaction] evidence of Zika virus in the fetal head. Those animals are born normal as far as we can tell,” he said.
The researchers are also engaged in preclinical evaluation of other antiviral agents as potential treatments for Zika infection. Some show even more potent anti-Zika activity than did sofosbuvir. But they have the disadvantage of being nonapproved investigational drugs and hence are far earlier in the developmental pipeline.
Dr. Muotri, whose research is supported by the National Institutes of Health, reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Preventing Zika in pregnancy: What you need to know
DENVER – Prevention of Zika virus infection in pregnancy is critical, given the lack of an effective treatment or vaccine, but it’s easier said than done.
“The particular mosquito that transmits Zika is really difficult because it tends to be indoors and live under the coffee table in your living room rather than outside. It bites in the day, as well as night, so it’s hard to prevent. Trying to consistently have repellent on [and] wear long-sleeved shirts and long pants, even when you’re indoors, in places that are typically quite warm – it’s challenging,” Margaret Honein, PhD, said at the annual meeting of the Teratology Society.
The CDC’s top Zika prevention advice is that pregnant women should not travel to any area where Zika is a risk. If they absolutely have to go, they should talk to their health care provider first, strictly follow measures to prevent mosquito bites during the trip, take steps to prevent sexual transmission – namely, use a condom – and talk with their health care provider once again upon their return.
It is now clear that Zika can be transmitted sexually. For this reason, even a pregnant woman who doesn’t visit an area with Zika risk, but whose partner has been to such a place, must also practice safe sex using a condom, even if the partner is asymptomatic.
In response to an audience question from a Washington, D.C.–area ob.gyn. who noted that there isn’t a Zika problem in his region, Dr. Honein said that her personal view is that pregnant women living in the vicinity of the nation’s capitol should also follow the CDC recommendations for travelers to, or residents of, areas where Zika is found.
“You have mosquito vectors that can transmit Zika in Washington, D.C., and a lot of other parts of the country,” she said. “There are travelers coming back from areas with risk for Zika all the time. If they get bit by a mosquito, which then bites another person and transmits the infection, there’s a problem. So, for pregnant women in areas that have a mosquito vector that can transmit the virus, I think it’s very wise advice to consistently use mosquito repellent and take the other protective measures. People should be doing everything they can to protect against Zika infection in pregnancy.”
DENVER – Prevention of Zika virus infection in pregnancy is critical, given the lack of an effective treatment or vaccine, but it’s easier said than done.
“The particular mosquito that transmits Zika is really difficult because it tends to be indoors and live under the coffee table in your living room rather than outside. It bites in the day, as well as night, so it’s hard to prevent. Trying to consistently have repellent on [and] wear long-sleeved shirts and long pants, even when you’re indoors, in places that are typically quite warm – it’s challenging,” Margaret Honein, PhD, said at the annual meeting of the Teratology Society.
The CDC’s top Zika prevention advice is that pregnant women should not travel to any area where Zika is a risk. If they absolutely have to go, they should talk to their health care provider first, strictly follow measures to prevent mosquito bites during the trip, take steps to prevent sexual transmission – namely, use a condom – and talk with their health care provider once again upon their return.
It is now clear that Zika can be transmitted sexually. For this reason, even a pregnant woman who doesn’t visit an area with Zika risk, but whose partner has been to such a place, must also practice safe sex using a condom, even if the partner is asymptomatic.
In response to an audience question from a Washington, D.C.–area ob.gyn. who noted that there isn’t a Zika problem in his region, Dr. Honein said that her personal view is that pregnant women living in the vicinity of the nation’s capitol should also follow the CDC recommendations for travelers to, or residents of, areas where Zika is found.
“You have mosquito vectors that can transmit Zika in Washington, D.C., and a lot of other parts of the country,” she said. “There are travelers coming back from areas with risk for Zika all the time. If they get bit by a mosquito, which then bites another person and transmits the infection, there’s a problem. So, for pregnant women in areas that have a mosquito vector that can transmit the virus, I think it’s very wise advice to consistently use mosquito repellent and take the other protective measures. People should be doing everything they can to protect against Zika infection in pregnancy.”
DENVER – Prevention of Zika virus infection in pregnancy is critical, given the lack of an effective treatment or vaccine, but it’s easier said than done.
“The particular mosquito that transmits Zika is really difficult because it tends to be indoors and live under the coffee table in your living room rather than outside. It bites in the day, as well as night, so it’s hard to prevent. Trying to consistently have repellent on [and] wear long-sleeved shirts and long pants, even when you’re indoors, in places that are typically quite warm – it’s challenging,” Margaret Honein, PhD, said at the annual meeting of the Teratology Society.
The CDC’s top Zika prevention advice is that pregnant women should not travel to any area where Zika is a risk. If they absolutely have to go, they should talk to their health care provider first, strictly follow measures to prevent mosquito bites during the trip, take steps to prevent sexual transmission – namely, use a condom – and talk with their health care provider once again upon their return.
It is now clear that Zika can be transmitted sexually. For this reason, even a pregnant woman who doesn’t visit an area with Zika risk, but whose partner has been to such a place, must also practice safe sex using a condom, even if the partner is asymptomatic.
In response to an audience question from a Washington, D.C.–area ob.gyn. who noted that there isn’t a Zika problem in his region, Dr. Honein said that her personal view is that pregnant women living in the vicinity of the nation’s capitol should also follow the CDC recommendations for travelers to, or residents of, areas where Zika is found.
“You have mosquito vectors that can transmit Zika in Washington, D.C., and a lot of other parts of the country,” she said. “There are travelers coming back from areas with risk for Zika all the time. If they get bit by a mosquito, which then bites another person and transmits the infection, there’s a problem. So, for pregnant women in areas that have a mosquito vector that can transmit the virus, I think it’s very wise advice to consistently use mosquito repellent and take the other protective measures. People should be doing everything they can to protect against Zika infection in pregnancy.”
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017
Asymptomatic maternal Zika infection doesn’t dampen birth defect risk
DENVER – One of many daunting challenges posed by the ongoing global Zika virus epidemic stems from the recent realization that the presence or absence of symptoms in women infected in pregnancy has no bearing on whether their babies will have Zika-associated birth defects, Margaret Honein, PhD, observed at the annual meeting of the Teratology Society.
This has profound clinical consequences because roughly 80% of all maternal Zika infections are asymptomatic or feature such mild symptoms that women don’t report them.
“There was, I think, some hope early on that symptoms in the mother would correlate with outcomes, but that has not been the case at all. In the U.S. population, we’ve seen about a 6% Zika-associated birth defects rate in both symptomatic and asymptomatic mothers,” said Dr. Honein, chief of the birth defects branch at the Centers for Disease Control and Prevention in Atlanta. “We have a huge challenge in identifying the women who have asymptomatic infections, yet they’re at the same risk of having an adverse outcome in their baby.”[[{"fid":"199780","view_mode":"medstat_image_flush_right","fields":
She provided conference attendees with the latest information on Zika, including preliminary results from ongoing CDC investigations. Along the way, she tackled many of the questions Zika experts hear most often from clinicians, while emphasizing that much about congenital Zika syndrome remains unknown.
Just how serious is the global threat of Zika virus infection?
On Feb. 8, 2016, the CDC activated a Level 1 emergency response to Zika. To put that into perspective, this is only the fourth time in history the agency has gone to Level 1. The other occasions were for Hurricane Katrina, the H1N1 pandemic flu, and Ebola.
“This is worse than thalidomide,” said Jan M. Friedman, MD, after listening to Dr. Honein and other speakers at the Zika update held during the conference. Dr. Friedman, a medical geneticist at the University of British Columbia, Vancouver, delivered the Robert L. Brent Lecture.
What is the level of risk for fetal/infant birth defects associated with maternal Zika virus infection?
The birth defect risk is somewhere between 5% and 10%, with the true figure probably being on the high end. Reports quoting risks on the lower end are based upon laboratory testing for maternal IgM antibodies, which couldn’t rule out cross reaction with other flaviviruses, including dengue virus, which is common in most of the same locales as Zika. Women who have been infected with dengue but not Zika are not at increased risk for birth defects. Zika is the first mosquito-borne virus to be recognized as teratogenic in humans.
The birth defects seen in conjunction with Zika infection are not unique. They can have many different causes. CDC investigators examined birth defects data from three states during the year before the Zika outbreak in the Western Hemisphere and determined that the background rate of microcephaly, neural tube defects, eye abnormalities, hearing loss, and other Zika-like birth defects was 3 per 1,000 live births. Among women with Zika virus infection in pregnancy, however, the rate is more than 20-fold higher at 50-100 per 1,000, according to Dr. Honein.
When during pregnancy does maternal Zika infection pose the highest risk to the fetus?
Studies published from Colombia and Brazil show the peak risk is when infection occurs during the first trimester or early in the second trimester. That’s consistent with the U.S. registry experience as well. Of note, the median time between development of maternal symptoms and the first notation of fetal microcephaly on ultrasound has been 18 weeks.
“This has important implications for women who’ve been infected. Just because they may have had two consecutive apparently normal monthly fetal ultrasounds doesn’t rule out by any means congenital Zika syndrome because there does appear to be a relatively long time period before these findings appear,” Dr. Honein noted.
What is the full range of potential health problems Zika infection can cause?
“What we’ve seen so far is definitely just the tip of the iceberg,” Dr. Honein cautioned. “It’s very severe, but I think we don’t yet know the full range of disabilities. There’s much more to come here.”
Most of the infants in the U.S. registry are just now reaching 1 year of age. Greater understanding of their neurodevelopment will require follow-up to age 2 or beyond.
Also, the information available to date on Zika-associated birth defects is based largely on scrutiny of infants with microcephaly along with any additional findings, such as chorioretinal scarring.
“We know relatively little about infants with only the other conditions – only hearing loss, for example, or only eye abnormalities,” Dr. Honein said. “While we know there are children who have microcephaly and they have needs, there may be a much larger number of children with lesser impairment, but who still have disabilities that are going to necessitate provision of services. Being prepared for that is very important.”
Reports from multiple countries make it clear that babies exposed to Zika in utero can have a normal-appearing head at birth but then become microcephalic later in their first year. The incidence of this phenomenon hasn’t yet been pinned down.
“We’ve learned in the last year and a-half that microcephaly is a key marker of some of the relevant underlying brain abnormalities, but microcephaly is not where our focus should be,” she said.
How long does Zika virus persist in the body?
The viremia typically lasts for anywhere from a few days up to 2 weeks. However, viral persistence for as long as 107 days has been documented in some pregnant women.
“I hesitate to put a number on it because every new publication has a longer figure,” Dr. Honein said.
It’s not yet known whether viral persistence in a woman infected prior to her pregnancy is associated with adverse fetal outcomes. The central nervous system is clearly a reservoir for persistent virus. Whole blood is now under study as possibly another. Semen poses a major challenge.
“There are case reports of Zika virus RNA being detected in semen for more than 6 months after the timing of infection, but we don’t yet know for how long it can be sexually transmitted. Is there really infectious virus present or just particles of RNA?” she said.
Resources
In partnership with the March of Dimes, the CDC has launched Zika Care Connect, a referral network of roughly 600 specialists in six high-risk states. Their ranks include specialists in maternal-fetal medicine, audiology, radiology, mental health, pediatric neurology, infectious diseases, developmental pediatrics, endocrinology, and pediatric ophthalmology. Another 10 states and at least 600 additional providers will soon be added to the referral network (www.zikacareconnect.org; 1-844-677-0447 toll-free).
Comprehensive, up-to-date Zika information is available to health care providers and the public through the CDC at http://www.cdc.gov/zika, at the Zika Pregnancy Hotline (770-488-7100), and by email at ZikaMCH@cdc.gov.
bjancin@frontlinemedcom.com
On Twitter @ObGynNews
DENVER – One of many daunting challenges posed by the ongoing global Zika virus epidemic stems from the recent realization that the presence or absence of symptoms in women infected in pregnancy has no bearing on whether their babies will have Zika-associated birth defects, Margaret Honein, PhD, observed at the annual meeting of the Teratology Society.
This has profound clinical consequences because roughly 80% of all maternal Zika infections are asymptomatic or feature such mild symptoms that women don’t report them.
“There was, I think, some hope early on that symptoms in the mother would correlate with outcomes, but that has not been the case at all. In the U.S. population, we’ve seen about a 6% Zika-associated birth defects rate in both symptomatic and asymptomatic mothers,” said Dr. Honein, chief of the birth defects branch at the Centers for Disease Control and Prevention in Atlanta. “We have a huge challenge in identifying the women who have asymptomatic infections, yet they’re at the same risk of having an adverse outcome in their baby.”[[{"fid":"199780","view_mode":"medstat_image_flush_right","fields":
She provided conference attendees with the latest information on Zika, including preliminary results from ongoing CDC investigations. Along the way, she tackled many of the questions Zika experts hear most often from clinicians, while emphasizing that much about congenital Zika syndrome remains unknown.
Just how serious is the global threat of Zika virus infection?
On Feb. 8, 2016, the CDC activated a Level 1 emergency response to Zika. To put that into perspective, this is only the fourth time in history the agency has gone to Level 1. The other occasions were for Hurricane Katrina, the H1N1 pandemic flu, and Ebola.
“This is worse than thalidomide,” said Jan M. Friedman, MD, after listening to Dr. Honein and other speakers at the Zika update held during the conference. Dr. Friedman, a medical geneticist at the University of British Columbia, Vancouver, delivered the Robert L. Brent Lecture.
What is the level of risk for fetal/infant birth defects associated with maternal Zika virus infection?
The birth defect risk is somewhere between 5% and 10%, with the true figure probably being on the high end. Reports quoting risks on the lower end are based upon laboratory testing for maternal IgM antibodies, which couldn’t rule out cross reaction with other flaviviruses, including dengue virus, which is common in most of the same locales as Zika. Women who have been infected with dengue but not Zika are not at increased risk for birth defects. Zika is the first mosquito-borne virus to be recognized as teratogenic in humans.
The birth defects seen in conjunction with Zika infection are not unique. They can have many different causes. CDC investigators examined birth defects data from three states during the year before the Zika outbreak in the Western Hemisphere and determined that the background rate of microcephaly, neural tube defects, eye abnormalities, hearing loss, and other Zika-like birth defects was 3 per 1,000 live births. Among women with Zika virus infection in pregnancy, however, the rate is more than 20-fold higher at 50-100 per 1,000, according to Dr. Honein.
When during pregnancy does maternal Zika infection pose the highest risk to the fetus?
Studies published from Colombia and Brazil show the peak risk is when infection occurs during the first trimester or early in the second trimester. That’s consistent with the U.S. registry experience as well. Of note, the median time between development of maternal symptoms and the first notation of fetal microcephaly on ultrasound has been 18 weeks.
“This has important implications for women who’ve been infected. Just because they may have had two consecutive apparently normal monthly fetal ultrasounds doesn’t rule out by any means congenital Zika syndrome because there does appear to be a relatively long time period before these findings appear,” Dr. Honein noted.
What is the full range of potential health problems Zika infection can cause?
“What we’ve seen so far is definitely just the tip of the iceberg,” Dr. Honein cautioned. “It’s very severe, but I think we don’t yet know the full range of disabilities. There’s much more to come here.”
Most of the infants in the U.S. registry are just now reaching 1 year of age. Greater understanding of their neurodevelopment will require follow-up to age 2 or beyond.
Also, the information available to date on Zika-associated birth defects is based largely on scrutiny of infants with microcephaly along with any additional findings, such as chorioretinal scarring.
“We know relatively little about infants with only the other conditions – only hearing loss, for example, or only eye abnormalities,” Dr. Honein said. “While we know there are children who have microcephaly and they have needs, there may be a much larger number of children with lesser impairment, but who still have disabilities that are going to necessitate provision of services. Being prepared for that is very important.”
Reports from multiple countries make it clear that babies exposed to Zika in utero can have a normal-appearing head at birth but then become microcephalic later in their first year. The incidence of this phenomenon hasn’t yet been pinned down.
“We’ve learned in the last year and a-half that microcephaly is a key marker of some of the relevant underlying brain abnormalities, but microcephaly is not where our focus should be,” she said.
How long does Zika virus persist in the body?
The viremia typically lasts for anywhere from a few days up to 2 weeks. However, viral persistence for as long as 107 days has been documented in some pregnant women.
“I hesitate to put a number on it because every new publication has a longer figure,” Dr. Honein said.
It’s not yet known whether viral persistence in a woman infected prior to her pregnancy is associated with adverse fetal outcomes. The central nervous system is clearly a reservoir for persistent virus. Whole blood is now under study as possibly another. Semen poses a major challenge.
“There are case reports of Zika virus RNA being detected in semen for more than 6 months after the timing of infection, but we don’t yet know for how long it can be sexually transmitted. Is there really infectious virus present or just particles of RNA?” she said.
Resources
In partnership with the March of Dimes, the CDC has launched Zika Care Connect, a referral network of roughly 600 specialists in six high-risk states. Their ranks include specialists in maternal-fetal medicine, audiology, radiology, mental health, pediatric neurology, infectious diseases, developmental pediatrics, endocrinology, and pediatric ophthalmology. Another 10 states and at least 600 additional providers will soon be added to the referral network (www.zikacareconnect.org; 1-844-677-0447 toll-free).
Comprehensive, up-to-date Zika information is available to health care providers and the public through the CDC at http://www.cdc.gov/zika, at the Zika Pregnancy Hotline (770-488-7100), and by email at ZikaMCH@cdc.gov.
bjancin@frontlinemedcom.com
On Twitter @ObGynNews
DENVER – One of many daunting challenges posed by the ongoing global Zika virus epidemic stems from the recent realization that the presence or absence of symptoms in women infected in pregnancy has no bearing on whether their babies will have Zika-associated birth defects, Margaret Honein, PhD, observed at the annual meeting of the Teratology Society.
This has profound clinical consequences because roughly 80% of all maternal Zika infections are asymptomatic or feature such mild symptoms that women don’t report them.
“There was, I think, some hope early on that symptoms in the mother would correlate with outcomes, but that has not been the case at all. In the U.S. population, we’ve seen about a 6% Zika-associated birth defects rate in both symptomatic and asymptomatic mothers,” said Dr. Honein, chief of the birth defects branch at the Centers for Disease Control and Prevention in Atlanta. “We have a huge challenge in identifying the women who have asymptomatic infections, yet they’re at the same risk of having an adverse outcome in their baby.”[[{"fid":"199780","view_mode":"medstat_image_flush_right","fields":
She provided conference attendees with the latest information on Zika, including preliminary results from ongoing CDC investigations. Along the way, she tackled many of the questions Zika experts hear most often from clinicians, while emphasizing that much about congenital Zika syndrome remains unknown.
Just how serious is the global threat of Zika virus infection?
On Feb. 8, 2016, the CDC activated a Level 1 emergency response to Zika. To put that into perspective, this is only the fourth time in history the agency has gone to Level 1. The other occasions were for Hurricane Katrina, the H1N1 pandemic flu, and Ebola.
“This is worse than thalidomide,” said Jan M. Friedman, MD, after listening to Dr. Honein and other speakers at the Zika update held during the conference. Dr. Friedman, a medical geneticist at the University of British Columbia, Vancouver, delivered the Robert L. Brent Lecture.
What is the level of risk for fetal/infant birth defects associated with maternal Zika virus infection?
The birth defect risk is somewhere between 5% and 10%, with the true figure probably being on the high end. Reports quoting risks on the lower end are based upon laboratory testing for maternal IgM antibodies, which couldn’t rule out cross reaction with other flaviviruses, including dengue virus, which is common in most of the same locales as Zika. Women who have been infected with dengue but not Zika are not at increased risk for birth defects. Zika is the first mosquito-borne virus to be recognized as teratogenic in humans.
The birth defects seen in conjunction with Zika infection are not unique. They can have many different causes. CDC investigators examined birth defects data from three states during the year before the Zika outbreak in the Western Hemisphere and determined that the background rate of microcephaly, neural tube defects, eye abnormalities, hearing loss, and other Zika-like birth defects was 3 per 1,000 live births. Among women with Zika virus infection in pregnancy, however, the rate is more than 20-fold higher at 50-100 per 1,000, according to Dr. Honein.
When during pregnancy does maternal Zika infection pose the highest risk to the fetus?
Studies published from Colombia and Brazil show the peak risk is when infection occurs during the first trimester or early in the second trimester. That’s consistent with the U.S. registry experience as well. Of note, the median time between development of maternal symptoms and the first notation of fetal microcephaly on ultrasound has been 18 weeks.
“This has important implications for women who’ve been infected. Just because they may have had two consecutive apparently normal monthly fetal ultrasounds doesn’t rule out by any means congenital Zika syndrome because there does appear to be a relatively long time period before these findings appear,” Dr. Honein noted.
What is the full range of potential health problems Zika infection can cause?
“What we’ve seen so far is definitely just the tip of the iceberg,” Dr. Honein cautioned. “It’s very severe, but I think we don’t yet know the full range of disabilities. There’s much more to come here.”
Most of the infants in the U.S. registry are just now reaching 1 year of age. Greater understanding of their neurodevelopment will require follow-up to age 2 or beyond.
Also, the information available to date on Zika-associated birth defects is based largely on scrutiny of infants with microcephaly along with any additional findings, such as chorioretinal scarring.
“We know relatively little about infants with only the other conditions – only hearing loss, for example, or only eye abnormalities,” Dr. Honein said. “While we know there are children who have microcephaly and they have needs, there may be a much larger number of children with lesser impairment, but who still have disabilities that are going to necessitate provision of services. Being prepared for that is very important.”
Reports from multiple countries make it clear that babies exposed to Zika in utero can have a normal-appearing head at birth but then become microcephalic later in their first year. The incidence of this phenomenon hasn’t yet been pinned down.
“We’ve learned in the last year and a-half that microcephaly is a key marker of some of the relevant underlying brain abnormalities, but microcephaly is not where our focus should be,” she said.
How long does Zika virus persist in the body?
The viremia typically lasts for anywhere from a few days up to 2 weeks. However, viral persistence for as long as 107 days has been documented in some pregnant women.
“I hesitate to put a number on it because every new publication has a longer figure,” Dr. Honein said.
It’s not yet known whether viral persistence in a woman infected prior to her pregnancy is associated with adverse fetal outcomes. The central nervous system is clearly a reservoir for persistent virus. Whole blood is now under study as possibly another. Semen poses a major challenge.
“There are case reports of Zika virus RNA being detected in semen for more than 6 months after the timing of infection, but we don’t yet know for how long it can be sexually transmitted. Is there really infectious virus present or just particles of RNA?” she said.
Resources
In partnership with the March of Dimes, the CDC has launched Zika Care Connect, a referral network of roughly 600 specialists in six high-risk states. Their ranks include specialists in maternal-fetal medicine, audiology, radiology, mental health, pediatric neurology, infectious diseases, developmental pediatrics, endocrinology, and pediatric ophthalmology. Another 10 states and at least 600 additional providers will soon be added to the referral network (www.zikacareconnect.org; 1-844-677-0447 toll-free).
Comprehensive, up-to-date Zika information is available to health care providers and the public through the CDC at http://www.cdc.gov/zika, at the Zika Pregnancy Hotline (770-488-7100), and by email at ZikaMCH@cdc.gov.
bjancin@frontlinemedcom.com
On Twitter @ObGynNews
EXPERT ANALYSIS FROM TERATOLOGY SOCIETY 2017