Women's Health

NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.

Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.

“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.

He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.

“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.

The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.

“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”

He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.

The scope of the problem

More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.

“The morbidity is huge and the costs are astonishing,” the geriatrician declared.

Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.

Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
 

The lowdown on DIAPERS

• Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
• Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
• “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
• Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
• “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
• Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
• They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
• “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
• Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
• Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
• Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
• In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.

Dr. Resnick reported having no financial conflicts of interest regarding his presentation.

[email protected]

NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.

Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.

“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.

He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.

“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.

The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.

“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”

He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.

The scope of the problem

More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.

“The morbidity is huge and the costs are astonishing,” the geriatrician declared.

Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.

Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
 

The lowdown on DIAPERS

• Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
• Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
• “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
• Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
• “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
• Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
• They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
• “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
• Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
• Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
• Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
• In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.

Dr. Resnick reported having no financial conflicts of interest regarding his presentation.

[email protected]

NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.

Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.

“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.

He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.

“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.

The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.

“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”

He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.

The scope of the problem

More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.

“The morbidity is huge and the costs are astonishing,” the geriatrician declared.

Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.

Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
 

The lowdown on DIAPERS

• Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
• Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
• “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
• Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
• “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
• Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
• They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
• “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
• Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
• Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
• Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
• In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.

Dr. Resnick reported having no financial conflicts of interest regarding his presentation.

[email protected]

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.

Antonio_Diaz/Thinkstock

Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.

Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.

Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).

Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).

The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).

The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.

Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.

Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).

Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.

Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].

The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.

Antonio_Diaz/Thinkstock

Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.

Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.

Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).

Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).

The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).

The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.

Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.

Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).

Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.

Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].

The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.

Antonio_Diaz/Thinkstock

Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.

Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.

Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).

Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).

The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).

The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.

Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.

Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).

Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.

Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].

Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.

Copyright Michelle Redmond

“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.

Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.

There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.

The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.

“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”

They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.

“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”

“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.

Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.

“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”

Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.

“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”

This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.

SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.

Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.

Copyright Michelle Redmond

“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.

Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.

There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.

The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.

“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”

They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.

“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”

“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.

Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.

“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”

Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.

“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”

This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.

SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.

Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.

Copyright Michelle Redmond

“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.

Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.

There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.

The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.

“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”

They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.

“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”

“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.

Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.

“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”

Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.

“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”

This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.

SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

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Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .

The statement, accompanying evidence report, and a modeling study were published online in JAMA.

Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.

The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.

To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.

In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.

Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.

In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”

The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.

The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.

Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.

In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.

However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.

The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.

“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.

“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.

The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.

SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .

The statement, accompanying evidence report, and a modeling study were published online in JAMA.

Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.

The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.

To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.

In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.

Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.

In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”

The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.

The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.

Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.

In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.

However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.

The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.

“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.

“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.

The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.

SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .

The statement, accompanying evidence report, and a modeling study were published online in JAMA.

Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.

The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.

To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.

In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.

Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.

In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”

The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.

The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.

Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.

In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.

However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.

The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.

“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.

“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.

The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.

SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.

The human papillomavirus vaccine does not appear to be associated with an increased risk of ovarian insufficiency, according to researchers.

Choreograph/Thinkstock

Allison L. Naleway, PhD, of the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore., and her coauthors wrote that a previous case series had raised concerns about a possible link between the human papillomavirus (HPV) vaccine and primary ovarian insufficiency (POI) in six young women who developed the condition within 12 months of vaccination.

Using EHR data, researchers identified 46 women aged 11-34 years with idiopathic POI – 33 probable cases and 13 possible cases – after excluding cases with known causes. Eighteen of these cases also were excluded because they were diagnosed before the HPV vaccine was available.

They found that only 1 of the remaining 28 patients had been vaccinated against HPV before the symptom onset: a 16-year-old girl who was vaccinated about 23 months before the first clinical evaluation for delayed menarche. Their report was published in Pediatrics.

The adjusted hazard ratio for POI was therefore 0.30 after HPV vaccine, compared with 0.88 after Tdap, 1.42 after inactivated influenza vaccine, and 0.94 after meningococcal conjugate vaccine.

More than one-half of the 46 confirmed POI cases were diagnosed at age 27 years or older, and only one patient was diagnosed under 15 years of age.

“If POI is triggered by HPV or other adolescent vaccine exposure, we would have expected to see elevated incidence in the younger women who were most likely to be vaccinated, but instead we observed higher incidence in older women (greater than 26 years of age), which is consistent with 1 other population-based study of POI prevalence,” the authors wrote.

They acknowledged that studying POI as a vaccine-related adverse event was challenging because the time from symptom onset to diagnosis was variable. However, they said that 81% of their cohort was followed up for more than 2 years, and a mean of 5.14 years, so the potential for misclassification was “minimal.”

Dr. Naleway and her associates also noted that diagnoses of POI can be difficult to accurately identify, and symptoms may be masked by oral contraceptive use.

“Despite the challenges and limitations discussed above, we believe this study should lessen concern surrounding potential impact on fertility from HPV or other adolescent vaccination,” they wrote.

The Centers for Disease Control and Prevention supported the study. Three authors declared funding from pharmaceutical companies for unrelated studies. No other conflicts of interest were declared.

SOURCE: Naleway A et al. Pediatrics 2018;42(3):e20180943.

The human papillomavirus vaccine does not appear to be associated with an increased risk of ovarian insufficiency, according to researchers.

Choreograph/Thinkstock

Allison L. Naleway, PhD, of the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore., and her coauthors wrote that a previous case series had raised concerns about a possible link between the human papillomavirus (HPV) vaccine and primary ovarian insufficiency (POI) in six young women who developed the condition within 12 months of vaccination.

Using EHR data, researchers identified 46 women aged 11-34 years with idiopathic POI – 33 probable cases and 13 possible cases – after excluding cases with known causes. Eighteen of these cases also were excluded because they were diagnosed before the HPV vaccine was available.

They found that only 1 of the remaining 28 patients had been vaccinated against HPV before the symptom onset: a 16-year-old girl who was vaccinated about 23 months before the first clinical evaluation for delayed menarche. Their report was published in Pediatrics.

The adjusted hazard ratio for POI was therefore 0.30 after HPV vaccine, compared with 0.88 after Tdap, 1.42 after inactivated influenza vaccine, and 0.94 after meningococcal conjugate vaccine.

More than one-half of the 46 confirmed POI cases were diagnosed at age 27 years or older, and only one patient was diagnosed under 15 years of age.

“If POI is triggered by HPV or other adolescent vaccine exposure, we would have expected to see elevated incidence in the younger women who were most likely to be vaccinated, but instead we observed higher incidence in older women (greater than 26 years of age), which is consistent with 1 other population-based study of POI prevalence,” the authors wrote.

They acknowledged that studying POI as a vaccine-related adverse event was challenging because the time from symptom onset to diagnosis was variable. However, they said that 81% of their cohort was followed up for more than 2 years, and a mean of 5.14 years, so the potential for misclassification was “minimal.”

Dr. Naleway and her associates also noted that diagnoses of POI can be difficult to accurately identify, and symptoms may be masked by oral contraceptive use.

“Despite the challenges and limitations discussed above, we believe this study should lessen concern surrounding potential impact on fertility from HPV or other adolescent vaccination,” they wrote.

The Centers for Disease Control and Prevention supported the study. Three authors declared funding from pharmaceutical companies for unrelated studies. No other conflicts of interest were declared.

SOURCE: Naleway A et al. Pediatrics 2018;42(3):e20180943.

The human papillomavirus vaccine does not appear to be associated with an increased risk of ovarian insufficiency, according to researchers.

Choreograph/Thinkstock

Allison L. Naleway, PhD, of the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore., and her coauthors wrote that a previous case series had raised concerns about a possible link between the human papillomavirus (HPV) vaccine and primary ovarian insufficiency (POI) in six young women who developed the condition within 12 months of vaccination.

Using EHR data, researchers identified 46 women aged 11-34 years with idiopathic POI – 33 probable cases and 13 possible cases – after excluding cases with known causes. Eighteen of these cases also were excluded because they were diagnosed before the HPV vaccine was available.

They found that only 1 of the remaining 28 patients had been vaccinated against HPV before the symptom onset: a 16-year-old girl who was vaccinated about 23 months before the first clinical evaluation for delayed menarche. Their report was published in Pediatrics.

The adjusted hazard ratio for POI was therefore 0.30 after HPV vaccine, compared with 0.88 after Tdap, 1.42 after inactivated influenza vaccine, and 0.94 after meningococcal conjugate vaccine.

More than one-half of the 46 confirmed POI cases were diagnosed at age 27 years or older, and only one patient was diagnosed under 15 years of age.

“If POI is triggered by HPV or other adolescent vaccine exposure, we would have expected to see elevated incidence in the younger women who were most likely to be vaccinated, but instead we observed higher incidence in older women (greater than 26 years of age), which is consistent with 1 other population-based study of POI prevalence,” the authors wrote.

They acknowledged that studying POI as a vaccine-related adverse event was challenging because the time from symptom onset to diagnosis was variable. However, they said that 81% of their cohort was followed up for more than 2 years, and a mean of 5.14 years, so the potential for misclassification was “minimal.”

Dr. Naleway and her associates also noted that diagnoses of POI can be difficult to accurately identify, and symptoms may be masked by oral contraceptive use.

“Despite the challenges and limitations discussed above, we believe this study should lessen concern surrounding potential impact on fertility from HPV or other adolescent vaccination,” they wrote.

The Centers for Disease Control and Prevention supported the study. Three authors declared funding from pharmaceutical companies for unrelated studies. No other conflicts of interest were declared.

SOURCE: Naleway A et al. Pediatrics 2018;42(3):e20180943.

Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.

Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.

There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally, there’s also good evidence that 81 mg of aspirin is a minimum dose for effectiveness and that higher doses – as much as 150 mg – are probably more effective.

Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.

Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.


 

Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin

The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).

Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).

It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.

The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).

Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.

The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.

The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.

Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.

Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.

Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.

When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).

In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.

What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).

My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
 

Dr. Abbott: Messaging and education to reduce disparities

Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).

At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.

To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.

To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.

Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.

We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”

Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].

Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.

Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.

There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally, there’s also good evidence that 81 mg of aspirin is a minimum dose for effectiveness and that higher doses – as much as 150 mg – are probably more effective.

Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.

Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.


 

Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin

The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).

Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).

It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.

The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).

Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.

The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.

The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.

Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.

Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.

Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.

When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).

In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.

What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).

My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
 

Dr. Abbott: Messaging and education to reduce disparities

Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).

At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.

To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.

To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.

Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.

We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”

Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].

Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.

Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.

There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally, there’s also good evidence that 81 mg of aspirin is a minimum dose for effectiveness and that higher doses – as much as 150 mg – are probably more effective.

Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.

Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.


 

Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin

The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).

Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).

It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.

The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).

Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.

The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.

The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.

Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.

Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.

Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.

When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).

In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.

What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).

My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
 

Dr. Abbott: Messaging and education to reduce disparities

Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).

At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.

To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.

To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.

Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.

We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”

Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].

Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.

Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.

It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.

To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.

Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.

It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.

To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.

Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.

It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.

To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.

Smithore

In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.

Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.

“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.

In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.

The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.

The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.

Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.

“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”

The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
 

SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.

Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.

Smithore

In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.

Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.

“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.

In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.

The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.

The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.

Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.

“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”

The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
 

SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.

Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.

Smithore

In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.

Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.

“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.

In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.

The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.

The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.

Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.

“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”

The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
 

SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.