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The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The next 20 years will see a big shift in cancer type rankings, researchers predict.

At the moment, the most common cancers in the United States are breast, lung, prostate, colorectal, and melanoma.

By 2040, melanoma will have become the second most common cancer type, while prostate cancer will drop in incidence all the way to 14, the study authors predicted. Breast cancer will remain the top cancer to be diagnosed, lung cancer will drop from second to third, and colorectal cancer will remain at fourth.

These predicted rankings of cancer types by their total number of annual cases were published online April 7, 2021, in JAMA Network Open.

The authors also rank cancer type by mortality. Currently, most cancer deaths are caused by lung cancer, followed by colorectal, pancreatic, and breast. By 2040, the most notable change in cancer deaths is that liver and intrahepatic bile duct cancer, currently at sixth, will jump up to third.

Two decades from now, the ranking in terms of cancer deaths will be lung, pancreatic, liver and intrahepatic bile duct, and colorectal.

“Our findings reflect the shifting dynamics of cancer screening and treatment,” lead author Lola Rahib, PhD, a pancreatic cancer scientist at Cancer Commons, the advocacy nonprofit, commented in a press statement.

The new analysis used population-growth projections (based on 2010 U.S. Census data) and current population-based cancer incidence and death rates (from Surveillance, Epidemiology, and End Results 2014-2016) to calculate the changes in incidences and deaths to the year 2040.

The projected, estimated numbers are not ironclad, the researchers acknowledged.

“Our projections assume that the observed rates and trends [from recent years] don’t change over time,” Dr. Rahib said in an interview, but she pointed out that change may indeed happen.

“Any long-term projections should be considered with a grain of salt,” said Kim Miller, MPH, a surveillance research scientist at the American Cancer Society, who was approached for comment.

Dr. Miller explained that “cancer trends can sometimes rapidly change within a few years.” Projections just 2-4 years ahead are “extremely difficult” and those 20 years ahead are even more so, she added in an interview.

“We’re encouraged to see the projected decreases in deaths from lung, colorectal, and breast cancer in the coming years,” said coauthor Lynn Matrisian, PhD, MBA, chief science officer at the Pancreatic Cancer Action Network. “It’s time to shift focus to some of the less commonly diagnosed cancers with the lowest survival rates, like pancreatic and liver cancer.”
 

Difference in opinion on prostate cancer

The huge fall in the incidence of prostate cancer that the authors predict will come about as a result of changes in prostate-specific antigen (PSA)–screening recommendations over the last 15 years, they suggested.

“The most recent change in 2018 recommends that men aged 55-69 can make their own decisions regarding screening, but previous changes recommended against PSA screening,” said Dr. Rahib.

“These changes in screening guidelines have influenced the number of diagnoses of prostate cancer in recent years and will continue to do so to 2040,” Dr. Rahib commented.

Dr. Miller casts doubt on this prediction.

Using data through 2017, “we have seen that the patterns in prostate cancer incidence are already shifting from the steep declines we saw in the early 2010s,” she said. “I would use caution when interpreting the overall trends for prostate, because this cancer in particular is dramatically affected by changes in recommendations for screening with the PSA test.”

Screening has also influenced colorectal cancer incidence, the authors pointed out, saying that the uptake of colorectal cancer screening is associated with a decrease in the number of colorectal cancers and deaths out to 2040, as a result of effectiveness of screening.

For breast cancer, the authors highlighted the fact that, although the number of breast cancers will continue to increase, the number of breast cancer deaths will decrease. That ongoing trend is most likely attributable to increased screening and advancements in treatment.

The study was supported by the National Institutes of Health, National Cancer Institute, the Cancer Prevention and Research Institute of Texas, Cancer Commons and the Pancreatic Cancer Action Network. The study authors and Dr. Miller disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has lifted in-person dispensing requirements for mifepristone when used for medical termination of early pregnancy.  
In an April 12, 2021, letter to the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine, acting commissioner of food and drugs Janet Woodcock stated that the FDA would exercise discretion to permit the dispensing of mifepristone through the mail when done by or under the supervision of a certified prescriber; or through a mail-order pharmacy under the supervision of a certified prescriber.  
The decision follows a trial period of suspension of the in-person dispensing requirement in response to safety concerns for patients as well as providers associated with in-person clinic visits during the COVID-19 pandemic. The Center for Drug Evaluation and Research reviewed safety and clinical outcomes data on mifepristone use when prescriptions were handled by mail or mail-order pharmacy and found that "the small number of adverse events reported to FDA during the COVID-19 public health emergency [PHE] provide no indication that any program deviation or noncompliance with the mifepristone [Risk Evaluation and Mitigation Strategy] program contributed to the reported adverse events," according to the letter. The analysis covers Mifeprex and the approved generic, mifepristone tablets, both 200-mg doses. 
As long as other mifepristone REMS criteria are met, the FDA will continue to permit mail and mail-order prescriptions, according to the letter. 
"By halting enforcement of the in-person dispensing requirement during the COVID-19 pandemic, the FDA is recognizing and responding to the available evidence - which has clearly and definitively demonstrated that the in-person dispensing requirement for mifepristone is unnecessary and restrictive," Maureen G. Phipps, MD, MPH, CEO of ACOG, said in a statement in response to the FDA decision.  
ACOG petitioned the FDA to suspend the in-person requirement to reduce the risk of transmission in the wake of the COVID-19 pandemic, given safety concerns and the potential impact on hard-hit communities, particularly communities of color, Dr. Phipps emphasized. Data from a review period with a suspension of the in-person requirement yielded no additional safety concerns with mifepristone use, and contributed to the FDA decision to lift the requirement. 
"Thanks to the FDA's intent to exercise discretion in enforcing the in-person dispensing requirement, those in need of an abortion or miscarriage management will be able to do so safety and effectively by acquiring mifepristone though the mail - just as they would any other medication with a similarly strong safety profile," said Dr. Phipps. "We are pleased to see mifepristone regulated on the basis of the scientific evidence during the pandemic, rather than political bias against comprehensive reproductive health care, and we look forward to working with policy makers to ensure this principle governs postpandemic care."  
CDER is communicating the decision to all approved application holders subject to the mifepristone REMS program, according to the letter.  
obnews@mdedge.com

The Food and Drug Administration has lifted in-person dispensing requirements for mifepristone when used for medical termination of early pregnancy.  
In an April 12, 2021, letter to the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine, acting commissioner of food and drugs Janet Woodcock stated that the FDA would exercise discretion to permit the dispensing of mifepristone through the mail when done by or under the supervision of a certified prescriber; or through a mail-order pharmacy under the supervision of a certified prescriber.  
The decision follows a trial period of suspension of the in-person dispensing requirement in response to safety concerns for patients as well as providers associated with in-person clinic visits during the COVID-19 pandemic. The Center for Drug Evaluation and Research reviewed safety and clinical outcomes data on mifepristone use when prescriptions were handled by mail or mail-order pharmacy and found that "the small number of adverse events reported to FDA during the COVID-19 public health emergency [PHE] provide no indication that any program deviation or noncompliance with the mifepristone [Risk Evaluation and Mitigation Strategy] program contributed to the reported adverse events," according to the letter. The analysis covers Mifeprex and the approved generic, mifepristone tablets, both 200-mg doses. 
As long as other mifepristone REMS criteria are met, the FDA will continue to permit mail and mail-order prescriptions, according to the letter. 
"By halting enforcement of the in-person dispensing requirement during the COVID-19 pandemic, the FDA is recognizing and responding to the available evidence - which has clearly and definitively demonstrated that the in-person dispensing requirement for mifepristone is unnecessary and restrictive," Maureen G. Phipps, MD, MPH, CEO of ACOG, said in a statement in response to the FDA decision.  
ACOG petitioned the FDA to suspend the in-person requirement to reduce the risk of transmission in the wake of the COVID-19 pandemic, given safety concerns and the potential impact on hard-hit communities, particularly communities of color, Dr. Phipps emphasized. Data from a review period with a suspension of the in-person requirement yielded no additional safety concerns with mifepristone use, and contributed to the FDA decision to lift the requirement. 
"Thanks to the FDA's intent to exercise discretion in enforcing the in-person dispensing requirement, those in need of an abortion or miscarriage management will be able to do so safety and effectively by acquiring mifepristone though the mail - just as they would any other medication with a similarly strong safety profile," said Dr. Phipps. "We are pleased to see mifepristone regulated on the basis of the scientific evidence during the pandemic, rather than political bias against comprehensive reproductive health care, and we look forward to working with policy makers to ensure this principle governs postpandemic care."  
CDER is communicating the decision to all approved application holders subject to the mifepristone REMS program, according to the letter.  
obnews@mdedge.com

The Food and Drug Administration has lifted in-person dispensing requirements for mifepristone when used for medical termination of early pregnancy.  
In an April 12, 2021, letter to the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine, acting commissioner of food and drugs Janet Woodcock stated that the FDA would exercise discretion to permit the dispensing of mifepristone through the mail when done by or under the supervision of a certified prescriber; or through a mail-order pharmacy under the supervision of a certified prescriber.  
The decision follows a trial period of suspension of the in-person dispensing requirement in response to safety concerns for patients as well as providers associated with in-person clinic visits during the COVID-19 pandemic. The Center for Drug Evaluation and Research reviewed safety and clinical outcomes data on mifepristone use when prescriptions were handled by mail or mail-order pharmacy and found that "the small number of adverse events reported to FDA during the COVID-19 public health emergency [PHE] provide no indication that any program deviation or noncompliance with the mifepristone [Risk Evaluation and Mitigation Strategy] program contributed to the reported adverse events," according to the letter. The analysis covers Mifeprex and the approved generic, mifepristone tablets, both 200-mg doses. 
As long as other mifepristone REMS criteria are met, the FDA will continue to permit mail and mail-order prescriptions, according to the letter. 
"By halting enforcement of the in-person dispensing requirement during the COVID-19 pandemic, the FDA is recognizing and responding to the available evidence - which has clearly and definitively demonstrated that the in-person dispensing requirement for mifepristone is unnecessary and restrictive," Maureen G. Phipps, MD, MPH, CEO of ACOG, said in a statement in response to the FDA decision.  
ACOG petitioned the FDA to suspend the in-person requirement to reduce the risk of transmission in the wake of the COVID-19 pandemic, given safety concerns and the potential impact on hard-hit communities, particularly communities of color, Dr. Phipps emphasized. Data from a review period with a suspension of the in-person requirement yielded no additional safety concerns with mifepristone use, and contributed to the FDA decision to lift the requirement. 
"Thanks to the FDA's intent to exercise discretion in enforcing the in-person dispensing requirement, those in need of an abortion or miscarriage management will be able to do so safety and effectively by acquiring mifepristone though the mail - just as they would any other medication with a similarly strong safety profile," said Dr. Phipps. "We are pleased to see mifepristone regulated on the basis of the scientific evidence during the pandemic, rather than political bias against comprehensive reproductive health care, and we look forward to working with policy makers to ensure this principle governs postpandemic care."  
CDER is communicating the decision to all approved application holders subject to the mifepristone REMS program, according to the letter.  
obnews@mdedge.com

It’s likely the United States will see another surge of COVID-19 this winter, warned Christopher Murray, MD, director of the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle.

Speaking at the national conference of State of Reform on April 8, Dr. Murray cited the seasonality of the SARS-CoV-2 virus, which wanes in the summer and waxes in the winter. The “optimistic forecast” of IHME, which has modeled the course of the pandemic for the past 13 months, is that daily deaths will rise a bit in the next month, then decline from May through August, he said.

“Summer should be fairly quiet in terms of COVID, if vaccinations rise and people don’t stop wearing masks,” Dr. Murray said.

But he added that “a considerable surge will occur over next winter,” because the new variants are more transmissible, and people will likely relax social distancing and mask wearing. The IHME predicts that the percentage of Americans who usually don masks will decline from 73% today to 21% by Aug. 1.

With a rapid decline in mask use and a rise in mobility, there will still be more than 1,000 deaths each day by July 1, Dr. Murray said. In a forecast released the day after Dr. Murray spoke, the IHME predicted that by Aug. 1, there will be a total of 618,523 U.S. deaths from COVID-19. Deaths could be as high as 696,651 if mobility among the vaccinated returns to prepandemic levels, the institute forecasts.

Based on cell phone data, Dr. Murray said, the amount of mobility in the United States has already risen to the level of March 2020, when the pandemic was just getting underway.
 

Decreased infections

If there’s one piece of good news in the latest IHME report, it’s that the estimated number of people infected (including those not tested) will drop from 111,581 today to a projected 17,502 on Aug. 1. But in a worst-case scenario, with sharply higher mobility among vaccinated people, the case count on that date would only fall to 73,842.

The SARS-CoV-2 variants are another factor of concern. Dr. Murray distinguished between variants like the one first identified in the U.K. (B.1.1.7) and other “escape variants.”

B.1.1.7, which is now the dominant strain in the United States, increases transmission but doesn’t necessarily escape the immune system or vaccines, he explained.

In contrast, if someone is infected with a variant such as the South African or the Brazilian mutations, he said, a previous COVID-19 infection might not protect the person, and vaccines are less effective against those variants.

Cross-variant immunity may range from 0% to 60% for escape variants, based on the slim amount of data now available, Dr. Murray said. In his view, these variants will be the long-term driver of the pandemic in the United States, while the United Kingdom variant is the short-term driver.

The latest data, he said, show that the Pfizer/BioNTech and Moderna vaccines are 75% effective against the escape variants, with lower efficacy for other vaccines. But booster shots may still be required to protect people against some variants.
 

Human factors

Human behavior will also help determine the course of the pandemic, he noted. Vaccine hesitancy, for example, is still high in the United States.

By the end of May, he predicted, about 180 million people will have received about two doses of vaccine. After that, he said, “vaccination will flatline due to lack of demand.” The two unknowns are how much campaigns to promote vaccination will increase vaccine confidence, and when children will be vaccinated.

In the United States, he said, 69% of adults have been vaccinated or want to get a shot. But that percentage has dropped 5 points since February, and vaccine confidence varies by state.

Dr. Murray emphasized that the winter surge he predicts can be blocked if people change their behaviors. These include a rise in vaccine confidence to 80% and continued mask wearing by most people.

However, if vaccine confidence and mask wearing decline, state governments continue to drop social distancing rules, and the uptake of boosters is low, the winter surge could be more serious, he said.
 

Double surge

Murray also raised the possibility of a double surge of COVID-19 and influenza this winter. Widely expected last winter, this double surge never materialized here or elsewhere, partly because of mask wearing. But Dr. Murray said it could happen this year: History shows that the flu tends to be stronger in years after weak outbreaks.

He advised hospitals to prepare now for whatever might come later this year. Public health authorities, he said, should speed up vaccination, monitor variants closely with additional sequencing, and try to modify behavior in high-risk groups.

Asked to explain the recent surge of COVID-19 cases in Michigan, Dr. Murray attributed it partly to the spread of the B.1.1.7 (U.K.) variant. But he noted that the U.K. variant has expanded even more widely in some other states that haven’t had an explosive surge like Michigan’s.

Moreover, he noted, Michigan doesn’t have low mask use or high mobility. So the upward spiral of COVID-19 infections there is very concerning, he said.

In regard to the role of children as reservoirs of the virus, Dr. Murray pointed out that views on this have changed around the world. For a while, people thought kids didn’t spread COVID-19 very much. That view shifted when U.K. data showed that child transmission of the B.1.1.7 variant increased by half to 9% of contacts in comparison with the original virus strain.

Dutch data, similarly, showed schools contributing to the latest outbreaks, and some European nations have closed schools. In the United States, the trend is to open them.

A version of this article first appeared on Medscape.com.

It’s likely the United States will see another surge of COVID-19 this winter, warned Christopher Murray, MD, director of the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle.

Speaking at the national conference of State of Reform on April 8, Dr. Murray cited the seasonality of the SARS-CoV-2 virus, which wanes in the summer and waxes in the winter. The “optimistic forecast” of IHME, which has modeled the course of the pandemic for the past 13 months, is that daily deaths will rise a bit in the next month, then decline from May through August, he said.

“Summer should be fairly quiet in terms of COVID, if vaccinations rise and people don’t stop wearing masks,” Dr. Murray said.

But he added that “a considerable surge will occur over next winter,” because the new variants are more transmissible, and people will likely relax social distancing and mask wearing. The IHME predicts that the percentage of Americans who usually don masks will decline from 73% today to 21% by Aug. 1.

With a rapid decline in mask use and a rise in mobility, there will still be more than 1,000 deaths each day by July 1, Dr. Murray said. In a forecast released the day after Dr. Murray spoke, the IHME predicted that by Aug. 1, there will be a total of 618,523 U.S. deaths from COVID-19. Deaths could be as high as 696,651 if mobility among the vaccinated returns to prepandemic levels, the institute forecasts.

Based on cell phone data, Dr. Murray said, the amount of mobility in the United States has already risen to the level of March 2020, when the pandemic was just getting underway.
 

Decreased infections

If there’s one piece of good news in the latest IHME report, it’s that the estimated number of people infected (including those not tested) will drop from 111,581 today to a projected 17,502 on Aug. 1. But in a worst-case scenario, with sharply higher mobility among vaccinated people, the case count on that date would only fall to 73,842.

The SARS-CoV-2 variants are another factor of concern. Dr. Murray distinguished between variants like the one first identified in the U.K. (B.1.1.7) and other “escape variants.”

B.1.1.7, which is now the dominant strain in the United States, increases transmission but doesn’t necessarily escape the immune system or vaccines, he explained.

In contrast, if someone is infected with a variant such as the South African or the Brazilian mutations, he said, a previous COVID-19 infection might not protect the person, and vaccines are less effective against those variants.

Cross-variant immunity may range from 0% to 60% for escape variants, based on the slim amount of data now available, Dr. Murray said. In his view, these variants will be the long-term driver of the pandemic in the United States, while the United Kingdom variant is the short-term driver.

The latest data, he said, show that the Pfizer/BioNTech and Moderna vaccines are 75% effective against the escape variants, with lower efficacy for other vaccines. But booster shots may still be required to protect people against some variants.
 

Human factors

Human behavior will also help determine the course of the pandemic, he noted. Vaccine hesitancy, for example, is still high in the United States.

By the end of May, he predicted, about 180 million people will have received about two doses of vaccine. After that, he said, “vaccination will flatline due to lack of demand.” The two unknowns are how much campaigns to promote vaccination will increase vaccine confidence, and when children will be vaccinated.

In the United States, he said, 69% of adults have been vaccinated or want to get a shot. But that percentage has dropped 5 points since February, and vaccine confidence varies by state.

Dr. Murray emphasized that the winter surge he predicts can be blocked if people change their behaviors. These include a rise in vaccine confidence to 80% and continued mask wearing by most people.

However, if vaccine confidence and mask wearing decline, state governments continue to drop social distancing rules, and the uptake of boosters is low, the winter surge could be more serious, he said.
 

Double surge

Murray also raised the possibility of a double surge of COVID-19 and influenza this winter. Widely expected last winter, this double surge never materialized here or elsewhere, partly because of mask wearing. But Dr. Murray said it could happen this year: History shows that the flu tends to be stronger in years after weak outbreaks.

He advised hospitals to prepare now for whatever might come later this year. Public health authorities, he said, should speed up vaccination, monitor variants closely with additional sequencing, and try to modify behavior in high-risk groups.

Asked to explain the recent surge of COVID-19 cases in Michigan, Dr. Murray attributed it partly to the spread of the B.1.1.7 (U.K.) variant. But he noted that the U.K. variant has expanded even more widely in some other states that haven’t had an explosive surge like Michigan’s.

Moreover, he noted, Michigan doesn’t have low mask use or high mobility. So the upward spiral of COVID-19 infections there is very concerning, he said.

In regard to the role of children as reservoirs of the virus, Dr. Murray pointed out that views on this have changed around the world. For a while, people thought kids didn’t spread COVID-19 very much. That view shifted when U.K. data showed that child transmission of the B.1.1.7 variant increased by half to 9% of contacts in comparison with the original virus strain.

Dutch data, similarly, showed schools contributing to the latest outbreaks, and some European nations have closed schools. In the United States, the trend is to open them.

A version of this article first appeared on Medscape.com.

It’s likely the United States will see another surge of COVID-19 this winter, warned Christopher Murray, MD, director of the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle.

Speaking at the national conference of State of Reform on April 8, Dr. Murray cited the seasonality of the SARS-CoV-2 virus, which wanes in the summer and waxes in the winter. The “optimistic forecast” of IHME, which has modeled the course of the pandemic for the past 13 months, is that daily deaths will rise a bit in the next month, then decline from May through August, he said.

“Summer should be fairly quiet in terms of COVID, if vaccinations rise and people don’t stop wearing masks,” Dr. Murray said.

But he added that “a considerable surge will occur over next winter,” because the new variants are more transmissible, and people will likely relax social distancing and mask wearing. The IHME predicts that the percentage of Americans who usually don masks will decline from 73% today to 21% by Aug. 1.

With a rapid decline in mask use and a rise in mobility, there will still be more than 1,000 deaths each day by July 1, Dr. Murray said. In a forecast released the day after Dr. Murray spoke, the IHME predicted that by Aug. 1, there will be a total of 618,523 U.S. deaths from COVID-19. Deaths could be as high as 696,651 if mobility among the vaccinated returns to prepandemic levels, the institute forecasts.

Based on cell phone data, Dr. Murray said, the amount of mobility in the United States has already risen to the level of March 2020, when the pandemic was just getting underway.
 

Decreased infections

If there’s one piece of good news in the latest IHME report, it’s that the estimated number of people infected (including those not tested) will drop from 111,581 today to a projected 17,502 on Aug. 1. But in a worst-case scenario, with sharply higher mobility among vaccinated people, the case count on that date would only fall to 73,842.

The SARS-CoV-2 variants are another factor of concern. Dr. Murray distinguished between variants like the one first identified in the U.K. (B.1.1.7) and other “escape variants.”

B.1.1.7, which is now the dominant strain in the United States, increases transmission but doesn’t necessarily escape the immune system or vaccines, he explained.

In contrast, if someone is infected with a variant such as the South African or the Brazilian mutations, he said, a previous COVID-19 infection might not protect the person, and vaccines are less effective against those variants.

Cross-variant immunity may range from 0% to 60% for escape variants, based on the slim amount of data now available, Dr. Murray said. In his view, these variants will be the long-term driver of the pandemic in the United States, while the United Kingdom variant is the short-term driver.

The latest data, he said, show that the Pfizer/BioNTech and Moderna vaccines are 75% effective against the escape variants, with lower efficacy for other vaccines. But booster shots may still be required to protect people against some variants.
 

Human factors

Human behavior will also help determine the course of the pandemic, he noted. Vaccine hesitancy, for example, is still high in the United States.

By the end of May, he predicted, about 180 million people will have received about two doses of vaccine. After that, he said, “vaccination will flatline due to lack of demand.” The two unknowns are how much campaigns to promote vaccination will increase vaccine confidence, and when children will be vaccinated.

In the United States, he said, 69% of adults have been vaccinated or want to get a shot. But that percentage has dropped 5 points since February, and vaccine confidence varies by state.

Dr. Murray emphasized that the winter surge he predicts can be blocked if people change their behaviors. These include a rise in vaccine confidence to 80% and continued mask wearing by most people.

However, if vaccine confidence and mask wearing decline, state governments continue to drop social distancing rules, and the uptake of boosters is low, the winter surge could be more serious, he said.
 

Double surge

Murray also raised the possibility of a double surge of COVID-19 and influenza this winter. Widely expected last winter, this double surge never materialized here or elsewhere, partly because of mask wearing. But Dr. Murray said it could happen this year: History shows that the flu tends to be stronger in years after weak outbreaks.

He advised hospitals to prepare now for whatever might come later this year. Public health authorities, he said, should speed up vaccination, monitor variants closely with additional sequencing, and try to modify behavior in high-risk groups.

Asked to explain the recent surge of COVID-19 cases in Michigan, Dr. Murray attributed it partly to the spread of the B.1.1.7 (U.K.) variant. But he noted that the U.K. variant has expanded even more widely in some other states that haven’t had an explosive surge like Michigan’s.

Moreover, he noted, Michigan doesn’t have low mask use or high mobility. So the upward spiral of COVID-19 infections there is very concerning, he said.

In regard to the role of children as reservoirs of the virus, Dr. Murray pointed out that views on this have changed around the world. For a while, people thought kids didn’t spread COVID-19 very much. That view shifted when U.K. data showed that child transmission of the B.1.1.7 variant increased by half to 9% of contacts in comparison with the original virus strain.

Dutch data, similarly, showed schools contributing to the latest outbreaks, and some European nations have closed schools. In the United States, the trend is to open them.

A version of this article first appeared on Medscape.com.

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A novel therapy combining platelet-rich plasma (PRP) with follicle-stimulating hormone that is injected directly into the ovaries has the potential to restore ovarian function for women who experience early menopause, possibly allowing for pregnancy without the need for donor eggs.

“The resumption of ovarian function in our participants means women with early menopause could have the opportunity to pursue pregnancy through IVF [in vitro fertilization] using their own eggs,” the authors of the groundbreaking pilot study report.

In the small study, published online March 29 in Menopause, menstruation resumed within a mean of about 5 weeks for 11 of 12 patients with early menopause who were treated with the technique. One patient achieved a clinical pregnancy.

In commenting on the study, Stephanie S. Faubion, MD, medical director of the North American Menopause Society, was cautious in her interpretation, noting the need for more research in larger samples.

“Any pregnancy that results from a regenerative therapy is novel,” she told this news organization. “Still, we are a long way away from this being a standard therapy for women with premature ovarian insufficiency.”
 

Pilot study: Platelet-rich plasma combination with FSH

Early menopause is the cessation of ovarian function at or before the age of 45 years. It is estimated that 12.2% of women experience early menopause. For these women, currently, the only chance of becoming pregnant is with donor eggs.

PRP, an autologous plasma preparation containing more than 10 times the concentration of growth factors and active metabolites than normal plasma, has recently been shown to have the potential to restore the menstrual cycles in perimenopausal women, allowing IVF. It has also been shown to benefit women with premature ovarian insufficiency (POI). However, there have been few reports of pregnancies or live births.

Chao Chin Hsu, MD, PhD, of the National Taiwan University Hospital, Taipei, and colleagues investigated whether the combination of the activated PRP treatment with gondatrophins such as FSH could provide a more robust effect so as to sufficiently stimulate follicles. They used the intraovarian injection of the combination to treat a 38-year-old woman with POI.

The effort was successful, and the woman gave birth to healthy twins.

To further evaluate the approach, the authors conducted a pilot study involving 12 women with early menopause (mean age, 44.4 years) between November 2018 and November 2019.

The women received intraovarian injection with PRP prepared from 40 mL of autologous peripheral blood combined with recombinant FSH.

Following the treatment, 11 of the 12 women experienced resumption of menstruation within a mean of 37 days. For seven patients, menstruation resumed within a month; for three, it resumed within about 2 months; and for one, it resumed after approximately 3 months.

Of note, the menstrual cycles were mostly irregular, with an interval of about 45.6 days.

The women’s average serum FSH level dropped significantly from 70.5 IU/L at baseline to 26.2 IU/L within days of treatment, as did the average luteinizing hormone level (34.8 before and 14.3 IU/L after treatment), indicative of improved ovary function.

For six participants, 10 oocyte retrieval procedures were performed after a mean of about 2 months. Thirteen mature eggs were retrieved, and fertilization via intracytoplasmic sperm injection was attempted, resulting in 10 fertilized oocytes.

Cleavage-stage embryos were transferred into two of the participants. One achieved a clinical pregnancy, defined as a pregnancy that was confirmed by ultrasound and by the presence of a fetal heartbeat. The pregnancy ended in miscarriage at 7 weeks’ gestation.

The length of controlled ovarian stimulation necessary for follicle growth ranged from 8 to 14 days, which the authors note is similar to that seen with women of normal reproductive age.

“Although the use of PRP in reproductive medicine is considered experimental, we demonstrated the restoration of ovarian function in early menopausal women who adopted whole dimension subcortical ovarian injection of PRP/gonadotropin,” the authors write.

“Most remarkably, an early menopausal woman achieved pregnancy after the treatment followed by IVF with her mature ovulating follicle,” they report.
 

Mechanisms, caveats

The mechanisms thought to underlie the success of the approach include increases in ovarian vascularization and stromal cell proliferation and reductions in oxidative stress and cell death in ovaries, the authors explain.

Key caveats with the treatment include the fact that anesthesia and laparoscopy are required, and precise administration is required at 15 injection sites in 1-2 mm of the ovarian subcortical area, which can be difficult to achieve, Dr. Hsu said in an interview.

“If a new instrument could be developed in which physicians can carry out this treatment through a vaginal approach, like the transvaginal retrieval of eggs in IVF treatments,” the approach could become more acceptable, Dr. Hsu added.

The authors call for studies with larger sample sizes and say it will also be interesting to determine effects in different groups: For example, women with cancer who have undergone chemotherapy.

Dr. Faubion, who is director of the Mayo Clinic Women’s Health, Rochester, Minn., says the causes of early menopause could be important in determining the treatment’s efficacy.

“[The therapy’s] success may depend on the reason the woman experienced early menopause: For instance, due to chemotherapy, radiation, virus, autoimmune disease, genetic mutation, or other cause,” she said.

She also noted that cost could be an important factor.

“I don’t see a cost estimate, but it will be substantial,” she said. “So, even if the success rate improves as this technique is further studied, cost and the invasive nature of the treatment may prove to be substantial barriers to this therapy becoming mainstream,” she said.

The authors and Dr. Faubion have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A version of this article first appeared on WebMD.com.

This article was updated 4/13/21.

A version of this article first appeared on WebMD.com.

This article was updated 4/13/21.

A version of this article first appeared on WebMD.com.

This article was updated 4/13/21.

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

 

 

Services that RHCs provide

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

 

 

Services that RHCs provide

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

 

 

Services that RHCs provide

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

 

 

Pregnancy and prevention

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

 

 

Pregnancy and prevention

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

 

 

Pregnancy and prevention

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●