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Does racial bias taint the Apgar score?
Experts say overhaul needed
In 1952, when Dr. Virginia Apgar developed her 10-point scale for assessing neonates’ health, the U.S. obstetrical anesthesiologst may not have foreseen it would one day become one of the commonest medical tests in the world.
Assigned even before the mother first holds her newborn, the score rapidly evaluates neonates with a score of 0-10, which leads to an algorithm of potential medical interventions. The scale evaluates heart rate, respiratory effort, muscle tone, reflex response, and skin coloring (typically described as blue body, pink body/blue limbs, or pink body).
“The Apgar is a very important tool used in millions of babies around the world in the very first minute after birth,” said Amos Grunebaum, MD, a professor of obstetrics and gynecology at Hofstra University, Hempstead, N.Y., and director of perinatal research at Northwell Lenox Hill Hospital in Manhattan.
But recently the venerable system has increasingly come under fire for colorism and racial bias, with some calling for an overhaul. That pressure is due to the 2 out of 10 points allotted to an overall “pink” skin tone, a measure that lowers the scores of non-White newborns and may expose them to unnecessary measures such as resuscitation, neonatal intensive care, and intubation.
“This is their first encounter with systemic racism,” said Dr. Grunebaum in an interview. “The score is prejudiced against Black babies because they can’t get perfect scores.”
Propagating ‘race-based medicine’
Concern about racial bias embedded in the Apgar score is not new, Dr. Grunebaum noted.
“Decades ago, when I was doing my training in Brooklyn, the nurses said that using skin color was ridiculous since Black and brown babies couldn’t be pink. And skin color looks different in different lighting. Dr. Apgar herself recognized the problem.”
Furthermore, men see color differently than women do, and some people are actually color-blind.“But nobody wanted to speak out,” Dr. Grunebaum said. “It was like the emperor’s new clothes scenario.”
In his view, embedding skin color scoring into basic data and health care decisions propagates race-based medicine. “It should not be used for White, Black, or brown babies,” he said.
Removing the skin color portion of the Apgar score – and its racial, colorist, and ethnic bias – will provide more accurate and equitable evaluation of newborn babies worldwide, Dr. Grunebaum said.
“I think there’s a pretty good argument to be made that the skin color measure should be eliminated,” agreed Sara E. Edwards, MD, an obstetrician-gynecologist at the University of Illinois Hospital in Chicago, who has also studied Apgar and racial bias in the clinical care of Black babies.
And such clinical bias may soon be illegal in the United States thanks to a proposed new antidiscrimination provision to the Affordable Care Act regarding the use of clinical algorithms in decision-making. The proposed section, § 92.210, states that a covered entity must not discriminate against any individual on the basis of race, color, national origin, sex, age, or disability through clinical algorithms used in decision-making. Hospitals may soon have to alter clinical algorithms in response.
Dr. Grunebaum’s research in the area of clinical racism includes a large 2022 cohort study of almost 10 million mothers and more than 8 million fathers using 2016-2019 natality data from the National Center for Health Statistics, and Division of Vital Statistics. This study found that Black newborns had a less than 50% chance of having a 5-minute Apgar score of 10, compared with White newborns. White babies, both non-Hispanic and Hispanic, had the highest proportion of perfect 10s.
But can the 2-point skin tone indicator be easily replaced? According to Dr. Grunebaum, substituting indicators such as oral mucosa color or oximetry readings are not satisfactory either. “For one thing, oximetry gives different readings in Black [people],” he said.
In her group’s Apgar research, Dr. Edwards found that care providers applied variable and inaccurate scores based on neonatal race – independently of clinical factors and umbilical-cord gas values.
“In Black neonates umbilical cord gases were not in agreement with lower Apgar scores,” she said. In her view, these inaccuracies point to the existence of colorism and racial bias among health care providers.
Bias ‘creeping in’ to neonatal care
Dr. Edwards’s research was prompted by anecdotal observations that Black babies generally had lower Apgar scores and were more frequently sent to the NICU. “Admission to the NICU can have a negative effect on maternal-child bonding and contribute to PTSD in mothers,” she said.
Her group looked at Apgar scores by race for the year 2019 in an academic hospital cohort of 977 neonates, of whom 56.5% were Black, while controlling for confounding clinical factors.
“Our anecdotal observations of how we score Black neonates were confirmed,” she said. Providers assigned Black babies significantly lower Apgar scores at 1 minute and 5 minutes (odds ratios, .63 and .64) when controlling for umbilical artery gases, gestational age, and maternal-fetal complications.
This difference was specifically associated with lower assigned color Apgar scores at 1 minute (odds ratio, .52). Moreover, full-term Black neonates were sent to neonatal intensive care at higher rates (odds ratio, 1.29) than non-Black neonates when controlling for all the above factors.
Providers applied inaccurate Apgar scores to Black neonates given that the umbilical cord gases were not in agreement with lower Apgar scores, suggesting that colorism and racial biases do exist among health care providers. “We saw bias creeping in because of subjective decisions about color,” Dr. Edwards said. But by the more objective measure of umbilical-cord gas, Black neonates did not have the abnormal values to support NICU admission. The mean umbilical artery pH was 7.259 for Black vs. 7.256 for non-Black neonates.
The solution may lie in switching to an 8 out of 8 score or looking at other indicators such as the eyes and the nail beds, she said. “Or there may be a way to score skin tone accurately when providers are appropriately trained to do so on neonates of all races, to recognize what a well-perfused skin color looks like in all babies.”
New scoring system needed
Interest in this issue continues. In 2022, a population study was conducted by Emma Gillette, MPH, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues in a cohort of almost 7 million singletons born in 2016-2017.
“We found that overall, Apgar scores were highly associated with mortality across the first year of life,” Ms. Gillette said in an interview. “But non-Hispanic Black infants were more likely to be assigned low Apgar scores compared to White infants, and the odds of death in the first year of life are not as strongly correlated with Apgar scores as in White infants.”
That finding was surprising. “Apgar scores are meant to be an indicator of newborn health and well-being and predictors of infant mortality, and therefore should not vary significantly by race or skin color,” she said. “So I think further study into the component scores of the Apgar score is warranted to try to tease out the reasons behind the differences we’re seeing.”
Ms. Gillette agreed that the skin coloring component of the variable could be inaccurate since variables related to skin color more generally are subjective and difficult to measure. What’s needed is a scoring system that performs equally well across racial groups.
In the meantime, some clinicians may be making practical accommodations. “I hate to tell you, but some people fake the skin score,” said Dr. Grunebaum. “I recently asked a doctor from Ethiopia how they handled it there, and he laughed and said they just automatically give skin color a 2. But faking it is not what you should have to do in medicine.”
Dr. Grunebaum, Dr. Edwards, and Ms. Gillette disclosed no relevant competing interests with respect to their comments.
Experts say overhaul needed
Experts say overhaul needed
In 1952, when Dr. Virginia Apgar developed her 10-point scale for assessing neonates’ health, the U.S. obstetrical anesthesiologst may not have foreseen it would one day become one of the commonest medical tests in the world.
Assigned even before the mother first holds her newborn, the score rapidly evaluates neonates with a score of 0-10, which leads to an algorithm of potential medical interventions. The scale evaluates heart rate, respiratory effort, muscle tone, reflex response, and skin coloring (typically described as blue body, pink body/blue limbs, or pink body).
“The Apgar is a very important tool used in millions of babies around the world in the very first minute after birth,” said Amos Grunebaum, MD, a professor of obstetrics and gynecology at Hofstra University, Hempstead, N.Y., and director of perinatal research at Northwell Lenox Hill Hospital in Manhattan.
But recently the venerable system has increasingly come under fire for colorism and racial bias, with some calling for an overhaul. That pressure is due to the 2 out of 10 points allotted to an overall “pink” skin tone, a measure that lowers the scores of non-White newborns and may expose them to unnecessary measures such as resuscitation, neonatal intensive care, and intubation.
“This is their first encounter with systemic racism,” said Dr. Grunebaum in an interview. “The score is prejudiced against Black babies because they can’t get perfect scores.”
Propagating ‘race-based medicine’
Concern about racial bias embedded in the Apgar score is not new, Dr. Grunebaum noted.
“Decades ago, when I was doing my training in Brooklyn, the nurses said that using skin color was ridiculous since Black and brown babies couldn’t be pink. And skin color looks different in different lighting. Dr. Apgar herself recognized the problem.”
Furthermore, men see color differently than women do, and some people are actually color-blind.“But nobody wanted to speak out,” Dr. Grunebaum said. “It was like the emperor’s new clothes scenario.”
In his view, embedding skin color scoring into basic data and health care decisions propagates race-based medicine. “It should not be used for White, Black, or brown babies,” he said.
Removing the skin color portion of the Apgar score – and its racial, colorist, and ethnic bias – will provide more accurate and equitable evaluation of newborn babies worldwide, Dr. Grunebaum said.
“I think there’s a pretty good argument to be made that the skin color measure should be eliminated,” agreed Sara E. Edwards, MD, an obstetrician-gynecologist at the University of Illinois Hospital in Chicago, who has also studied Apgar and racial bias in the clinical care of Black babies.
And such clinical bias may soon be illegal in the United States thanks to a proposed new antidiscrimination provision to the Affordable Care Act regarding the use of clinical algorithms in decision-making. The proposed section, § 92.210, states that a covered entity must not discriminate against any individual on the basis of race, color, national origin, sex, age, or disability through clinical algorithms used in decision-making. Hospitals may soon have to alter clinical algorithms in response.
Dr. Grunebaum’s research in the area of clinical racism includes a large 2022 cohort study of almost 10 million mothers and more than 8 million fathers using 2016-2019 natality data from the National Center for Health Statistics, and Division of Vital Statistics. This study found that Black newborns had a less than 50% chance of having a 5-minute Apgar score of 10, compared with White newborns. White babies, both non-Hispanic and Hispanic, had the highest proportion of perfect 10s.
But can the 2-point skin tone indicator be easily replaced? According to Dr. Grunebaum, substituting indicators such as oral mucosa color or oximetry readings are not satisfactory either. “For one thing, oximetry gives different readings in Black [people],” he said.
In her group’s Apgar research, Dr. Edwards found that care providers applied variable and inaccurate scores based on neonatal race – independently of clinical factors and umbilical-cord gas values.
“In Black neonates umbilical cord gases were not in agreement with lower Apgar scores,” she said. In her view, these inaccuracies point to the existence of colorism and racial bias among health care providers.
Bias ‘creeping in’ to neonatal care
Dr. Edwards’s research was prompted by anecdotal observations that Black babies generally had lower Apgar scores and were more frequently sent to the NICU. “Admission to the NICU can have a negative effect on maternal-child bonding and contribute to PTSD in mothers,” she said.
Her group looked at Apgar scores by race for the year 2019 in an academic hospital cohort of 977 neonates, of whom 56.5% were Black, while controlling for confounding clinical factors.
“Our anecdotal observations of how we score Black neonates were confirmed,” she said. Providers assigned Black babies significantly lower Apgar scores at 1 minute and 5 minutes (odds ratios, .63 and .64) when controlling for umbilical artery gases, gestational age, and maternal-fetal complications.
This difference was specifically associated with lower assigned color Apgar scores at 1 minute (odds ratio, .52). Moreover, full-term Black neonates were sent to neonatal intensive care at higher rates (odds ratio, 1.29) than non-Black neonates when controlling for all the above factors.
Providers applied inaccurate Apgar scores to Black neonates given that the umbilical cord gases were not in agreement with lower Apgar scores, suggesting that colorism and racial biases do exist among health care providers. “We saw bias creeping in because of subjective decisions about color,” Dr. Edwards said. But by the more objective measure of umbilical-cord gas, Black neonates did not have the abnormal values to support NICU admission. The mean umbilical artery pH was 7.259 for Black vs. 7.256 for non-Black neonates.
The solution may lie in switching to an 8 out of 8 score or looking at other indicators such as the eyes and the nail beds, she said. “Or there may be a way to score skin tone accurately when providers are appropriately trained to do so on neonates of all races, to recognize what a well-perfused skin color looks like in all babies.”
New scoring system needed
Interest in this issue continues. In 2022, a population study was conducted by Emma Gillette, MPH, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues in a cohort of almost 7 million singletons born in 2016-2017.
“We found that overall, Apgar scores were highly associated with mortality across the first year of life,” Ms. Gillette said in an interview. “But non-Hispanic Black infants were more likely to be assigned low Apgar scores compared to White infants, and the odds of death in the first year of life are not as strongly correlated with Apgar scores as in White infants.”
That finding was surprising. “Apgar scores are meant to be an indicator of newborn health and well-being and predictors of infant mortality, and therefore should not vary significantly by race or skin color,” she said. “So I think further study into the component scores of the Apgar score is warranted to try to tease out the reasons behind the differences we’re seeing.”
Ms. Gillette agreed that the skin coloring component of the variable could be inaccurate since variables related to skin color more generally are subjective and difficult to measure. What’s needed is a scoring system that performs equally well across racial groups.
In the meantime, some clinicians may be making practical accommodations. “I hate to tell you, but some people fake the skin score,” said Dr. Grunebaum. “I recently asked a doctor from Ethiopia how they handled it there, and he laughed and said they just automatically give skin color a 2. But faking it is not what you should have to do in medicine.”
Dr. Grunebaum, Dr. Edwards, and Ms. Gillette disclosed no relevant competing interests with respect to their comments.
In 1952, when Dr. Virginia Apgar developed her 10-point scale for assessing neonates’ health, the U.S. obstetrical anesthesiologst may not have foreseen it would one day become one of the commonest medical tests in the world.
Assigned even before the mother first holds her newborn, the score rapidly evaluates neonates with a score of 0-10, which leads to an algorithm of potential medical interventions. The scale evaluates heart rate, respiratory effort, muscle tone, reflex response, and skin coloring (typically described as blue body, pink body/blue limbs, or pink body).
“The Apgar is a very important tool used in millions of babies around the world in the very first minute after birth,” said Amos Grunebaum, MD, a professor of obstetrics and gynecology at Hofstra University, Hempstead, N.Y., and director of perinatal research at Northwell Lenox Hill Hospital in Manhattan.
But recently the venerable system has increasingly come under fire for colorism and racial bias, with some calling for an overhaul. That pressure is due to the 2 out of 10 points allotted to an overall “pink” skin tone, a measure that lowers the scores of non-White newborns and may expose them to unnecessary measures such as resuscitation, neonatal intensive care, and intubation.
“This is their first encounter with systemic racism,” said Dr. Grunebaum in an interview. “The score is prejudiced against Black babies because they can’t get perfect scores.”
Propagating ‘race-based medicine’
Concern about racial bias embedded in the Apgar score is not new, Dr. Grunebaum noted.
“Decades ago, when I was doing my training in Brooklyn, the nurses said that using skin color was ridiculous since Black and brown babies couldn’t be pink. And skin color looks different in different lighting. Dr. Apgar herself recognized the problem.”
Furthermore, men see color differently than women do, and some people are actually color-blind.“But nobody wanted to speak out,” Dr. Grunebaum said. “It was like the emperor’s new clothes scenario.”
In his view, embedding skin color scoring into basic data and health care decisions propagates race-based medicine. “It should not be used for White, Black, or brown babies,” he said.
Removing the skin color portion of the Apgar score – and its racial, colorist, and ethnic bias – will provide more accurate and equitable evaluation of newborn babies worldwide, Dr. Grunebaum said.
“I think there’s a pretty good argument to be made that the skin color measure should be eliminated,” agreed Sara E. Edwards, MD, an obstetrician-gynecologist at the University of Illinois Hospital in Chicago, who has also studied Apgar and racial bias in the clinical care of Black babies.
And such clinical bias may soon be illegal in the United States thanks to a proposed new antidiscrimination provision to the Affordable Care Act regarding the use of clinical algorithms in decision-making. The proposed section, § 92.210, states that a covered entity must not discriminate against any individual on the basis of race, color, national origin, sex, age, or disability through clinical algorithms used in decision-making. Hospitals may soon have to alter clinical algorithms in response.
Dr. Grunebaum’s research in the area of clinical racism includes a large 2022 cohort study of almost 10 million mothers and more than 8 million fathers using 2016-2019 natality data from the National Center for Health Statistics, and Division of Vital Statistics. This study found that Black newborns had a less than 50% chance of having a 5-minute Apgar score of 10, compared with White newborns. White babies, both non-Hispanic and Hispanic, had the highest proportion of perfect 10s.
But can the 2-point skin tone indicator be easily replaced? According to Dr. Grunebaum, substituting indicators such as oral mucosa color or oximetry readings are not satisfactory either. “For one thing, oximetry gives different readings in Black [people],” he said.
In her group’s Apgar research, Dr. Edwards found that care providers applied variable and inaccurate scores based on neonatal race – independently of clinical factors and umbilical-cord gas values.
“In Black neonates umbilical cord gases were not in agreement with lower Apgar scores,” she said. In her view, these inaccuracies point to the existence of colorism and racial bias among health care providers.
Bias ‘creeping in’ to neonatal care
Dr. Edwards’s research was prompted by anecdotal observations that Black babies generally had lower Apgar scores and were more frequently sent to the NICU. “Admission to the NICU can have a negative effect on maternal-child bonding and contribute to PTSD in mothers,” she said.
Her group looked at Apgar scores by race for the year 2019 in an academic hospital cohort of 977 neonates, of whom 56.5% were Black, while controlling for confounding clinical factors.
“Our anecdotal observations of how we score Black neonates were confirmed,” she said. Providers assigned Black babies significantly lower Apgar scores at 1 minute and 5 minutes (odds ratios, .63 and .64) when controlling for umbilical artery gases, gestational age, and maternal-fetal complications.
This difference was specifically associated with lower assigned color Apgar scores at 1 minute (odds ratio, .52). Moreover, full-term Black neonates were sent to neonatal intensive care at higher rates (odds ratio, 1.29) than non-Black neonates when controlling for all the above factors.
Providers applied inaccurate Apgar scores to Black neonates given that the umbilical cord gases were not in agreement with lower Apgar scores, suggesting that colorism and racial biases do exist among health care providers. “We saw bias creeping in because of subjective decisions about color,” Dr. Edwards said. But by the more objective measure of umbilical-cord gas, Black neonates did not have the abnormal values to support NICU admission. The mean umbilical artery pH was 7.259 for Black vs. 7.256 for non-Black neonates.
The solution may lie in switching to an 8 out of 8 score or looking at other indicators such as the eyes and the nail beds, she said. “Or there may be a way to score skin tone accurately when providers are appropriately trained to do so on neonates of all races, to recognize what a well-perfused skin color looks like in all babies.”
New scoring system needed
Interest in this issue continues. In 2022, a population study was conducted by Emma Gillette, MPH, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues in a cohort of almost 7 million singletons born in 2016-2017.
“We found that overall, Apgar scores were highly associated with mortality across the first year of life,” Ms. Gillette said in an interview. “But non-Hispanic Black infants were more likely to be assigned low Apgar scores compared to White infants, and the odds of death in the first year of life are not as strongly correlated with Apgar scores as in White infants.”
That finding was surprising. “Apgar scores are meant to be an indicator of newborn health and well-being and predictors of infant mortality, and therefore should not vary significantly by race or skin color,” she said. “So I think further study into the component scores of the Apgar score is warranted to try to tease out the reasons behind the differences we’re seeing.”
Ms. Gillette agreed that the skin coloring component of the variable could be inaccurate since variables related to skin color more generally are subjective and difficult to measure. What’s needed is a scoring system that performs equally well across racial groups.
In the meantime, some clinicians may be making practical accommodations. “I hate to tell you, but some people fake the skin score,” said Dr. Grunebaum. “I recently asked a doctor from Ethiopia how they handled it there, and he laughed and said they just automatically give skin color a 2. But faking it is not what you should have to do in medicine.”
Dr. Grunebaum, Dr. Edwards, and Ms. Gillette disclosed no relevant competing interests with respect to their comments.
OCD linked to adverse pregnancy and neonatal outcomes
In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.
“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.
The study was published online in JAMA Network Open.
Increased risk
OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.
The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.
In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.
The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).
These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
SRI medication
SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.
To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.
The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.
It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
‘Multifactorial’ reasons
In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.
Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.
However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders.
Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”
The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.
“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.
The study was published online in JAMA Network Open.
Increased risk
OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.
The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.
In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.
The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).
These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
SRI medication
SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.
To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.
The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.
It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
‘Multifactorial’ reasons
In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.
Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.
However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders.
Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”
The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an observational study that followed almost 3 million pregnancies in two countries over 20 years, children of women with OCD were at increased risk for low Apgar score at 5 minutes in Sweden (adjusted risk ratio [aRR], 1.62) and British Columbia, Canada (aRR, 2.30). The risks for adverse outcomes were greater among women with OCD who were taking serotonin reuptake inhibitors (SRIs), compared with those who were not.
“To me, the most relevant things to consider are the clinical implications of these findings,” lead author Lorena Fernández de la Cruz, PhD, principal researcher at Karolinska Institute in Stockholm, told this news organization. She noted that some of the outcomes, such as preeclampsia, can be prevented or improved with collaboration among clinicians and increased monitoring.
The study was published online in JAMA Network Open.
Increased risk
OCD affects roughly 1%-3% of the population. Although it is sometimes seen as a mild psychiatric disorder, OCD entails a range of adverse outcomes, and this research suggests that the adverse outcomes extend to maternal health, Dr. Fernández de la Cruz stressed.
The researchers drew data from population registers in Sweden and British Columbia for all singleton births over a roughly 20-year period ending in 2019, with subcohorts identified by formal OCD diagnosis and exposure to SRIs within 30 days before conception. Statistical analyses were performed on a range of pregnancy, delivery, and neonatal outcomes.
In an analysis adjusted for common risk factors such as age, BMI, and smoking, Swedish women with OCD had elevated risk for several adverse outcomes, including a 40% increased risk for gestational diabetes. In British Columbia, fewer adverse pregnancy outcomes for women were associated with an OCD diagnosis.
The study, which also tracked neonatal outcomes, found that infants of mothers with OCD in both Sweden and British Columbia had higher rates of preterm birth (Sweden: aRR, 1.33; BC: aRR, 1.58), low birth weight (Sweden: aRR, 1.28; BC: aRR, 1.40), and neonatal respiratory distress (Sweden: aRR, 1.63; BC: aRR, 1.47).
These results, the authors say, show a need for more monitoring of maternal OCD and collaboration among obstetricians and psychologists. “All this evidence shows that OCD should be detected and treated so that adverse outcomes can be prevented or properly handled,” said Dr. Fernández de la Cruz.
SRI medication
SRIs are frequently used to treat OCD. The subclass of selective SRIs, which includes common antidepressants, has been associated with worsened pregnancy outcomes, but it remains unclear whether all SRIs increase pregnancy risks.
To understand the role of SRIs better in this study, the authors compared the outcomes for women taking SRIs and those who were not prescribed the medication, which is a novel aspect of the study, according to Dr. Fernández de la Cruz. Women who took the medication were at greater risk for several adverse outcomes, although all women with an OCD diagnosis were at higher risk than were those without the condition. The investigators hope to continue studying the role of OCD medication during pregnancy in more detail.
The rates of SRI use varied between the two cohorts: 81% of Canadian patients took the medication, compared with 37% of Swedish patients. The disparate rates, along with other clinical practices, may have contributed to differences in outcomes for the two cohorts.
It is also important to bear in mind, however, that patients taking the medication tend to have more severe cases of OCD, said Dr. Fernández de la Cruz. Thus, the increased risk may or may not result from the medication itself. “It is important to understand that there may be other variables besides medication explaining why one group had higher risks than the other,” she said.
‘Multifactorial’ reasons
In addition to medication, other factors may play a role in the association between OCD and adverse pregnancy and neonatal outcomes, including genetics, lifestyle, and psychiatric comorbidities. The authors addressed some of these potential confounders in additional analyses, including sister and cousin comparisons in the Swedish arm of the study, which found weakened associations, compared with population wide statistics.
Commenting on the research, Benicio Frey, PhD, professor of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ont., said that acknowledging these confounding factors is a strength of the study. Psychiatric conditions such as depression and anxiety are common among patients with OCD. Of the patients with OCD in this study, 72% and 51% had other psychiatric diagnoses in Sweden and British Columbia, respectively. About 7% of the women without OCD had one of these conditions.
However, Dr. Frey said that the effect of adjusting for psychiatric comorbidities on some outcomes should be stated more clearly. “I see a clear difference,” he said. The relative risk for gestational diabetes among the Swedish cohort, for example, drops from a 40% increased risk to 19% increased when adjusted for mood and anxiety disorders.
Regardless of the cause, the results are important and demonstrate a need to provide additional care for pregnant women with psychiatric conditions, said Dr. Frey. “The important take-home message for policymakers and health care providers is to make sure that they assess for OCD and then monitor those individuals very closely. What I would suggest as a caution is that the reasons behind it are multifactorial.”
The study was supported by the Swedish Research Council for Health, Working Life, and Welfare and by the Canadian Institute of Health Research. Dr. Fernández de la Cruz and Dr. Frey reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Peripartum cardiomyopathy raises risks at future pregnancy despite LV recovery
, a new study suggests.
Researchers looked at the long-term outcomes in a cohort of women who had developed PPCM and became pregnant again several years later, comparing those with LV function that had “normalized” in the interim against those with persisting LV dysfunction.
In their analysis, adverse maternal outcomes 5 years after an index pregnancy were significantly worse among those in whom LV dysfunction had persisted, compared with those with recovered LV function. The risk of relapsed PPCM persisted out to 8 years. Mortality remained high in both groups through the follow-up.
The study suggests that “women with PPCM need long-term follow-up by cardiology, as mortality does not abate over time,” Kalgi Modi, MD, Louisiana State University, Shreveport, said in an interview.
Women with a history of PPCM, she said, need “multidisciplinary and shared decision-making for family planning, because normalization of left ventricular function after index pregnancy does not guarantee a favorable outcome in the subsequent pregnancies.”
Dr. Modi is senior author on the study published online in the Journal of the American College of Cardiology.
The current findings are important to women with a history of PPCM who are “contemplating future pregnancy,” Afshan Hameed, MD, a maternal-fetal medicine specialist and cardiologist at the University of California, Irvine, said in an interview. The investigators suggest that “complete recovery of cardiac function after PPCM does not guarantee a favorable outcome in future pregnancy,” agreed Dr. Hameed, who was not involved in the current study. Future pregnancies must therefore “be highly discouraged or considered with caution even in patients who have recovered their cardiac function.”
To investigate the impact of PPCM on risk at subsequent pregnancies, the researchers studied 45 patients with PPCM who had gone on to have at least one more pregnancy, the first a median of 28 months later. Their mean age was 27 and 80% were Black; they were followed a median of 8 years.
Peripartum cardiomyopathy, defined as idiopathic heart failure with LV ejection fraction (LVEF) 45% or less in the last month of pregnancy through the following 5 months, was diagnosed post partum in 93.3% and antepartum in the remaining 6.7% (mean time of diagnosis, 6 weeks post partum).
The mean LVEF fell from 45.1% at the index pregnancy to 41.2% (P = .009) at subsequent pregnancies. The “recovery group” included the 30 women with LVEF recovery to 50% or higher after the index pregnancy, and the remaining 15 with persisting LV dysfunction – defined as LVEF < 50% – made up the “nonrecovery group.”
Recovery of LVEF was associated with a reduced risk of persisting LV dysfunction, the report states, at a hazard ratio of 0.08 (95% CI, 0.01-0.64; P = .02) after adjustment for hypertension, diabetes, and history of preeclampsia. But that risk went up sharply in association with illicit drug use, similarly adjusted, with an HR of 9.08 (95% CI, 1.38-59.8; P = .02).
The nonrecovery group, compared with the recovery group, experienced significantly higher rates of adverse maternal outcomes (53.3% vs. 20.0%; P = .04) – a composite endpoint that included relapse PPCM (33.3% vs. 3.3%; P = .01), HF (53.3% vs. 20.0%; P = .03), cardiogenic shock, thromboembolic events, and death – at 5 years. However, all-cause mortality was nonsignificantly different between the two groups (13.3% vs. 3.3%; P = .25)
All-cause mortality was nonsignificantly different between the two groups at a median of 8 years (20.0% vs. 20.0%; P = 1.00), and the difference in overall adverse maternal outcomes had gone from significant to nonsignificant (53.3% vs. 33.3%; P = .20). The difference in relapse PPCM between groups remained significant after 8 years (53.3% vs. 23.3%; P = .04)
The study is limited by its retrospective nature, a relatively small population, and lack of racial diversity, the report notes.
Indeed, most of the study’s subjects were Black, and previous studies have demonstrated a “different phenotypic presentation and outcome in African American women with PPCM, compared with non–African American women,” an accompanying editorial states.
Therefore, applicability of its findings to other populations “needs to be examined by urgently needed national prospective registries with long-term follow-up,” writes Uri Elkayam, MD, University of Southern California, Los Angeles.
Moreover, the study questions “whether the reverse remodeling and improvement of [LVEF] in women with PPCM represent a true recovery.” Prior studies “have shown an impaired contractile reserve as well as abnormal myocardial strain and reduced exercise capacity and even mortality in women with PPCM after RLV,” Dr. Elkayam notes.
It’s therefore possible – as with other forms of dilated cardiomyopathy – that LVEF normalization “does not represent a true recovery but a new steady state with subclinical myocardial dysfunction that is prone to development of recurrent [LV dysfunction] and clinical deterioration in response to various triggers such as long-standing hypertension, obesity, diabetes, illicit drug use,” and, “more importantly,” subsequent pregnancies.
The study points to “the need for a close long-term follow-up of women with PPCM” and provides “a rationale for early initiation of guideline-directed medical therapy after the diagnosis of PPCM and possible continuation even after improvement of LVEF.”
No funding source was reported. Dr. Modi and coauthors, Dr. Elkayam, and Dr. Hameed declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a new study suggests.
Researchers looked at the long-term outcomes in a cohort of women who had developed PPCM and became pregnant again several years later, comparing those with LV function that had “normalized” in the interim against those with persisting LV dysfunction.
In their analysis, adverse maternal outcomes 5 years after an index pregnancy were significantly worse among those in whom LV dysfunction had persisted, compared with those with recovered LV function. The risk of relapsed PPCM persisted out to 8 years. Mortality remained high in both groups through the follow-up.
The study suggests that “women with PPCM need long-term follow-up by cardiology, as mortality does not abate over time,” Kalgi Modi, MD, Louisiana State University, Shreveport, said in an interview.
Women with a history of PPCM, she said, need “multidisciplinary and shared decision-making for family planning, because normalization of left ventricular function after index pregnancy does not guarantee a favorable outcome in the subsequent pregnancies.”
Dr. Modi is senior author on the study published online in the Journal of the American College of Cardiology.
The current findings are important to women with a history of PPCM who are “contemplating future pregnancy,” Afshan Hameed, MD, a maternal-fetal medicine specialist and cardiologist at the University of California, Irvine, said in an interview. The investigators suggest that “complete recovery of cardiac function after PPCM does not guarantee a favorable outcome in future pregnancy,” agreed Dr. Hameed, who was not involved in the current study. Future pregnancies must therefore “be highly discouraged or considered with caution even in patients who have recovered their cardiac function.”
To investigate the impact of PPCM on risk at subsequent pregnancies, the researchers studied 45 patients with PPCM who had gone on to have at least one more pregnancy, the first a median of 28 months later. Their mean age was 27 and 80% were Black; they were followed a median of 8 years.
Peripartum cardiomyopathy, defined as idiopathic heart failure with LV ejection fraction (LVEF) 45% or less in the last month of pregnancy through the following 5 months, was diagnosed post partum in 93.3% and antepartum in the remaining 6.7% (mean time of diagnosis, 6 weeks post partum).
The mean LVEF fell from 45.1% at the index pregnancy to 41.2% (P = .009) at subsequent pregnancies. The “recovery group” included the 30 women with LVEF recovery to 50% or higher after the index pregnancy, and the remaining 15 with persisting LV dysfunction – defined as LVEF < 50% – made up the “nonrecovery group.”
Recovery of LVEF was associated with a reduced risk of persisting LV dysfunction, the report states, at a hazard ratio of 0.08 (95% CI, 0.01-0.64; P = .02) after adjustment for hypertension, diabetes, and history of preeclampsia. But that risk went up sharply in association with illicit drug use, similarly adjusted, with an HR of 9.08 (95% CI, 1.38-59.8; P = .02).
The nonrecovery group, compared with the recovery group, experienced significantly higher rates of adverse maternal outcomes (53.3% vs. 20.0%; P = .04) – a composite endpoint that included relapse PPCM (33.3% vs. 3.3%; P = .01), HF (53.3% vs. 20.0%; P = .03), cardiogenic shock, thromboembolic events, and death – at 5 years. However, all-cause mortality was nonsignificantly different between the two groups (13.3% vs. 3.3%; P = .25)
All-cause mortality was nonsignificantly different between the two groups at a median of 8 years (20.0% vs. 20.0%; P = 1.00), and the difference in overall adverse maternal outcomes had gone from significant to nonsignificant (53.3% vs. 33.3%; P = .20). The difference in relapse PPCM between groups remained significant after 8 years (53.3% vs. 23.3%; P = .04)
The study is limited by its retrospective nature, a relatively small population, and lack of racial diversity, the report notes.
Indeed, most of the study’s subjects were Black, and previous studies have demonstrated a “different phenotypic presentation and outcome in African American women with PPCM, compared with non–African American women,” an accompanying editorial states.
Therefore, applicability of its findings to other populations “needs to be examined by urgently needed national prospective registries with long-term follow-up,” writes Uri Elkayam, MD, University of Southern California, Los Angeles.
Moreover, the study questions “whether the reverse remodeling and improvement of [LVEF] in women with PPCM represent a true recovery.” Prior studies “have shown an impaired contractile reserve as well as abnormal myocardial strain and reduced exercise capacity and even mortality in women with PPCM after RLV,” Dr. Elkayam notes.
It’s therefore possible – as with other forms of dilated cardiomyopathy – that LVEF normalization “does not represent a true recovery but a new steady state with subclinical myocardial dysfunction that is prone to development of recurrent [LV dysfunction] and clinical deterioration in response to various triggers such as long-standing hypertension, obesity, diabetes, illicit drug use,” and, “more importantly,” subsequent pregnancies.
The study points to “the need for a close long-term follow-up of women with PPCM” and provides “a rationale for early initiation of guideline-directed medical therapy after the diagnosis of PPCM and possible continuation even after improvement of LVEF.”
No funding source was reported. Dr. Modi and coauthors, Dr. Elkayam, and Dr. Hameed declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, a new study suggests.
Researchers looked at the long-term outcomes in a cohort of women who had developed PPCM and became pregnant again several years later, comparing those with LV function that had “normalized” in the interim against those with persisting LV dysfunction.
In their analysis, adverse maternal outcomes 5 years after an index pregnancy were significantly worse among those in whom LV dysfunction had persisted, compared with those with recovered LV function. The risk of relapsed PPCM persisted out to 8 years. Mortality remained high in both groups through the follow-up.
The study suggests that “women with PPCM need long-term follow-up by cardiology, as mortality does not abate over time,” Kalgi Modi, MD, Louisiana State University, Shreveport, said in an interview.
Women with a history of PPCM, she said, need “multidisciplinary and shared decision-making for family planning, because normalization of left ventricular function after index pregnancy does not guarantee a favorable outcome in the subsequent pregnancies.”
Dr. Modi is senior author on the study published online in the Journal of the American College of Cardiology.
The current findings are important to women with a history of PPCM who are “contemplating future pregnancy,” Afshan Hameed, MD, a maternal-fetal medicine specialist and cardiologist at the University of California, Irvine, said in an interview. The investigators suggest that “complete recovery of cardiac function after PPCM does not guarantee a favorable outcome in future pregnancy,” agreed Dr. Hameed, who was not involved in the current study. Future pregnancies must therefore “be highly discouraged or considered with caution even in patients who have recovered their cardiac function.”
To investigate the impact of PPCM on risk at subsequent pregnancies, the researchers studied 45 patients with PPCM who had gone on to have at least one more pregnancy, the first a median of 28 months later. Their mean age was 27 and 80% were Black; they were followed a median of 8 years.
Peripartum cardiomyopathy, defined as idiopathic heart failure with LV ejection fraction (LVEF) 45% or less in the last month of pregnancy through the following 5 months, was diagnosed post partum in 93.3% and antepartum in the remaining 6.7% (mean time of diagnosis, 6 weeks post partum).
The mean LVEF fell from 45.1% at the index pregnancy to 41.2% (P = .009) at subsequent pregnancies. The “recovery group” included the 30 women with LVEF recovery to 50% or higher after the index pregnancy, and the remaining 15 with persisting LV dysfunction – defined as LVEF < 50% – made up the “nonrecovery group.”
Recovery of LVEF was associated with a reduced risk of persisting LV dysfunction, the report states, at a hazard ratio of 0.08 (95% CI, 0.01-0.64; P = .02) after adjustment for hypertension, diabetes, and history of preeclampsia. But that risk went up sharply in association with illicit drug use, similarly adjusted, with an HR of 9.08 (95% CI, 1.38-59.8; P = .02).
The nonrecovery group, compared with the recovery group, experienced significantly higher rates of adverse maternal outcomes (53.3% vs. 20.0%; P = .04) – a composite endpoint that included relapse PPCM (33.3% vs. 3.3%; P = .01), HF (53.3% vs. 20.0%; P = .03), cardiogenic shock, thromboembolic events, and death – at 5 years. However, all-cause mortality was nonsignificantly different between the two groups (13.3% vs. 3.3%; P = .25)
All-cause mortality was nonsignificantly different between the two groups at a median of 8 years (20.0% vs. 20.0%; P = 1.00), and the difference in overall adverse maternal outcomes had gone from significant to nonsignificant (53.3% vs. 33.3%; P = .20). The difference in relapse PPCM between groups remained significant after 8 years (53.3% vs. 23.3%; P = .04)
The study is limited by its retrospective nature, a relatively small population, and lack of racial diversity, the report notes.
Indeed, most of the study’s subjects were Black, and previous studies have demonstrated a “different phenotypic presentation and outcome in African American women with PPCM, compared with non–African American women,” an accompanying editorial states.
Therefore, applicability of its findings to other populations “needs to be examined by urgently needed national prospective registries with long-term follow-up,” writes Uri Elkayam, MD, University of Southern California, Los Angeles.
Moreover, the study questions “whether the reverse remodeling and improvement of [LVEF] in women with PPCM represent a true recovery.” Prior studies “have shown an impaired contractile reserve as well as abnormal myocardial strain and reduced exercise capacity and even mortality in women with PPCM after RLV,” Dr. Elkayam notes.
It’s therefore possible – as with other forms of dilated cardiomyopathy – that LVEF normalization “does not represent a true recovery but a new steady state with subclinical myocardial dysfunction that is prone to development of recurrent [LV dysfunction] and clinical deterioration in response to various triggers such as long-standing hypertension, obesity, diabetes, illicit drug use,” and, “more importantly,” subsequent pregnancies.
The study points to “the need for a close long-term follow-up of women with PPCM” and provides “a rationale for early initiation of guideline-directed medical therapy after the diagnosis of PPCM and possible continuation even after improvement of LVEF.”
No funding source was reported. Dr. Modi and coauthors, Dr. Elkayam, and Dr. Hameed declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
‘Artificial pancreas’ for all type 1 diabetes pregnancies?
In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.
Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.
The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.
CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”
The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.
Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”
However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
Two experts weigh in
Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.
“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.
“If a woman is on an AID system – except for DIY loop – I have them stop the automation and adjust manually,” she said in an email. “My [patients] do amazingly well in pregnancy – most can get their A1cs below 6%,” she noted. “But if someone can’t do that and their A1cs are higher, automation can help.
“It is always about individualizing care,” said Dr. Peters. “The one thing that helps the most is continuous glucose monitoring (CGM). And I do have patients who remain on [insulin] injections throughout pregnancy.”
And Sarit Polsky, MD, MPH, who was also not involved with the current study, agrees that “AID with CamAPS, which has an option to customize the glucose target in the pregnancy-specific range, appears to be safe and effective in pregnancy and should be offered” to patients in Europe and the United Kingdom.
“Whether other AID systems should be recommended in pregnancy is still unclear, said Dr. Polsky, associate professor of medicine and pediatrics at Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus.
“Around 48% of [global] pregnancies are unplanned,” Dr. Polsky said in an interview. “Many women do indeed become pregnant while using AID systems and many opt to continue use of these systems.
“Off-label use of these products can be beneficial in pregnancy in select cases, but the systems generally need the use of assistive techniques, which we previously published, to help get glucose levels to pregnancy-specific targets,” she noted in an email.
Study rationale, method, and findings
Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.
“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.
Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin.
As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.
Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.
They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.
A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).
Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.
The effect was consistent across clinical sites and maternal age and A1c categories.
Ongoing studies, off-label use
Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”
There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.
The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.
“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.
“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.
The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.
A version of this article first appeared on Medscape.com.
In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.
Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.
The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.
CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”
The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.
Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”
However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
Two experts weigh in
Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.
“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.
“If a woman is on an AID system – except for DIY loop – I have them stop the automation and adjust manually,” she said in an email. “My [patients] do amazingly well in pregnancy – most can get their A1cs below 6%,” she noted. “But if someone can’t do that and their A1cs are higher, automation can help.
“It is always about individualizing care,” said Dr. Peters. “The one thing that helps the most is continuous glucose monitoring (CGM). And I do have patients who remain on [insulin] injections throughout pregnancy.”
And Sarit Polsky, MD, MPH, who was also not involved with the current study, agrees that “AID with CamAPS, which has an option to customize the glucose target in the pregnancy-specific range, appears to be safe and effective in pregnancy and should be offered” to patients in Europe and the United Kingdom.
“Whether other AID systems should be recommended in pregnancy is still unclear, said Dr. Polsky, associate professor of medicine and pediatrics at Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus.
“Around 48% of [global] pregnancies are unplanned,” Dr. Polsky said in an interview. “Many women do indeed become pregnant while using AID systems and many opt to continue use of these systems.
“Off-label use of these products can be beneficial in pregnancy in select cases, but the systems generally need the use of assistive techniques, which we previously published, to help get glucose levels to pregnancy-specific targets,” she noted in an email.
Study rationale, method, and findings
Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.
“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.
Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin.
As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.
Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.
They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.
A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).
Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.
The effect was consistent across clinical sites and maternal age and A1c categories.
Ongoing studies, off-label use
Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”
There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.
The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.
“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.
“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.
The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.
A version of this article first appeared on Medscape.com.
In the largest randomized controlled trial of an automated insulin delivery (AID) system (hybrid closed-loop) versus standard insulin delivery in pregnant women with type 1 diabetes, the automated CamAPS FX system prevailed.
Helen R. Murphy, MD, presented these topline findings from the Automated Insulin Delivery Amongst Pregnant Women With Type 1 Diabetes (AiDAPT) trial during an e-poster session at the annual scientific sessions of the American Diabetes Association.
The “hybrid closed-loop significantly improved maternal glucose and should be offered to all pregnant women with type 1 diabetes,” concluded Dr. Murphy, professor of medicine at the University of East Anglia and a clinician at Norfolk and Norwich University Hospital in the United Kingdom.
CamAPS FX is the only AID system approved in Europe and the United Kingdom for type 1 diabetes from age 1 and during pregnancy. The hybrid closed-loop system is not available in the United States but other systems are available and sometimes used off label in pregnancy. Such systems are sometimes known colloquially as an “artificial pancreas.”
The researchers said their findings provide evidence for the UK National Institute of Clinical Excellence (NICE) to recommend that all pregnant women with type 1 diabetes should be offered the CamAPS FX system.
Asked by an audience member about type 2 diabetes in pregnancy, Dr. Murphy said: “I don’t think we can necessarily extend these data to women with type 2 diabetes. We just don’t have enough data on glucose profiles in type 2 to train an algorithm yet.”
However, the data provide support for earlier use of closed-loop therapy in type 1 diabetes, she said. “The ideal time to start closed-loop is not necessarily between 8 and 12 weeks. Half of all pregnancies are unplanned,” she noted, “so start [AID] as early as possible [in patients with type 1 diabetes].”
Two experts weigh in
Whether pregnant women with type 1 diabetes should be offered hybrid closed-loop therapy “depends,” said Anne L. Peters, MD, who was not involved with the research.
“It is all about being able to set [blood glucose] targets,” according to Dr. Peters, director of the University of Southern California Westside Center for Diabetes in Los Angeles.
“If a woman is on an AID system – except for DIY loop – I have them stop the automation and adjust manually,” she said in an email. “My [patients] do amazingly well in pregnancy – most can get their A1cs below 6%,” she noted. “But if someone can’t do that and their A1cs are higher, automation can help.
“It is always about individualizing care,” said Dr. Peters. “The one thing that helps the most is continuous glucose monitoring (CGM). And I do have patients who remain on [insulin] injections throughout pregnancy.”
And Sarit Polsky, MD, MPH, who was also not involved with the current study, agrees that “AID with CamAPS, which has an option to customize the glucose target in the pregnancy-specific range, appears to be safe and effective in pregnancy and should be offered” to patients in Europe and the United Kingdom.
“Whether other AID systems should be recommended in pregnancy is still unclear, said Dr. Polsky, associate professor of medicine and pediatrics at Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus.
“Around 48% of [global] pregnancies are unplanned,” Dr. Polsky said in an interview. “Many women do indeed become pregnant while using AID systems and many opt to continue use of these systems.
“Off-label use of these products can be beneficial in pregnancy in select cases, but the systems generally need the use of assistive techniques, which we previously published, to help get glucose levels to pregnancy-specific targets,” she noted in an email.
Study rationale, method, and findings
Pregnant women with diabetes are advised to aim for very tight glucose targets throughout pregnancy and avoid hyperglycemia, to reduce risk of preterm delivery, neonatal weight > 90th percentile, and neonatal morbidity, according to Dr. Murphy and colleagues.
“However, despite increased use of [CGM], continuous subcutaneous insulin infusion (CSII), and improved insulin analogs, achieving and maintaining the recommended glucose targets remains challenging for most pregnant women with type 1 diabetes,” they wrote in their abstract.
Researchers randomized 124 women who had type 1 diabetes for at least 12 months, were at < 13 weeks’ to 6 days’ gestation, and had an A1c of 6.5% to < 10% who were taking intensive standard insulin therapy at nine antenatal clinics in the United Kingdom. Half of the women were using CSII and half were receiving multiple daily injections of insulin.
As explained in the published study protocol, the women were randomized to continue their standard insulin delivery or switch to a closed-loop system consisting of the study insulin pump (Dana Diabecare RS), a CGM transmitter, and an app (CamAPS FX) on an Android smartphone that communicates wirelessly with the insulin pump and CGM transmitter.
Participants in both groups used the same CGM system and received support for insulin dose adjustment from their antenatal clinical care team.
They were a mean age of 31 years, had a mean A1c of 7.7%, and had had type 1 diabetes for 17 years on average. Their body mass index varied; 37% had normal weight, 27% had overweight, and 26% had obesity.
A significantly higher percentage of women in the AID group than in the control group had blood glucose in target range more than 70% of the time (46% vs. 10%; P < .001).
Compared with women in the control group, those in the AID group had larger reductions in hyperglycemia (–11%; P < .001), higher overnight time-in-range (13%; P < .001), and lower A1c (–0.34%; P < .001), without additional insulin, weight gain, or hypoglycemia.
The effect was consistent across clinical sites and maternal age and A1c categories.
Ongoing studies, off-label use
Hybrid closed-loop systems “including Tandem Control IQ, the Omnipod 5, and the Medtronic 780G give insulin continuously on the basis of values obtained from a sensor,” Dr. Peters explained in a recent commentary. “These aren’t fully closed-loop systems because the individual still has to interact with the system and give doses for meals, and then adjust doses for exercise.”
There are currently three studies using commercially available AID systems without pregnancy-specific glucose targets, in type 1 diabetes pregnancies, Dr. Polsky noted.
The Pregnancy Intervention With a Closed-Loop System (PICLS) trial used the Medtronic 670G system in pregnancy and was conducted in the United States. The Closed-Loop Insulin Delivery in Pregnant Women With Type 1 Diabetes (CRISTAL) study is using the Medtronic 780G system in pregnancy and is being conducted in Belgium and the Netherlands. And the Closed-Loop Insulin Delivery in Type 1 Diabetes Pregnancies (CIRCUIT) study is using the Tandem Control IQ system in pregnancy and is being conducted in Canada, she explained.
“The decision to continue to use or to initiate (off-label) use of any of these systems in pregnancy should be individualized, and pregnant individuals should make these decisions by working with an experienced endocrine/diabetes team,” Dr. Polsky stressed.
“The hope is that the results of these exciting trials will show safe and effective use of these systems throughout gestation with improvements in glucose control and quality of life,” she concluded.
The study was funded by the UK National Institute for Health Research, JDRF, and Diabetes Research and Wellness Foundation. Dr. Murphy has reported being on the advisory panel for Medtronic and receiving research support from Dexcom. Dr. Peters disclosed that she served as a consultant for Blue Circle Health, Vertex, and Abbott Diabetes Care, received a research grant from Abbott Diabetes Care, and received stock options from Teladoc and Omada Health. Dr. Polsky has disclosed that she is a contributing writer for diaTribe, was on a medical advisory board for Medtronic MiniMed, has received research funding from DexCom, Eli Lilly, JDRF, Leona & Harry Helmsley Charitable Trust, NIDDK, and Sanofi, and has received research support from Diasome Pharmaceuticals, LabStyle Innovation, Lexicon, Medtronic MiniMed, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM ADA 2023
Do oral contraceptives increase depression risk?
In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.
The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.
Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.
This effect remained, even after analysis of potential familial confounding.
“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.
The study was published online in Epidemiology and Psychiatric Sciences.
Inconsistent findings
Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.
The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.
They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.
Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.
The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.
They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.
Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.
They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
Adolescents at highest risk
Of the participants, 80.6% had used OCs at some point.
The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).
Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).
Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).
Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.
OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).
Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).
In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.
The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
Flawed study
In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”
She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”
The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.
Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.
And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.
“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.
The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.
The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.
Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.
This effect remained, even after analysis of potential familial confounding.
“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.
The study was published online in Epidemiology and Psychiatric Sciences.
Inconsistent findings
Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.
The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.
They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.
Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.
The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.
They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.
Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.
They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
Adolescents at highest risk
Of the participants, 80.6% had used OCs at some point.
The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).
Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).
Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).
Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.
OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).
Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).
In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.
The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
Flawed study
In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”
She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”
The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.
Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.
And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.
“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.
The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, OC use in adolescence has been tied to an increased risk for depression later in life. However, some experts believe the study’s methodology may be flawed.
The investigators tracked more than 250,000 women from birth to menopause, gathering information about their use of combined contraceptive pills (progesterone and estrogen), the timing of the initial depression diagnosis, and the onset of depressive symptoms that were not formally diagnosed.
Women who began using these OCs before or at the age of 20 experienced a 130% higher incidence of depressive symptoms, whereas adult users saw a 92% increase. But the higher occurrence of depression tended to decline after the first 2 years of use, except in teenagers, who maintained an increased incidence of depression even after discontinuation.
This effect remained, even after analysis of potential familial confounding.
“Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life,” Therese Johansson, of the department of immunology, genetics, and pathology, Science for Life Laboratory, Uppsala (Sweden) University, and colleagues wrote.
The study was published online in Epidemiology and Psychiatric Sciences.
Inconsistent findings
Previous studies suggest an association between adolescent use of hormonal contraceptives (HCs) and increased depression risk, but it’s “less clear” whether these effects are similar in adults, the authors wrote. Randomized clinical trials have “shown little or no effect” of HCs on mood. However, most of these studies didn’t consider previous use of HC.
The researchers wanted to estimate the incidence rate of depression associated with first initiation of OC use as well as the lifetime risk associated with use.
They studied 264,557 female participants in the UK Biobank (aged 37-71 years), collecting data from questionnaires, interviews, physical health measures, biological samples, imaging, and linked health records.
Most participants taking OCs had initiated use during the 1970s/early 1980s when second-generation OCs were predominantly used, consisting of levonorgestrel and ethinyl estradiol.
The researchers conducted a secondary outcome analysis on women who completed the UK Biobank Mental Health Questionnaire (MHQ) to evaluate depressive symptoms.
They estimated the associated risk for depression within 2 years after starting OCs in all women, as well as in groups stratified by age at initiation: before age 20 (adolescents) and age 20 and older (adults). In addition, the investigators estimated the lifetime risk for depression.
Time-dependent analysis compared the effect of OC use at initiation to the effect during the remaining years of use in recent and previous users.
They analyzed a subcohort of female siblings, utilizing “inference about causation from examination of familial confounding,” defined by the authors as a “regression-based approach for determining causality through the use of paired observational data collected from related individuals.”
Adolescents at highest risk
Of the participants, 80.6% had used OCs at some point.
The first 2 years of use were associated with a higher rate of depression among users, compared with never-users (hazard ration, 1.79; 95% confidence interval, 1.63-1.96). Although the risk became less pronounced after that, ever-use was still associated with increased lifetime risk for depression (HR, 1.05; 95% CI, 1.01-1.09).
Adolescents and adult OC users both experienced higher rates of depression during the first 2 years, with a more marked effect in adolescents than in adults (HR, 1.95; 95% CI, 1.64-2.32; and HR, 1.74; 95% CI, 1.54-1.95, respectively).
Previous users of OCs had a higher lifetime risk for depression, compared with never-users (HR, 1.05; 95% CI, 1.01-1.09).
Of the subcohort of women who completed the MHQ (n = 82,232), about half reported experiencing at least one of the core depressive symptoms.
OC initiation was associated with an increased risk for depressive symptoms during the first 2 years in ever- versus never-users (HR, 2.00; 95% CI, 1.91-2.10).
Those who began using OCs during adolescence had a dramatically higher rate of depressive symptoms, compared with never-users (HR, 2.30; 95% CI, 2.11-2.51), as did adult initiators (HR, 1.92; 95% CI, 2.11-2.51).
In the analysis of 7,354 first-degree sister pairs, 81% had initiated OCs. A sibling’s OC use was positively associated with a depression diagnosis, and the cosibling’s OC use was also associated with the sibling’s depression diagnosis. “These results support the hypothesis of a causal relationship between OC use and depression, such that OC use increases the risk of depression,” the authors wrote.
The main limitation is the potential for recall bias in the self-reported data, and that the UK Biobank sample consists of a healthier population than the overall U.K. population, which “hampers the generalizability” of the findings, the authors stated.
Flawed study
In a comment, Natalie Rasgon, MD, founder and director of the Stanford (Calif.) Center for Neuroscience in Women’s Health, said the study was “well researched” and “well written” but had “methodological issues.”
She questioned the sibling component, “which the researchers regard as confirming causality.” The effect may be “important but not causative.” Causality in people who are recalling retrospectively “is highly questionable by any adept researcher because it’s subject to memory. Different siblings may have different recall.”
The authors also didn’t study the indication for OC use. Several medical conditions are treated with OCs, including premenstrual dysphoric disorder, the “number one mood disorder among women of reproductive age.” Including this “could have made a huge difference in outcome data,” said Dr. Rasgon, who was not involved with the study.
Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology, University of Washington, Seattle, noted participants were asked to recall depressive symptoms and OC use as far back as 20-30 years ago, which lends itself to inaccurate recall.
And the researchers didn’t ascertain whether the contraceptives had been used continuously or had been started, stopped, and restarted. Nor did they look at different formulations and doses. And the observational nature of the study “limits the ability to infer causation,” continued Dr. Oelschlager, chair of the American College of Obstetrics and Gynecology Clinical Consensus Gynecology Committee. She was not involved with the study.
“This study is too flawed to use meaningfully in clinical practice,” Dr. Oelschlager concluded.
The study was primarily funded by the Swedish Research Council, the Swedish Brain Foundation, and the Uppsala University Center for Women ‘s Mental Health during the Reproductive Lifespan. The authors, Dr. Rasgon, and Dr. Oelschlager declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EPIDEMIOLOGY AND PSYCHIATRIC SCIENCES
New clues to an old mystery: Recent gains in endometriosis
In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?
Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.
John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.
Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.
Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.
Is Fusobacterium the new Helicobacter pylori?
The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples.
They uncovered an interesting chain of cellular events: macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis.
Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.
“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”
After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.
To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.
Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.
“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”
Don’t write off gut microbiota
Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.
A key difference between his work and Dr. Kondo’s is his focus on gut microbiota, whereas the Japanese team looked at bacteria in the vagina and endometrium. But Dr. Kommagani said he thinks both could play a role. “Maybe the vaginal microbiome might have a direct impact on disease similar to what we showed on the gut,” he said.
But he said at least part of the answer to why some women develop endometriosis may have to do more with the balance of beneficial and harmful bacteria in the gut rather than because of a single family of microbes like Fusobacterium.
Most recently, by dovetailing a mouse model for inducing endometriosis in mice treated with antibiotics to deplete their gut microbiome, Dr. Kommagani’s lab expanded on its previous work: They showed that the animals developed fewer of the typical lesions seen in endometriosis than those that did not receive antibiotics before all of the mice underwent the surgical procedure used by researchers to induce endometriosis – possibly because they had no bacteria in their gut triggering the inflammatory response required for the development of endometriosis.
But after oral feedings with fecal matter from mice without endometriosis, the microbiota-depleted rodents began developing lesions typical of endometriosis, suggesting that altered gut flora from mice with endometriosis appeared to promote the disorder. Meanwhile, their microbiota-depleted counterparts who were fed fecal matter from mice without endometriosis did not develop the typical lesions.
Dr. Kommagani’s team then compared metabolites from bacteria in stool from mice with and without endometriosis and investigated the in vitro effect of these metabolites on cells from human endometriotic lesions. One of them, quinic acid, increased the proliferation of human endometriotic epithelial cells.
“Some metabolites such as fiber-derived short-chain fatty acids have beneficial effects; they inhibit the disease,” Dr. Kommagani said. “But maybe an amino acid derivative such as quinic acid, [may] promote disease, and these are generated because there is a gut dysbiosis.”
This statement hints at some of the possible therapeutic approaches for endometriosis, such as a high-fiber diet to promote healthy gut flora, or perhaps antibiotics to eradicate unhealthy bacteria. But as with other conditions that have been linked to dysbiosis, like inflammatory bowel disease, use of antibiotics is a bit like balancing on a tightrope; although antibiotics may remove harmful bacteria, their use may negatively affect the beneficial bacteria.
Clues in genetic variants
Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.
“It’s one thing identifying risk variants and the next question is, okay, well, what do those variants actually do in terms of biology?” Dr. Zondervan said. The Oxford team next explored how the identified genetic variants affect gene expression and the proteins generated, drawing on previously collected data on gene expression from samples of human blood and endometrial and uterine tissue.
They found many of the genes implicated in the risk for endometriosis code for proteins that affect sex hormones, uterine development, transformation of healthy cells into cancerous tissue, inflammatory adhesion molecules, and factors promoting development of new blood vessels. All of that, she said, explains how a few endometrial cells making their way into the pelvis can attach to ovaries, ligaments, and peritoneal surfaces; proliferate; and acquire a blood supply to ensure their survival.
“We were able to identify a whole host of things that were likely causal to the disease,” Dr. Zondervan said. And that finding led to her next question: “Are there particular genes or areas around them that can be targeted with certain medications?”
The surprising answer was that several of the genes linked to endometriosis share pathways with clinical syndromes that often occur in women with endometriosis. Many of these are chronic pain conditions – such as migraines, headaches, and back pain – but also include inflammatory illnesses such as asthma and osteoarthritis.
As Dr. Zondervan explained, “A lot of the variance that we see for endometriosis is also experienced for low back pain and migraine, and that clearly has something to do with pain perception and pain mechanisms.”
A connection between the development of neural pathways and endometriosis has been proposed before, as researchers have found that endometriotic lesions can develop their own nerve supply, creating a direct interaction between the lesions and the central nervous system. And some clinicians have been employing treatment strategies that employ multimodal therapies – employing physical therapists, mental health practitioners, nutritionists, and pain specialists prior to and following surgical removal of lesions – to improve overall success rates of treatment.
But Dr. Zondervan’s team is the first to uncover an important clue about how this happens.
The study findings also provide solid clues to researchers about which genes and proteins to focus on for drug target discovery. In particular, the gene pathways shared by endometriosis and various pain conditions could allow for repurposing of drugs developed for other conditions for treating endometriosis, reported Dr. Zondervan.
Dr. Zondervan’s other important conclusion, echoed by Dr. Kondo and Dr. Kommagani, is that endometriosis is not one disease. Rather, it appears to be akin to cancer in terms of the heterogeneity of how it presents and the different subtypes of diseases. The Oxford study corroborated this belief, identifying certain genes that were closely associated with cystic lesions in ovaries, but failing to turn up a genetic link to other types of lesions in the pelvis long considered to be part of the spectrum of endometriosis disease.
Dr. Zondervan agreed that the potential link with Fusobacterium is a fascinating area given the critical role of inflammation in the pathogenesis of endometriosis, although she’d like to see the work replicated with larger sample sizes. “From a personal point of view, I’d be really fascinated to see how genetics interplays with this,” she added.
What’s next?
The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.
Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.
Could stool samples be the answer?
The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.
“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said.
Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.
“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.
Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).
Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.
Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.
A version of this article originally appeared on Medscape.com.
In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?
Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.
John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.
Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.
Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.
Is Fusobacterium the new Helicobacter pylori?
The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples.
They uncovered an interesting chain of cellular events: macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis.
Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.
“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”
After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.
To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.
Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.
“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”
Don’t write off gut microbiota
Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.
A key difference between his work and Dr. Kondo’s is his focus on gut microbiota, whereas the Japanese team looked at bacteria in the vagina and endometrium. But Dr. Kommagani said he thinks both could play a role. “Maybe the vaginal microbiome might have a direct impact on disease similar to what we showed on the gut,” he said.
But he said at least part of the answer to why some women develop endometriosis may have to do more with the balance of beneficial and harmful bacteria in the gut rather than because of a single family of microbes like Fusobacterium.
Most recently, by dovetailing a mouse model for inducing endometriosis in mice treated with antibiotics to deplete their gut microbiome, Dr. Kommagani’s lab expanded on its previous work: They showed that the animals developed fewer of the typical lesions seen in endometriosis than those that did not receive antibiotics before all of the mice underwent the surgical procedure used by researchers to induce endometriosis – possibly because they had no bacteria in their gut triggering the inflammatory response required for the development of endometriosis.
But after oral feedings with fecal matter from mice without endometriosis, the microbiota-depleted rodents began developing lesions typical of endometriosis, suggesting that altered gut flora from mice with endometriosis appeared to promote the disorder. Meanwhile, their microbiota-depleted counterparts who were fed fecal matter from mice without endometriosis did not develop the typical lesions.
Dr. Kommagani’s team then compared metabolites from bacteria in stool from mice with and without endometriosis and investigated the in vitro effect of these metabolites on cells from human endometriotic lesions. One of them, quinic acid, increased the proliferation of human endometriotic epithelial cells.
“Some metabolites such as fiber-derived short-chain fatty acids have beneficial effects; they inhibit the disease,” Dr. Kommagani said. “But maybe an amino acid derivative such as quinic acid, [may] promote disease, and these are generated because there is a gut dysbiosis.”
This statement hints at some of the possible therapeutic approaches for endometriosis, such as a high-fiber diet to promote healthy gut flora, or perhaps antibiotics to eradicate unhealthy bacteria. But as with other conditions that have been linked to dysbiosis, like inflammatory bowel disease, use of antibiotics is a bit like balancing on a tightrope; although antibiotics may remove harmful bacteria, their use may negatively affect the beneficial bacteria.
Clues in genetic variants
Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.
“It’s one thing identifying risk variants and the next question is, okay, well, what do those variants actually do in terms of biology?” Dr. Zondervan said. The Oxford team next explored how the identified genetic variants affect gene expression and the proteins generated, drawing on previously collected data on gene expression from samples of human blood and endometrial and uterine tissue.
They found many of the genes implicated in the risk for endometriosis code for proteins that affect sex hormones, uterine development, transformation of healthy cells into cancerous tissue, inflammatory adhesion molecules, and factors promoting development of new blood vessels. All of that, she said, explains how a few endometrial cells making their way into the pelvis can attach to ovaries, ligaments, and peritoneal surfaces; proliferate; and acquire a blood supply to ensure their survival.
“We were able to identify a whole host of things that were likely causal to the disease,” Dr. Zondervan said. And that finding led to her next question: “Are there particular genes or areas around them that can be targeted with certain medications?”
The surprising answer was that several of the genes linked to endometriosis share pathways with clinical syndromes that often occur in women with endometriosis. Many of these are chronic pain conditions – such as migraines, headaches, and back pain – but also include inflammatory illnesses such as asthma and osteoarthritis.
As Dr. Zondervan explained, “A lot of the variance that we see for endometriosis is also experienced for low back pain and migraine, and that clearly has something to do with pain perception and pain mechanisms.”
A connection between the development of neural pathways and endometriosis has been proposed before, as researchers have found that endometriotic lesions can develop their own nerve supply, creating a direct interaction between the lesions and the central nervous system. And some clinicians have been employing treatment strategies that employ multimodal therapies – employing physical therapists, mental health practitioners, nutritionists, and pain specialists prior to and following surgical removal of lesions – to improve overall success rates of treatment.
But Dr. Zondervan’s team is the first to uncover an important clue about how this happens.
The study findings also provide solid clues to researchers about which genes and proteins to focus on for drug target discovery. In particular, the gene pathways shared by endometriosis and various pain conditions could allow for repurposing of drugs developed for other conditions for treating endometriosis, reported Dr. Zondervan.
Dr. Zondervan’s other important conclusion, echoed by Dr. Kondo and Dr. Kommagani, is that endometriosis is not one disease. Rather, it appears to be akin to cancer in terms of the heterogeneity of how it presents and the different subtypes of diseases. The Oxford study corroborated this belief, identifying certain genes that were closely associated with cystic lesions in ovaries, but failing to turn up a genetic link to other types of lesions in the pelvis long considered to be part of the spectrum of endometriosis disease.
Dr. Zondervan agreed that the potential link with Fusobacterium is a fascinating area given the critical role of inflammation in the pathogenesis of endometriosis, although she’d like to see the work replicated with larger sample sizes. “From a personal point of view, I’d be really fascinated to see how genetics interplays with this,” she added.
What’s next?
The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.
Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.
Could stool samples be the answer?
The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.
“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said.
Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.
“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.
Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).
Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.
Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.
A version of this article originally appeared on Medscape.com.
In 1927, American gynecologist John Sampson published his theory of the etiology of endometriosis, postulating that retrograde flow of endometrial debris flows backward through the fallopian tubes during menses into the peritoneal cavity. Dr. Sampson’s notion remains the main paradigm today, mentioned still in recent articles on the topic, but it has a flaw: Although the theory may account for how endometrial tissue escapes the uterus, a 1984 study revealed that this phenomenon occurs in 90% of women. Why, then, do only 10% of women suffer from endometriosis?
Endometriosis describes a condition in which endometrial tissue lining the uterus is found outside the uterus. The disease can be painful, even crippling. As many as 30% of women in their reproductive years who have endometriosis are infertile as a consequence. The hallmarks of the condition are superficial peritoneal lesions of varying color, cysts in the ovaries, deeper nodules accompanied by scarring and adhesion, primarily in the pelvis but sometimes appearing outside the pelvis. The syndrome can be challenging to identify, requiring laparoscopy for definitive diagnosis.
John Sampson aside, scientists have struggled for the past century to identify the cause, or causes, of endometriosis. Hormones clearly play a role in its development, and women with endometriosis have an elevated risk of clear-cell and endometrioid ovarian cancer and autoimmune diseases. Immunodeficiency also could be to blame, if a faulty immune system fails to find and remove endometrial tissue outside of the uterus. A class of chemicals known as endocrine disruptors have been linked to endometriosis, but not definitively. Twin studies have demonstrated that as many as 50% of cases have a genetic basis, while mice with surgically induced endometriosis have been found to have a higher ratio of harmful to beneficial bacteria in their gut.
Several studies published this year point to new insights into the old mystery – with possible implications for ways to treat the disorder.
Perhaps the most surprising came out earlier this year in Science Translational Medicine, as a team of researchers in Japan reported that invasive infection by bacteria of the genus Fusobacterium may cause at least some cases of endometriosis.
Is Fusobacterium the new Helicobacter pylori?
The researchers, from Nagoya University, are the first to suggest that not only might a single bacterial genus cause endometriosis, but that antibiotic treatment could prevent progression of the disease. Using endometrial tissue obtained from 79 women undergoing hysterectomy for endometriosis and 76 women undergoing hysterectomy for other reasons (such as cervical cancer), the team started with gene expression profiling to explore differences between the two sets of samples.
They uncovered an interesting chain of cellular events: macrophages found in endometriotic lesions were secreting transforming growth factor-beta (TGF-beta). TGF-beta in turn stimulated high levels of expression of a gene called TAGLN in fibroblast cells from women with endometriosis but not in fibroblasts from women without endometriosis.
Turning on TAGLN transformed these previously inactive cells into active myofibroblasts, leading to increased proliferation, mobility, and attachment to mesothelial cells, the layer of cells that line body cavities and internal organs. In short, they identified some key players in an environment that seemed very favorable to the development of endometriosis.
“So, the question is: Why are macrophages activated?” said Yutaka Kondo, MD, PhD, the senior author of the study and a professor in the division of cancer biology at the Nagoya (Japan) University Graduate School of Medicine. “We think that there are always bacteria in the endometrium.”
After reviewing data from a previously published study, they used quantitative polymerase chain reaction to rule out one candidate, Erysipelothrix, but scored on their next attempt, identifying Fusobacterium species in endometrial tissue from 64% of the women with endometriosis, compared with fewer than 10% of the controls.
To confirm that the bacteria could cause disease and were not simply bystanders, Dr. Kondo’s team turned to a mouse model for endometriosis, in which endometrial cells are surgically removed from the uteri of mice and injected into the peritoneum of recipient mice, leading to the formation of endometriotic lesions. When mice received further injections of uterine tissue from mice that were infected with F. nucleatum, their lesions were more numerous when compared with mice that received injections of uninfected uterine tissue. Furthermore, antibiotic treatment with metronidazole or chloramphenicol immediately after surgery largely prevented progression to endometriosis, Dr. Kondo and his colleagues reported.
Dr. Kondo likened this relationship between Fusobacterium and endometriosis to that of the link between Helicobacter pylori and peptic ulcers but acknowledged that he doesn’t have all the answers.
“We need more clinical trials, and also we have to know what kind of treatment might be the most effective for the treatment of endometriosis,” Dr. Kondo said, pointing out that other therapies should still be pursued in addition to antibiotics, as not all the samples from women with endometriosis harbored Fusobacterium. “It might be possible that other mechanisms are also involved.”
Don’t write off gut microbiota
Ramakrishna Kommagani, PhD, associate professor of pathology and immunology at Baylor College of Medicine in Houston, agreed. “Endometriosis is a complex disease, which appears to be impacted by many factors, including genetic, epigenetic, and environmental factors,” Dr. Kommagani said.
A key difference between his work and Dr. Kondo’s is his focus on gut microbiota, whereas the Japanese team looked at bacteria in the vagina and endometrium. But Dr. Kommagani said he thinks both could play a role. “Maybe the vaginal microbiome might have a direct impact on disease similar to what we showed on the gut,” he said.
But he said at least part of the answer to why some women develop endometriosis may have to do more with the balance of beneficial and harmful bacteria in the gut rather than because of a single family of microbes like Fusobacterium.
Most recently, by dovetailing a mouse model for inducing endometriosis in mice treated with antibiotics to deplete their gut microbiome, Dr. Kommagani’s lab expanded on its previous work: They showed that the animals developed fewer of the typical lesions seen in endometriosis than those that did not receive antibiotics before all of the mice underwent the surgical procedure used by researchers to induce endometriosis – possibly because they had no bacteria in their gut triggering the inflammatory response required for the development of endometriosis.
But after oral feedings with fecal matter from mice without endometriosis, the microbiota-depleted rodents began developing lesions typical of endometriosis, suggesting that altered gut flora from mice with endometriosis appeared to promote the disorder. Meanwhile, their microbiota-depleted counterparts who were fed fecal matter from mice without endometriosis did not develop the typical lesions.
Dr. Kommagani’s team then compared metabolites from bacteria in stool from mice with and without endometriosis and investigated the in vitro effect of these metabolites on cells from human endometriotic lesions. One of them, quinic acid, increased the proliferation of human endometriotic epithelial cells.
“Some metabolites such as fiber-derived short-chain fatty acids have beneficial effects; they inhibit the disease,” Dr. Kommagani said. “But maybe an amino acid derivative such as quinic acid, [may] promote disease, and these are generated because there is a gut dysbiosis.”
This statement hints at some of the possible therapeutic approaches for endometriosis, such as a high-fiber diet to promote healthy gut flora, or perhaps antibiotics to eradicate unhealthy bacteria. But as with other conditions that have been linked to dysbiosis, like inflammatory bowel disease, use of antibiotics is a bit like balancing on a tightrope; although antibiotics may remove harmful bacteria, their use may negatively affect the beneficial bacteria.
Clues in genetic variants
Krina Zondervan, DPhil, professor and head of the department of reproductive and genomic epidemiology at the University of Oxford (England), focuses on genomic, molecular, and epidemiologic approaches to understanding endometriosis.
“It’s one thing identifying risk variants and the next question is, okay, well, what do those variants actually do in terms of biology?” Dr. Zondervan said. The Oxford team next explored how the identified genetic variants affect gene expression and the proteins generated, drawing on previously collected data on gene expression from samples of human blood and endometrial and uterine tissue.
They found many of the genes implicated in the risk for endometriosis code for proteins that affect sex hormones, uterine development, transformation of healthy cells into cancerous tissue, inflammatory adhesion molecules, and factors promoting development of new blood vessels. All of that, she said, explains how a few endometrial cells making their way into the pelvis can attach to ovaries, ligaments, and peritoneal surfaces; proliferate; and acquire a blood supply to ensure their survival.
“We were able to identify a whole host of things that were likely causal to the disease,” Dr. Zondervan said. And that finding led to her next question: “Are there particular genes or areas around them that can be targeted with certain medications?”
The surprising answer was that several of the genes linked to endometriosis share pathways with clinical syndromes that often occur in women with endometriosis. Many of these are chronic pain conditions – such as migraines, headaches, and back pain – but also include inflammatory illnesses such as asthma and osteoarthritis.
As Dr. Zondervan explained, “A lot of the variance that we see for endometriosis is also experienced for low back pain and migraine, and that clearly has something to do with pain perception and pain mechanisms.”
A connection between the development of neural pathways and endometriosis has been proposed before, as researchers have found that endometriotic lesions can develop their own nerve supply, creating a direct interaction between the lesions and the central nervous system. And some clinicians have been employing treatment strategies that employ multimodal therapies – employing physical therapists, mental health practitioners, nutritionists, and pain specialists prior to and following surgical removal of lesions – to improve overall success rates of treatment.
But Dr. Zondervan’s team is the first to uncover an important clue about how this happens.
The study findings also provide solid clues to researchers about which genes and proteins to focus on for drug target discovery. In particular, the gene pathways shared by endometriosis and various pain conditions could allow for repurposing of drugs developed for other conditions for treating endometriosis, reported Dr. Zondervan.
Dr. Zondervan’s other important conclusion, echoed by Dr. Kondo and Dr. Kommagani, is that endometriosis is not one disease. Rather, it appears to be akin to cancer in terms of the heterogeneity of how it presents and the different subtypes of diseases. The Oxford study corroborated this belief, identifying certain genes that were closely associated with cystic lesions in ovaries, but failing to turn up a genetic link to other types of lesions in the pelvis long considered to be part of the spectrum of endometriosis disease.
Dr. Zondervan agreed that the potential link with Fusobacterium is a fascinating area given the critical role of inflammation in the pathogenesis of endometriosis, although she’d like to see the work replicated with larger sample sizes. “From a personal point of view, I’d be really fascinated to see how genetics interplays with this,” she added.
What’s next?
The chief limitation of human studies looking at mechanisms of endometriosis is that they are correlational: Tissue samples are collected from women with and without endometriosis, often through an invasive procedure such as laparoscopy or biopsy, at one point in time. Currently, the best tools for proving causation are animal models of endometriosis, such as the those used by Dr. Kondo’s and Dr. Kommagani’s teams.
Better diagnostic tools would solve that problem. The ultimate goal is a noninvasive test for endometriosis that would allow clinicians to follow women over time and permit the monitoring of disease progression, or regression, without the need for painful procedures. Such a diagnostic tool would facilitate rigorous longitudinal studies evaluating mechanisms of disease, as well as monitoring outcomes of clinical trials of new treatments.
Could stool samples be the answer?
The Japanese team found that women harboring Fusobacterium in endometrial tissue also had Fusobacterium in vaginal samples taken at the time of their hysterectomy – and stool samples can pick up changes in the gut microbiome.
“Vaginal swab or stool tests are probably the best and easiest for noninvasive early detection,” Dr. Kommagani said.
Spit tests for DNA would be even easier to obtain. Polygenic risk scores could be developed to estimate an individual’s risk of disease based on the number of variants, but Dr. Zondervan cautioned that not all the genes that account for endometriosis are known.
“The things that we found altogether explain about 5% of disease variability, basically – which is still not an awful lot,” she said.
Dr. Kondo’s work was supported by the Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, and the Research Grant of the Princess Takamatsu Cancer Research Fund. A patent method for detecting bacteria of genus Fusobacterium in order to diagnose endometriosis (WO2023/ 042714), was submitted (international publication date, March 23, 2023).
Dr. Kommagani’s work was funded, in part, by National Institutes of Health/National Institute of Child Health and Human Development grants R01HD102680, R01HD065435, and R00HD080742. He has no other conflicts of interest. Dr. Zondervan received funding from the Wellcome Trust (216767; 104036; 084766; 212904; 076113 and 085475) and also reported grants from Bayer AG, AbbVie, Volition Rx, MDNA Life Sciences, and Roche Diagnostics outside the submitted work.
Dr. Thomas is a pediatrician and epidemiologist living in Portland, Ore.
A version of this article originally appeared on Medscape.com.
HT, even short-term use, linked to dementia risk in women
Short-term and cyclical use of estrogen and progestin therapy for menopausal symptoms is linked to an increased risk of dementia, results of a large observational study show.
(AD) 20 years later, compared with those who didn’t use HT. The risk was present even in women who used HT for brief periods at menopause onset.
However, both the investigators and experts not involved in the research caution that further studies are needed to explore whether the increased risk of dementia stems from HT use or whether women in need of HT have other underlying dementia risk factors.
“We cannot guarantee that our findings illustrate a causal relationship or if they represent underlying disposition to dementia in women in need of [HT],” lead investigator Nelsan Pourhadi, MD, from the Danish Dementia Research Centre at Copenhagen University Hospital Rigshospitalet, told this news organization.
Still, he added, the findings supported evidence from the Women’s Health Initiative Memory Study (WHIMS), the largest randomized trial on menopausal hormone therapy and dementia.
The findings were published online in BMJ.
Conflicting findings
Before WHIMS was published in 2003, HT was widely prescribed to relieve menopausal symptoms. However, WHIMS, which included more than 4,000 women aged 65 years or older, revealed that HT was associated with a twofold increased risk of dementia.
Studies published since then have yielded mixed results, adding to the controversy surrounding the safety of HT.
To discover whether age of initiation or length of duration of HT affects health outcomes, Dr. Pourhadi and his team undertook the observational study.
Between 2000 and 2018, the researchers tracked more than 60,000 Danish women aged 50-60 years using diagnosis and prescription information from Denmark’s National Registry of Patients.
The registry records showed that nearly 5,600 women developed dementia and 56,000 did not develop dementia. Of the 5,600 women with dementia, 1,460 had a diagnosis of AD.
Nearly 18,000 participants in the study sample received HT – 1,790 (29%) in the dementia group and 16,150 (32%) in the control group. Half started treatment before age 53 years and half stopped within 4 years. Roughly 90% used oral medications, which included a combination of estrogen and progestin.
The median age at which participants started HT was 53 years for both cases and controls, and the median duration of use was 4 years.
Longer use equals greater risk
Compared with those who did not use HT, those who used estrogen-progestin therapy had a 24% increased risk of developing all-cause dementia (hazard ratio, 1.24; 95% confidence interval, 1.17-1.44).
The increased dementia risk was similar between continuous (estrogen and progestin taken daily) and cyclic (daily estrogen with progestin taken 10-14 days a month) treatment regimens.
Longer durations of HT use were associated with increased risk, ranging from a 21% increased risk (HR, 1.21; 95% CI, 1.09-1.35) for those who used it for 1 year or less to a 74% increased risk (HR, 1.74; 95% CI, 1.45-2.10) for use lasting 12 years or more.
Women who started HT between the age of 45 and 50 had a 26% increased risk of developing all-cause dementia (HR, 1.26; 95% CI, 1.13-1.41) while women who initiated HT between age 51 and 60 had a 21% greater risk (HR, 1.21; 95% CI, 1.12-1.29).
Progestin-only or vaginal-estrogen-only therapy was not associated with the development of dementia.
The investigators noted that because this is an observational study, “further studies are warranted to explore if the observed association in this study between menopausal hormone therapy use and increased risk of dementia illustrates a causal effect.”
No causal relationship
In an accompanying editorial, Kejal Kantarci, MD, a professor of radiology at the Mayo Clinic, Rochester, Minn., noted that three clinical trials, including the WHIMS of Younger Women (WHIMS-Y) in 2013, did not show a link between cognitive function and HT.
“Although [Dr.] Pourhadi and colleagues’ study was done carefully using national registries, the observed associations could be artefactual and should not be used to infer a causal relationship between hormone therapy and dementia risk. These findings cannot inform shared decision-making about use of hormone therapy for menopausal symptoms,” she states in the editorial.
Also commenting on the findings, Amanda Heslegrave, PhD, a senior research fellow at the U.K. Dementia Research Institute, London, said in a release from the U.K.’s Science Media Centre that while the study “may cause alarm for women taking [HT], it highlights just how much we still don’t know about the effects of hormones on women’s brain health, and with promising treatments on the horizon, it should be a call to action to make this a priority area of research.”
There was no specific funding for the study. Dr. Kantarci reported working on an unpaid educational activity on Alzheimer’s disease for Biogen and is the PI on a study of a PET imaging ligand for Alzheimer’s disease, to which Eli Lilly and Avid Radiopharmaceuticals donated supplies.
A version of this article originally appeared on Medscape.com.
Short-term and cyclical use of estrogen and progestin therapy for menopausal symptoms is linked to an increased risk of dementia, results of a large observational study show.
(AD) 20 years later, compared with those who didn’t use HT. The risk was present even in women who used HT for brief periods at menopause onset.
However, both the investigators and experts not involved in the research caution that further studies are needed to explore whether the increased risk of dementia stems from HT use or whether women in need of HT have other underlying dementia risk factors.
“We cannot guarantee that our findings illustrate a causal relationship or if they represent underlying disposition to dementia in women in need of [HT],” lead investigator Nelsan Pourhadi, MD, from the Danish Dementia Research Centre at Copenhagen University Hospital Rigshospitalet, told this news organization.
Still, he added, the findings supported evidence from the Women’s Health Initiative Memory Study (WHIMS), the largest randomized trial on menopausal hormone therapy and dementia.
The findings were published online in BMJ.
Conflicting findings
Before WHIMS was published in 2003, HT was widely prescribed to relieve menopausal symptoms. However, WHIMS, which included more than 4,000 women aged 65 years or older, revealed that HT was associated with a twofold increased risk of dementia.
Studies published since then have yielded mixed results, adding to the controversy surrounding the safety of HT.
To discover whether age of initiation or length of duration of HT affects health outcomes, Dr. Pourhadi and his team undertook the observational study.
Between 2000 and 2018, the researchers tracked more than 60,000 Danish women aged 50-60 years using diagnosis and prescription information from Denmark’s National Registry of Patients.
The registry records showed that nearly 5,600 women developed dementia and 56,000 did not develop dementia. Of the 5,600 women with dementia, 1,460 had a diagnosis of AD.
Nearly 18,000 participants in the study sample received HT – 1,790 (29%) in the dementia group and 16,150 (32%) in the control group. Half started treatment before age 53 years and half stopped within 4 years. Roughly 90% used oral medications, which included a combination of estrogen and progestin.
The median age at which participants started HT was 53 years for both cases and controls, and the median duration of use was 4 years.
Longer use equals greater risk
Compared with those who did not use HT, those who used estrogen-progestin therapy had a 24% increased risk of developing all-cause dementia (hazard ratio, 1.24; 95% confidence interval, 1.17-1.44).
The increased dementia risk was similar between continuous (estrogen and progestin taken daily) and cyclic (daily estrogen with progestin taken 10-14 days a month) treatment regimens.
Longer durations of HT use were associated with increased risk, ranging from a 21% increased risk (HR, 1.21; 95% CI, 1.09-1.35) for those who used it for 1 year or less to a 74% increased risk (HR, 1.74; 95% CI, 1.45-2.10) for use lasting 12 years or more.
Women who started HT between the age of 45 and 50 had a 26% increased risk of developing all-cause dementia (HR, 1.26; 95% CI, 1.13-1.41) while women who initiated HT between age 51 and 60 had a 21% greater risk (HR, 1.21; 95% CI, 1.12-1.29).
Progestin-only or vaginal-estrogen-only therapy was not associated with the development of dementia.
The investigators noted that because this is an observational study, “further studies are warranted to explore if the observed association in this study between menopausal hormone therapy use and increased risk of dementia illustrates a causal effect.”
No causal relationship
In an accompanying editorial, Kejal Kantarci, MD, a professor of radiology at the Mayo Clinic, Rochester, Minn., noted that three clinical trials, including the WHIMS of Younger Women (WHIMS-Y) in 2013, did not show a link between cognitive function and HT.
“Although [Dr.] Pourhadi and colleagues’ study was done carefully using national registries, the observed associations could be artefactual and should not be used to infer a causal relationship between hormone therapy and dementia risk. These findings cannot inform shared decision-making about use of hormone therapy for menopausal symptoms,” she states in the editorial.
Also commenting on the findings, Amanda Heslegrave, PhD, a senior research fellow at the U.K. Dementia Research Institute, London, said in a release from the U.K.’s Science Media Centre that while the study “may cause alarm for women taking [HT], it highlights just how much we still don’t know about the effects of hormones on women’s brain health, and with promising treatments on the horizon, it should be a call to action to make this a priority area of research.”
There was no specific funding for the study. Dr. Kantarci reported working on an unpaid educational activity on Alzheimer’s disease for Biogen and is the PI on a study of a PET imaging ligand for Alzheimer’s disease, to which Eli Lilly and Avid Radiopharmaceuticals donated supplies.
A version of this article originally appeared on Medscape.com.
Short-term and cyclical use of estrogen and progestin therapy for menopausal symptoms is linked to an increased risk of dementia, results of a large observational study show.
(AD) 20 years later, compared with those who didn’t use HT. The risk was present even in women who used HT for brief periods at menopause onset.
However, both the investigators and experts not involved in the research caution that further studies are needed to explore whether the increased risk of dementia stems from HT use or whether women in need of HT have other underlying dementia risk factors.
“We cannot guarantee that our findings illustrate a causal relationship or if they represent underlying disposition to dementia in women in need of [HT],” lead investigator Nelsan Pourhadi, MD, from the Danish Dementia Research Centre at Copenhagen University Hospital Rigshospitalet, told this news organization.
Still, he added, the findings supported evidence from the Women’s Health Initiative Memory Study (WHIMS), the largest randomized trial on menopausal hormone therapy and dementia.
The findings were published online in BMJ.
Conflicting findings
Before WHIMS was published in 2003, HT was widely prescribed to relieve menopausal symptoms. However, WHIMS, which included more than 4,000 women aged 65 years or older, revealed that HT was associated with a twofold increased risk of dementia.
Studies published since then have yielded mixed results, adding to the controversy surrounding the safety of HT.
To discover whether age of initiation or length of duration of HT affects health outcomes, Dr. Pourhadi and his team undertook the observational study.
Between 2000 and 2018, the researchers tracked more than 60,000 Danish women aged 50-60 years using diagnosis and prescription information from Denmark’s National Registry of Patients.
The registry records showed that nearly 5,600 women developed dementia and 56,000 did not develop dementia. Of the 5,600 women with dementia, 1,460 had a diagnosis of AD.
Nearly 18,000 participants in the study sample received HT – 1,790 (29%) in the dementia group and 16,150 (32%) in the control group. Half started treatment before age 53 years and half stopped within 4 years. Roughly 90% used oral medications, which included a combination of estrogen and progestin.
The median age at which participants started HT was 53 years for both cases and controls, and the median duration of use was 4 years.
Longer use equals greater risk
Compared with those who did not use HT, those who used estrogen-progestin therapy had a 24% increased risk of developing all-cause dementia (hazard ratio, 1.24; 95% confidence interval, 1.17-1.44).
The increased dementia risk was similar between continuous (estrogen and progestin taken daily) and cyclic (daily estrogen with progestin taken 10-14 days a month) treatment regimens.
Longer durations of HT use were associated with increased risk, ranging from a 21% increased risk (HR, 1.21; 95% CI, 1.09-1.35) for those who used it for 1 year or less to a 74% increased risk (HR, 1.74; 95% CI, 1.45-2.10) for use lasting 12 years or more.
Women who started HT between the age of 45 and 50 had a 26% increased risk of developing all-cause dementia (HR, 1.26; 95% CI, 1.13-1.41) while women who initiated HT between age 51 and 60 had a 21% greater risk (HR, 1.21; 95% CI, 1.12-1.29).
Progestin-only or vaginal-estrogen-only therapy was not associated with the development of dementia.
The investigators noted that because this is an observational study, “further studies are warranted to explore if the observed association in this study between menopausal hormone therapy use and increased risk of dementia illustrates a causal effect.”
No causal relationship
In an accompanying editorial, Kejal Kantarci, MD, a professor of radiology at the Mayo Clinic, Rochester, Minn., noted that three clinical trials, including the WHIMS of Younger Women (WHIMS-Y) in 2013, did not show a link between cognitive function and HT.
“Although [Dr.] Pourhadi and colleagues’ study was done carefully using national registries, the observed associations could be artefactual and should not be used to infer a causal relationship between hormone therapy and dementia risk. These findings cannot inform shared decision-making about use of hormone therapy for menopausal symptoms,” she states in the editorial.
Also commenting on the findings, Amanda Heslegrave, PhD, a senior research fellow at the U.K. Dementia Research Institute, London, said in a release from the U.K.’s Science Media Centre that while the study “may cause alarm for women taking [HT], it highlights just how much we still don’t know about the effects of hormones on women’s brain health, and with promising treatments on the horizon, it should be a call to action to make this a priority area of research.”
There was no specific funding for the study. Dr. Kantarci reported working on an unpaid educational activity on Alzheimer’s disease for Biogen and is the PI on a study of a PET imaging ligand for Alzheimer’s disease, to which Eli Lilly and Avid Radiopharmaceuticals donated supplies.
A version of this article originally appeared on Medscape.com.
Should breast cancer screening start at a younger age?
The US Preventive Services Task Force (USPSTF) recently issued draft recommendations on breast cancer screening that lower the starting age for routine mammography screening for those at average risk.1 The proposed recommendations are an update to USPSTF’s 2016 guidance on this topic.
What’s different. There are 2 major differences in the new recommendations:
- Recommendation for routine mammography starting at age 40 for women at average risk for breast cancer (eg, no personal or family history or genetic risk factors). This is a “B” recommendation (offer or provide the service). Previously, the recommended age to start routine mammography was 50 years, with a “C” recommendation (individual decision-making) for those ages 40 to 49 years.
- No mention of digital tomosynthesis. Previously, this screening modality was rated as an “I” (insufficient evidence to assess). While the new draft recommendation does not mention tomosynthesis, the related evidence report concludes that there is still insufficient evidence to assess it.2
What’s the same. Several important recommendations have not changed. The USPSTF continues to state that the evidence is insufficient to assess the value of (1) supplemental screening with breast ultrasonography and magnetic resonance imaging in women with dense breasts and negative mammograms and (2) mammography in women ages 75 years and older.
And, most importantly, the USPSTF continues to recommend biennial, rather than annual, mammography screening. This recommendation is based on studies that show very little difference in outcomes between these strategies but higher rates of false-positive tests and subsequent biopsies with annual testing.2
What others say. USPSTF’s draft recommendations continue to differ from those of the American Cancer Society, which for average-risk women recommend individual decision-making from ages 40 to 45 years; routine annual mammography for those ages 45 to 54 years; annual or biennial mammography for those ages 55 years and older; and continued screening for women older than 75 years who are in good health and have a life expectancy ≥ 10 years.3
The USPSTF’s rationale for lowering the age at which to start routine mammography is a little puzzling. Several conclusions in the draft evidence report seem to contradict this recommendation:
In the summary of screening effectiveness, the report states “For women ages 39 to 49 years, the combined [relative risk] for breast cancer mortality was 0.92 (95% CI, 0.75 to 1.02; 9 trials); absolute breast cancer mortality reduction was 2.9 (95% CI, –0.6 to 8.9) deaths prevented per 10,000 women over 10 years. None of the trials indicated statistically significantly reduced breast cancer mortality with screening….”2
And in a summary of screening harms, it states that for “every case of invasive breast cancer detected by mammography screening in women age[s] 40 to 49 years, 464 women had screening mammography, 58 were recommended for additional diagnostic imaging, and 10 were recommended for biopsies.”2
The USPSTF apparently based its decision on a modeling study conducted by the Cancer Intervention and Surveillance Modeling Network (CISNET) at USPSTF’s request. This analysis found that screening biennially from ages 50 to 74 years resulted in about 7 breast cancer deaths averted over the lifetimes of 1000 females and that 1 additional death was averted if the starting age for screening was 40 years.4
Financial implications. The USPSTF’s change from a “C” to a “B” recommendation for women ages 40 to 49 years has financial implications. The Affordable Care Act mandates that all “A” and “B” recommendations by the USPSTF have to be provided by commercial health plans with no out-of-pocket costs. (This is currently being challenged in the courts.) However, any follow-up testing for abnormal results is not subject to this provision—so false-positive work-ups and biopsies may result in out-of-pocket costs.
What to discuss with your patients. For women ages 40 to 50 years, discuss the differences in mammography recommendations and the potential risks and benefits of the procedure, as well as financial implications; respect the patient’s decision.
For those ages 50 to 74 years, recommend biennial mammography.
For those older than 74 years, assess life expectancy and other health problems. Discuss the potential risks and benefits of the procedure and respect the patient’s decision.
For all patients, document all discussions and decisions.
1. USPSTF. Breast cancer: screening. Draft recommendation statement. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults
2. Henderson JT, Webber, EM, Weyrich M, et al. Screening for breast cancer: a comparative effectiveness review for the US Preventive Services Task Force. Evidence Synthesis No. 231. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-evidence-review/breast-cancer-screening-adults
3. American Cancer Society. American Cancer Society recommendations for the early detection of breast cancer. Revised January 14, 2022. Accessed June 20, 2023. https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html
4. Trentham Dietz A, Chapman CH, Jayasekera J, et al. Breast cancer screening with mammography: an updated decision analysis for the US Preventive Services Task Force. Technical report. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-modeling-report/breast-cancer-screening-adults
The US Preventive Services Task Force (USPSTF) recently issued draft recommendations on breast cancer screening that lower the starting age for routine mammography screening for those at average risk.1 The proposed recommendations are an update to USPSTF’s 2016 guidance on this topic.
What’s different. There are 2 major differences in the new recommendations:
- Recommendation for routine mammography starting at age 40 for women at average risk for breast cancer (eg, no personal or family history or genetic risk factors). This is a “B” recommendation (offer or provide the service). Previously, the recommended age to start routine mammography was 50 years, with a “C” recommendation (individual decision-making) for those ages 40 to 49 years.
- No mention of digital tomosynthesis. Previously, this screening modality was rated as an “I” (insufficient evidence to assess). While the new draft recommendation does not mention tomosynthesis, the related evidence report concludes that there is still insufficient evidence to assess it.2
What’s the same. Several important recommendations have not changed. The USPSTF continues to state that the evidence is insufficient to assess the value of (1) supplemental screening with breast ultrasonography and magnetic resonance imaging in women with dense breasts and negative mammograms and (2) mammography in women ages 75 years and older.
And, most importantly, the USPSTF continues to recommend biennial, rather than annual, mammography screening. This recommendation is based on studies that show very little difference in outcomes between these strategies but higher rates of false-positive tests and subsequent biopsies with annual testing.2
What others say. USPSTF’s draft recommendations continue to differ from those of the American Cancer Society, which for average-risk women recommend individual decision-making from ages 40 to 45 years; routine annual mammography for those ages 45 to 54 years; annual or biennial mammography for those ages 55 years and older; and continued screening for women older than 75 years who are in good health and have a life expectancy ≥ 10 years.3
The USPSTF’s rationale for lowering the age at which to start routine mammography is a little puzzling. Several conclusions in the draft evidence report seem to contradict this recommendation:
In the summary of screening effectiveness, the report states “For women ages 39 to 49 years, the combined [relative risk] for breast cancer mortality was 0.92 (95% CI, 0.75 to 1.02; 9 trials); absolute breast cancer mortality reduction was 2.9 (95% CI, –0.6 to 8.9) deaths prevented per 10,000 women over 10 years. None of the trials indicated statistically significantly reduced breast cancer mortality with screening….”2
And in a summary of screening harms, it states that for “every case of invasive breast cancer detected by mammography screening in women age[s] 40 to 49 years, 464 women had screening mammography, 58 were recommended for additional diagnostic imaging, and 10 were recommended for biopsies.”2
The USPSTF apparently based its decision on a modeling study conducted by the Cancer Intervention and Surveillance Modeling Network (CISNET) at USPSTF’s request. This analysis found that screening biennially from ages 50 to 74 years resulted in about 7 breast cancer deaths averted over the lifetimes of 1000 females and that 1 additional death was averted if the starting age for screening was 40 years.4
Financial implications. The USPSTF’s change from a “C” to a “B” recommendation for women ages 40 to 49 years has financial implications. The Affordable Care Act mandates that all “A” and “B” recommendations by the USPSTF have to be provided by commercial health plans with no out-of-pocket costs. (This is currently being challenged in the courts.) However, any follow-up testing for abnormal results is not subject to this provision—so false-positive work-ups and biopsies may result in out-of-pocket costs.
What to discuss with your patients. For women ages 40 to 50 years, discuss the differences in mammography recommendations and the potential risks and benefits of the procedure, as well as financial implications; respect the patient’s decision.
For those ages 50 to 74 years, recommend biennial mammography.
For those older than 74 years, assess life expectancy and other health problems. Discuss the potential risks and benefits of the procedure and respect the patient’s decision.
For all patients, document all discussions and decisions.
The US Preventive Services Task Force (USPSTF) recently issued draft recommendations on breast cancer screening that lower the starting age for routine mammography screening for those at average risk.1 The proposed recommendations are an update to USPSTF’s 2016 guidance on this topic.
What’s different. There are 2 major differences in the new recommendations:
- Recommendation for routine mammography starting at age 40 for women at average risk for breast cancer (eg, no personal or family history or genetic risk factors). This is a “B” recommendation (offer or provide the service). Previously, the recommended age to start routine mammography was 50 years, with a “C” recommendation (individual decision-making) for those ages 40 to 49 years.
- No mention of digital tomosynthesis. Previously, this screening modality was rated as an “I” (insufficient evidence to assess). While the new draft recommendation does not mention tomosynthesis, the related evidence report concludes that there is still insufficient evidence to assess it.2
What’s the same. Several important recommendations have not changed. The USPSTF continues to state that the evidence is insufficient to assess the value of (1) supplemental screening with breast ultrasonography and magnetic resonance imaging in women with dense breasts and negative mammograms and (2) mammography in women ages 75 years and older.
And, most importantly, the USPSTF continues to recommend biennial, rather than annual, mammography screening. This recommendation is based on studies that show very little difference in outcomes between these strategies but higher rates of false-positive tests and subsequent biopsies with annual testing.2
What others say. USPSTF’s draft recommendations continue to differ from those of the American Cancer Society, which for average-risk women recommend individual decision-making from ages 40 to 45 years; routine annual mammography for those ages 45 to 54 years; annual or biennial mammography for those ages 55 years and older; and continued screening for women older than 75 years who are in good health and have a life expectancy ≥ 10 years.3
The USPSTF’s rationale for lowering the age at which to start routine mammography is a little puzzling. Several conclusions in the draft evidence report seem to contradict this recommendation:
In the summary of screening effectiveness, the report states “For women ages 39 to 49 years, the combined [relative risk] for breast cancer mortality was 0.92 (95% CI, 0.75 to 1.02; 9 trials); absolute breast cancer mortality reduction was 2.9 (95% CI, –0.6 to 8.9) deaths prevented per 10,000 women over 10 years. None of the trials indicated statistically significantly reduced breast cancer mortality with screening….”2
And in a summary of screening harms, it states that for “every case of invasive breast cancer detected by mammography screening in women age[s] 40 to 49 years, 464 women had screening mammography, 58 were recommended for additional diagnostic imaging, and 10 were recommended for biopsies.”2
The USPSTF apparently based its decision on a modeling study conducted by the Cancer Intervention and Surveillance Modeling Network (CISNET) at USPSTF’s request. This analysis found that screening biennially from ages 50 to 74 years resulted in about 7 breast cancer deaths averted over the lifetimes of 1000 females and that 1 additional death was averted if the starting age for screening was 40 years.4
Financial implications. The USPSTF’s change from a “C” to a “B” recommendation for women ages 40 to 49 years has financial implications. The Affordable Care Act mandates that all “A” and “B” recommendations by the USPSTF have to be provided by commercial health plans with no out-of-pocket costs. (This is currently being challenged in the courts.) However, any follow-up testing for abnormal results is not subject to this provision—so false-positive work-ups and biopsies may result in out-of-pocket costs.
What to discuss with your patients. For women ages 40 to 50 years, discuss the differences in mammography recommendations and the potential risks and benefits of the procedure, as well as financial implications; respect the patient’s decision.
For those ages 50 to 74 years, recommend biennial mammography.
For those older than 74 years, assess life expectancy and other health problems. Discuss the potential risks and benefits of the procedure and respect the patient’s decision.
For all patients, document all discussions and decisions.
1. USPSTF. Breast cancer: screening. Draft recommendation statement. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults
2. Henderson JT, Webber, EM, Weyrich M, et al. Screening for breast cancer: a comparative effectiveness review for the US Preventive Services Task Force. Evidence Synthesis No. 231. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-evidence-review/breast-cancer-screening-adults
3. American Cancer Society. American Cancer Society recommendations for the early detection of breast cancer. Revised January 14, 2022. Accessed June 20, 2023. https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html
4. Trentham Dietz A, Chapman CH, Jayasekera J, et al. Breast cancer screening with mammography: an updated decision analysis for the US Preventive Services Task Force. Technical report. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-modeling-report/breast-cancer-screening-adults
1. USPSTF. Breast cancer: screening. Draft recommendation statement. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults
2. Henderson JT, Webber, EM, Weyrich M, et al. Screening for breast cancer: a comparative effectiveness review for the US Preventive Services Task Force. Evidence Synthesis No. 231. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-evidence-review/breast-cancer-screening-adults
3. American Cancer Society. American Cancer Society recommendations for the early detection of breast cancer. Revised January 14, 2022. Accessed June 20, 2023. https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html
4. Trentham Dietz A, Chapman CH, Jayasekera J, et al. Breast cancer screening with mammography: an updated decision analysis for the US Preventive Services Task Force. Technical report. Agency for Healthcare Research and Quality; 2023. Published May 9, 2023. Accessed June 19, 2023. https://www.uspreventiveservicestaskforce.org/uspstf/document/draft-modeling-report/breast-cancer-screening-adults
HPV rates skyrocket despite safe, effective vaccine
An epidemic of sexually transmitted HPV is now swirling around the United States and the United Kingdom, with some serious cases leading to oropharyngeal cancer, which can affect the back of the throat, tonsils, and tongue.
HPV is the leading cause (70%) of this oropharyngeal cancer, according to the CDC. It is the most common sexually transmitted disease in the nation, and around 3.6% of women and 10% of men report oral HPV specifically. But over the past decade, oropharyngeal cases have been steadily falling a little under 4% and 2%, respectively, according to the National Cancer Institute.
HPV is often undetectable and can clear up within a few months. But unfortunately for some, serious disease, such as throat cancer, can develop.
Studies show the HPV vaccine to be extremely effective in lowering sexually transmitted HPV cases. Yet, only 54.5% of young people aged 13-15 have taken the recommended two to three doses, according to the National Cancer Institute.
Why aren’t more young people taking the vaccine?
Low public awareness of the dangers of HPV may be behind young people’s poor vaccination rates, according to Teresa Lee, MD, of the Fox Chase Cancer Center in Philadelphia. “For example, while the link with head and neck cancers has been well-studied, the FDA labeling was not changed to reflect this as an indication until 2020,” she said.
Other reasons can include one’s socioeconomic background, poor health literacy, cultural or religious stigmas around vaccines, and lack of quality, low-cost health care, says Emmanuel Aguh, MD, a board-certified family medicine physician. “Some individuals and families are still resistant to vaccines and the noted lack of uptake.”
Doctors and other health care professionals should also be sure to tell patients of all ages about the risks of HPV infection and how well the vaccine works, Dr. Lee said. “Not everyone who is now eligible may have been offered the vaccine as a child, and the first time young adults may receive counseling on this subject may not be until they are entering a very busy period of their lives with many responsibilities – when it may be hard to fit in things like health maintenance.”
How safe is the HPV vaccine?
The Food and Drug Administration and Centers for Disease Control and Prevention have studied the HPV vaccine for years to find out how safe it is and how well it works, Dr. Aguh said. No major side effects have been reported, and the most common side effect is soreness where you get the shot (which is normal after most vaccines). Some dizziness and fainting in adolescents can also occur, so young people are usually asked to sit or lie down during the shot and for 15 minutes afterward, he said.
“Serious adverse events have not been reported at higher rates than expected following HPV vaccination, meaning there is no clear evidence they are related to the vaccine,” Dr. Lee said. “The vaccine is highly effective in decreasing rates of detectable infection with the high-risk HPV strains responsible for HPV-associated cancers.”
The HPV vaccine is largely recommended for people aged 9-26, and sometimes up to age 45, depending on the individual, Dr. Aguh said. If you are over 26, talk to your doctor about whether you should consider getting the vaccine.
“It is usually given in two doses for complete protection if taken before the 15th birthday,” Dr. Aguh said. “If taken afterward, or in those with a weak immune system, they might require three doses to be fully protected.”
The vaccine produces antibodies that can stop HPV from infecting cells and lowers your chances of catching an HPV-related cancer, such as throat cancer or cancer of the cervix, he said.
While the vaccine is not guaranteed to protect you from the more than 100 strains of HPV, it can protect you from HPV 16 and HPV 18 – two high-risk strains that cause around 70% of cervical cancers.
What is fueling the rise of HPV cases?
A misconception that oral sex is somehow a “safe and risk-free” alternative to anal or vaginal sex could be one reason, Dr. Aguh said.
“It is important to know that, with oral sex, you are exposed to many of the risks associated with vaginal intercourse, especially if you do not take any measures to protect yourself and/or your partner,” Dr. Aguh said. “[With oral sex] it is possible to end up contracting an infection like chlamydia, gonorrhea, and even HPV, leading to an increased risk of HPV-associated oropharyngeal cancers.”
A lack of public awareness of what can cause throat cancer could also explain this phenomenon. The number of people you have oral sex with, along with the age you begin sexual activity, can greatly determine your risk of the disease, according to Dr. Lee. She echoes a report by Hisham Mehanna, PhD, in The Conversation.
“For oropharyngeal cancer, the main risk factor is the number of lifetime sexual partners, especially oral sex,” wrote Dr. Mehanna, a professor at the Institute of Cancer and Genomic Sciences at the University of Birmingham (England). “Those with six or more lifetime oral-sex partners are 8.5 times more likely to develop oropharyngeal cancer than those who do not practice oral sex.”
What are symptoms of oropharyngeal cancer?
Labored breathing or swallowing, a cough that won’t go away, and crackling or hoarseness of your voice could all be signs of throat cancer. Other symptoms include earaches, swelling of the head or neck, and enlarged lymph nodes, among others, Dr. Aguh said.
“The signs and symptoms of HPV-related throat cancers can be difficult to identify and recognize, as they can be vague and are also associated with other medical conditions. Sometimes, there are no signs at all, or they are not easily noticeable due to the location,” he said.
You should go see your doctor if you have any of these ailments for an extended period.
How to reduce your risk
In addition to having six or more oral-sex partners, smoking and drinking heavily could also raise your risk of throat cancer, said Dr. Lee. Proper dental health – like seeing your dentist regularly and practicing proper oral hygiene – can also shave your risk.
“[Good dental health] can help not just with head and neck cancer risk, but with many other inflammation-related diseases,” Dr. Lee said.
Using dental dams and condoms can also be a good method of protection, Dr. Aguh said. A dental dam is a stretchy sheet of latex, or polyurethane plastic, in the shape of a square that is made for blocking body fluid to lower your risk of contracting an STD via oral sex.
Keep in mind: Even with these protections, make sure you and your partner discuss each other’s sexual history, any prior or current STDs and their preferred protection from STDs, said Dr. Aguh.
If you or your partner is being treated for an STD, consider opting out of oral sex and consulting a doctor.
The HPV vaccine is another common method of protection. The shot is “approved for prevention of nine of the most high-risk strains of HPV,” or those that are most commonly linked to cancer, according to Dr. Lee. The vaccine “reduces the frequency of infection” with these viruses, which can ultimately lower the risk of cancers linked to HPV, including cervical, anal, and vulvar and vaginal cancers, she said.
“The best time to receive treatment for prevention of disease is prior to onset of sexual intercourse,” said Dr. Lee.
To get your HPV vaccine, head to your family doctor, school- or community-based health center, or state health department, suggests the CDC.
A version of this article originally appeared on WebMD.com.
An epidemic of sexually transmitted HPV is now swirling around the United States and the United Kingdom, with some serious cases leading to oropharyngeal cancer, which can affect the back of the throat, tonsils, and tongue.
HPV is the leading cause (70%) of this oropharyngeal cancer, according to the CDC. It is the most common sexually transmitted disease in the nation, and around 3.6% of women and 10% of men report oral HPV specifically. But over the past decade, oropharyngeal cases have been steadily falling a little under 4% and 2%, respectively, according to the National Cancer Institute.
HPV is often undetectable and can clear up within a few months. But unfortunately for some, serious disease, such as throat cancer, can develop.
Studies show the HPV vaccine to be extremely effective in lowering sexually transmitted HPV cases. Yet, only 54.5% of young people aged 13-15 have taken the recommended two to three doses, according to the National Cancer Institute.
Why aren’t more young people taking the vaccine?
Low public awareness of the dangers of HPV may be behind young people’s poor vaccination rates, according to Teresa Lee, MD, of the Fox Chase Cancer Center in Philadelphia. “For example, while the link with head and neck cancers has been well-studied, the FDA labeling was not changed to reflect this as an indication until 2020,” she said.
Other reasons can include one’s socioeconomic background, poor health literacy, cultural or religious stigmas around vaccines, and lack of quality, low-cost health care, says Emmanuel Aguh, MD, a board-certified family medicine physician. “Some individuals and families are still resistant to vaccines and the noted lack of uptake.”
Doctors and other health care professionals should also be sure to tell patients of all ages about the risks of HPV infection and how well the vaccine works, Dr. Lee said. “Not everyone who is now eligible may have been offered the vaccine as a child, and the first time young adults may receive counseling on this subject may not be until they are entering a very busy period of their lives with many responsibilities – when it may be hard to fit in things like health maintenance.”
How safe is the HPV vaccine?
The Food and Drug Administration and Centers for Disease Control and Prevention have studied the HPV vaccine for years to find out how safe it is and how well it works, Dr. Aguh said. No major side effects have been reported, and the most common side effect is soreness where you get the shot (which is normal after most vaccines). Some dizziness and fainting in adolescents can also occur, so young people are usually asked to sit or lie down during the shot and for 15 minutes afterward, he said.
“Serious adverse events have not been reported at higher rates than expected following HPV vaccination, meaning there is no clear evidence they are related to the vaccine,” Dr. Lee said. “The vaccine is highly effective in decreasing rates of detectable infection with the high-risk HPV strains responsible for HPV-associated cancers.”
The HPV vaccine is largely recommended for people aged 9-26, and sometimes up to age 45, depending on the individual, Dr. Aguh said. If you are over 26, talk to your doctor about whether you should consider getting the vaccine.
“It is usually given in two doses for complete protection if taken before the 15th birthday,” Dr. Aguh said. “If taken afterward, or in those with a weak immune system, they might require three doses to be fully protected.”
The vaccine produces antibodies that can stop HPV from infecting cells and lowers your chances of catching an HPV-related cancer, such as throat cancer or cancer of the cervix, he said.
While the vaccine is not guaranteed to protect you from the more than 100 strains of HPV, it can protect you from HPV 16 and HPV 18 – two high-risk strains that cause around 70% of cervical cancers.
What is fueling the rise of HPV cases?
A misconception that oral sex is somehow a “safe and risk-free” alternative to anal or vaginal sex could be one reason, Dr. Aguh said.
“It is important to know that, with oral sex, you are exposed to many of the risks associated with vaginal intercourse, especially if you do not take any measures to protect yourself and/or your partner,” Dr. Aguh said. “[With oral sex] it is possible to end up contracting an infection like chlamydia, gonorrhea, and even HPV, leading to an increased risk of HPV-associated oropharyngeal cancers.”
A lack of public awareness of what can cause throat cancer could also explain this phenomenon. The number of people you have oral sex with, along with the age you begin sexual activity, can greatly determine your risk of the disease, according to Dr. Lee. She echoes a report by Hisham Mehanna, PhD, in The Conversation.
“For oropharyngeal cancer, the main risk factor is the number of lifetime sexual partners, especially oral sex,” wrote Dr. Mehanna, a professor at the Institute of Cancer and Genomic Sciences at the University of Birmingham (England). “Those with six or more lifetime oral-sex partners are 8.5 times more likely to develop oropharyngeal cancer than those who do not practice oral sex.”
What are symptoms of oropharyngeal cancer?
Labored breathing or swallowing, a cough that won’t go away, and crackling or hoarseness of your voice could all be signs of throat cancer. Other symptoms include earaches, swelling of the head or neck, and enlarged lymph nodes, among others, Dr. Aguh said.
“The signs and symptoms of HPV-related throat cancers can be difficult to identify and recognize, as they can be vague and are also associated with other medical conditions. Sometimes, there are no signs at all, or they are not easily noticeable due to the location,” he said.
You should go see your doctor if you have any of these ailments for an extended period.
How to reduce your risk
In addition to having six or more oral-sex partners, smoking and drinking heavily could also raise your risk of throat cancer, said Dr. Lee. Proper dental health – like seeing your dentist regularly and practicing proper oral hygiene – can also shave your risk.
“[Good dental health] can help not just with head and neck cancer risk, but with many other inflammation-related diseases,” Dr. Lee said.
Using dental dams and condoms can also be a good method of protection, Dr. Aguh said. A dental dam is a stretchy sheet of latex, or polyurethane plastic, in the shape of a square that is made for blocking body fluid to lower your risk of contracting an STD via oral sex.
Keep in mind: Even with these protections, make sure you and your partner discuss each other’s sexual history, any prior or current STDs and their preferred protection from STDs, said Dr. Aguh.
If you or your partner is being treated for an STD, consider opting out of oral sex and consulting a doctor.
The HPV vaccine is another common method of protection. The shot is “approved for prevention of nine of the most high-risk strains of HPV,” or those that are most commonly linked to cancer, according to Dr. Lee. The vaccine “reduces the frequency of infection” with these viruses, which can ultimately lower the risk of cancers linked to HPV, including cervical, anal, and vulvar and vaginal cancers, she said.
“The best time to receive treatment for prevention of disease is prior to onset of sexual intercourse,” said Dr. Lee.
To get your HPV vaccine, head to your family doctor, school- or community-based health center, or state health department, suggests the CDC.
A version of this article originally appeared on WebMD.com.
An epidemic of sexually transmitted HPV is now swirling around the United States and the United Kingdom, with some serious cases leading to oropharyngeal cancer, which can affect the back of the throat, tonsils, and tongue.
HPV is the leading cause (70%) of this oropharyngeal cancer, according to the CDC. It is the most common sexually transmitted disease in the nation, and around 3.6% of women and 10% of men report oral HPV specifically. But over the past decade, oropharyngeal cases have been steadily falling a little under 4% and 2%, respectively, according to the National Cancer Institute.
HPV is often undetectable and can clear up within a few months. But unfortunately for some, serious disease, such as throat cancer, can develop.
Studies show the HPV vaccine to be extremely effective in lowering sexually transmitted HPV cases. Yet, only 54.5% of young people aged 13-15 have taken the recommended two to three doses, according to the National Cancer Institute.
Why aren’t more young people taking the vaccine?
Low public awareness of the dangers of HPV may be behind young people’s poor vaccination rates, according to Teresa Lee, MD, of the Fox Chase Cancer Center in Philadelphia. “For example, while the link with head and neck cancers has been well-studied, the FDA labeling was not changed to reflect this as an indication until 2020,” she said.
Other reasons can include one’s socioeconomic background, poor health literacy, cultural or religious stigmas around vaccines, and lack of quality, low-cost health care, says Emmanuel Aguh, MD, a board-certified family medicine physician. “Some individuals and families are still resistant to vaccines and the noted lack of uptake.”
Doctors and other health care professionals should also be sure to tell patients of all ages about the risks of HPV infection and how well the vaccine works, Dr. Lee said. “Not everyone who is now eligible may have been offered the vaccine as a child, and the first time young adults may receive counseling on this subject may not be until they are entering a very busy period of their lives with many responsibilities – when it may be hard to fit in things like health maintenance.”
How safe is the HPV vaccine?
The Food and Drug Administration and Centers for Disease Control and Prevention have studied the HPV vaccine for years to find out how safe it is and how well it works, Dr. Aguh said. No major side effects have been reported, and the most common side effect is soreness where you get the shot (which is normal after most vaccines). Some dizziness and fainting in adolescents can also occur, so young people are usually asked to sit or lie down during the shot and for 15 minutes afterward, he said.
“Serious adverse events have not been reported at higher rates than expected following HPV vaccination, meaning there is no clear evidence they are related to the vaccine,” Dr. Lee said. “The vaccine is highly effective in decreasing rates of detectable infection with the high-risk HPV strains responsible for HPV-associated cancers.”
The HPV vaccine is largely recommended for people aged 9-26, and sometimes up to age 45, depending on the individual, Dr. Aguh said. If you are over 26, talk to your doctor about whether you should consider getting the vaccine.
“It is usually given in two doses for complete protection if taken before the 15th birthday,” Dr. Aguh said. “If taken afterward, or in those with a weak immune system, they might require three doses to be fully protected.”
The vaccine produces antibodies that can stop HPV from infecting cells and lowers your chances of catching an HPV-related cancer, such as throat cancer or cancer of the cervix, he said.
While the vaccine is not guaranteed to protect you from the more than 100 strains of HPV, it can protect you from HPV 16 and HPV 18 – two high-risk strains that cause around 70% of cervical cancers.
What is fueling the rise of HPV cases?
A misconception that oral sex is somehow a “safe and risk-free” alternative to anal or vaginal sex could be one reason, Dr. Aguh said.
“It is important to know that, with oral sex, you are exposed to many of the risks associated with vaginal intercourse, especially if you do not take any measures to protect yourself and/or your partner,” Dr. Aguh said. “[With oral sex] it is possible to end up contracting an infection like chlamydia, gonorrhea, and even HPV, leading to an increased risk of HPV-associated oropharyngeal cancers.”
A lack of public awareness of what can cause throat cancer could also explain this phenomenon. The number of people you have oral sex with, along with the age you begin sexual activity, can greatly determine your risk of the disease, according to Dr. Lee. She echoes a report by Hisham Mehanna, PhD, in The Conversation.
“For oropharyngeal cancer, the main risk factor is the number of lifetime sexual partners, especially oral sex,” wrote Dr. Mehanna, a professor at the Institute of Cancer and Genomic Sciences at the University of Birmingham (England). “Those with six or more lifetime oral-sex partners are 8.5 times more likely to develop oropharyngeal cancer than those who do not practice oral sex.”
What are symptoms of oropharyngeal cancer?
Labored breathing or swallowing, a cough that won’t go away, and crackling or hoarseness of your voice could all be signs of throat cancer. Other symptoms include earaches, swelling of the head or neck, and enlarged lymph nodes, among others, Dr. Aguh said.
“The signs and symptoms of HPV-related throat cancers can be difficult to identify and recognize, as they can be vague and are also associated with other medical conditions. Sometimes, there are no signs at all, or they are not easily noticeable due to the location,” he said.
You should go see your doctor if you have any of these ailments for an extended period.
How to reduce your risk
In addition to having six or more oral-sex partners, smoking and drinking heavily could also raise your risk of throat cancer, said Dr. Lee. Proper dental health – like seeing your dentist regularly and practicing proper oral hygiene – can also shave your risk.
“[Good dental health] can help not just with head and neck cancer risk, but with many other inflammation-related diseases,” Dr. Lee said.
Using dental dams and condoms can also be a good method of protection, Dr. Aguh said. A dental dam is a stretchy sheet of latex, or polyurethane plastic, in the shape of a square that is made for blocking body fluid to lower your risk of contracting an STD via oral sex.
Keep in mind: Even with these protections, make sure you and your partner discuss each other’s sexual history, any prior or current STDs and their preferred protection from STDs, said Dr. Aguh.
If you or your partner is being treated for an STD, consider opting out of oral sex and consulting a doctor.
The HPV vaccine is another common method of protection. The shot is “approved for prevention of nine of the most high-risk strains of HPV,” or those that are most commonly linked to cancer, according to Dr. Lee. The vaccine “reduces the frequency of infection” with these viruses, which can ultimately lower the risk of cancers linked to HPV, including cervical, anal, and vulvar and vaginal cancers, she said.
“The best time to receive treatment for prevention of disease is prior to onset of sexual intercourse,” said Dr. Lee.
To get your HPV vaccine, head to your family doctor, school- or community-based health center, or state health department, suggests the CDC.
A version of this article originally appeared on WebMD.com.
Vaginal microbiota transfer may affect neurodevelopment in cesarean infants
Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
FROM CELL HOST & MICROBE