Women's Health

Physicians could be doing a better job of counseling patients with obesity and overweight on weight loss and fertility. A study of 48 women seeking infertility care at a large academic center found that less than half received advice on weight loss from their primary ob.gyn. prior to referral for infertility treatment.

Patients are thinking about this – many attempt to lose weight independently of support from their health care providers, said lead study author Margaret R. O’Neill, MD, a resident at the University of Massachusetts Medical Center in Worcester. Dr. O’Neill discussed these results at the American Society of Reproductive Medicine’s 2021 meeting.

Nearly half of all U.S. women of reproductive age have overweight or obesity, with a body mass index of >25 kg/m². Menstrual irregularity, ovulatory dysfunction, reduced fecundity, and lower efficacy of infertility treatment are some of the consequences of obesity on fertility, said Dr. O’Neill. Obesity also affects the health of expectant mothers and fetuses, increasing the likelihood of gestational diabetes, preterm delivery, and preeclampsia, and increased incidence of fetal anomalies.

“Unfortunately, even though the prevalence of obesity has been increasing substantially in our country, there’s not excellent rates of this being addressed by physicians,” said Dr. O’Neill. BMI is often left out of documentation and rates of referrals to weight loss specialists are also low.

Conversations have been taking place about IVF centers instituting different BMI cutoffs for certain types of assisted reproductive technology, she noted.

Dr. O’Neill and her colleagues undertook a survey to see what advice community providers were dispensing about weight management on fertility.
 

Infertility specialists offer the most guidance

The prospective study included 48 nonpregnant women of reproductive age women presenting for IVF who needed an anesthesia consultation because of elevated BMI (> 35) prior to initiation of IVF. Mean age was 36 years and mean BMI was 38.5. More than 70% of the patients were White and they were predominantly English speakers.

All participants had attempted weight loss, including an attempt in the last year, and 93.8% reported trying to lose weight in the last year. On average, patients weighed about 20 pounds less than their heaviest adult weight. Nineteen percent of the participants were at their heaviest adult weight.

While 60% said they’d received weight loss/infertility counseling by any health care provider, just 41.7% reported that their primary ob.gyn. counseled them about weight loss before referring them for treatment. Infertility specialists seem to provide the most assistance: Nearly 70% of the respondents said they’ve been counseled by these providers.

Women with a higher-than-average BMI (39) were more likely to report a referral to weight loss counseling compared with women not referred (37.9, P = .2). 

Investigators also asked patients about their knowledge of obesity and its relationship to other health conditions. About 90% understood that infertility and excess weight were related. Overall, they were less sure about the link between obesity and still birth, breast cancer, and birth defects. Only 37% were able to identify a normal BMI range.
 

Avoiding a touchy subject

BMI is a highly sensitive area for many women, despite its detrimental effect on fertility, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“By the time their journey has led them to an infertility specialist, most women are very anxious to begin treatment,” said Dr. Trolice, who was not involved in the survey. These patients, however, could interpret any medical advice to achieve a more optimal BMI and healthier lifestyle as a negative judgment that could delay their goal of having a healthy child, he said.

Physicians in turn may avoid these conversations because they don’t want to encourage the ire of patients and/or risk a negative online rating review, he added.

Don’t say ‘just lose weight’

When asked what type of counseling works best, many said that nonspecific recommendations such as “you need to lose weight” or “exercise more” were the least helpful. Targeted advice such as “avoid eating at night and take walks every day,” works more effectively. “Any kind of referral to a bariatrics team or weight loss program was seen as helpful by patients,” said Dr. O’Neill.

Suggestions that considered the difficulty of this process, such as seeking therapy, were also helpful. “Patients appreciated empathy, compassion, and encouragement” from their physicians, she said.
 

The role of physicians in weight loss

Physicians can make a difference. Studies show that patients who received weight loss counseling were more likely to attempt weight loss and report clinically significant weight loss.

The American College of Obstetricians and Gynecologists and ASRM recommend counseling patients with overweight and obesity to lose weight before getting pregnant. A modest weight loss of 10% is associated with improved ovulatory function and higher pregnancy rates, said Dr. O’Neill.

“Appropriately, the infertility specialist should strongly recommend [that women who are obese] obtain a more optimal BMI prior to fertility treatment. While there is no guarantee of decreased infertility and decreased pregnancy complications following weight loss, a lower BMI improves outcomes,” said Dr. Trolice.

Future research should address the fertility outcomes of women who have been counseled by their providers to lose weight and the most effective method of counseling, noted Dr. O’Neill. “We have to find the best ways to address this at each fertility institution.”

The study had limited generalizability because of its narrow patient population and regional differences in access to insurance and weight loss specialists. COVID-19 also reduced the sample size, said Dr. O’Neill. She noted that patient perceptions might not equate with actual counseling delivered.

Dr. O’Neill and Dr. Trolice had no disclosures.

Physicians could be doing a better job of counseling patients with obesity and overweight on weight loss and fertility. A study of 48 women seeking infertility care at a large academic center found that less than half received advice on weight loss from their primary ob.gyn. prior to referral for infertility treatment.

Patients are thinking about this – many attempt to lose weight independently of support from their health care providers, said lead study author Margaret R. O’Neill, MD, a resident at the University of Massachusetts Medical Center in Worcester. Dr. O’Neill discussed these results at the American Society of Reproductive Medicine’s 2021 meeting.

Nearly half of all U.S. women of reproductive age have overweight or obesity, with a body mass index of >25 kg/m². Menstrual irregularity, ovulatory dysfunction, reduced fecundity, and lower efficacy of infertility treatment are some of the consequences of obesity on fertility, said Dr. O’Neill. Obesity also affects the health of expectant mothers and fetuses, increasing the likelihood of gestational diabetes, preterm delivery, and preeclampsia, and increased incidence of fetal anomalies.

“Unfortunately, even though the prevalence of obesity has been increasing substantially in our country, there’s not excellent rates of this being addressed by physicians,” said Dr. O’Neill. BMI is often left out of documentation and rates of referrals to weight loss specialists are also low.

Conversations have been taking place about IVF centers instituting different BMI cutoffs for certain types of assisted reproductive technology, she noted.

Dr. O’Neill and her colleagues undertook a survey to see what advice community providers were dispensing about weight management on fertility.
 

Infertility specialists offer the most guidance

The prospective study included 48 nonpregnant women of reproductive age women presenting for IVF who needed an anesthesia consultation because of elevated BMI (> 35) prior to initiation of IVF. Mean age was 36 years and mean BMI was 38.5. More than 70% of the patients were White and they were predominantly English speakers.

All participants had attempted weight loss, including an attempt in the last year, and 93.8% reported trying to lose weight in the last year. On average, patients weighed about 20 pounds less than their heaviest adult weight. Nineteen percent of the participants were at their heaviest adult weight.

While 60% said they’d received weight loss/infertility counseling by any health care provider, just 41.7% reported that their primary ob.gyn. counseled them about weight loss before referring them for treatment. Infertility specialists seem to provide the most assistance: Nearly 70% of the respondents said they’ve been counseled by these providers.

Women with a higher-than-average BMI (39) were more likely to report a referral to weight loss counseling compared with women not referred (37.9, P = .2). 

Investigators also asked patients about their knowledge of obesity and its relationship to other health conditions. About 90% understood that infertility and excess weight were related. Overall, they were less sure about the link between obesity and still birth, breast cancer, and birth defects. Only 37% were able to identify a normal BMI range.
 

Avoiding a touchy subject

BMI is a highly sensitive area for many women, despite its detrimental effect on fertility, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“By the time their journey has led them to an infertility specialist, most women are very anxious to begin treatment,” said Dr. Trolice, who was not involved in the survey. These patients, however, could interpret any medical advice to achieve a more optimal BMI and healthier lifestyle as a negative judgment that could delay their goal of having a healthy child, he said.

Physicians in turn may avoid these conversations because they don’t want to encourage the ire of patients and/or risk a negative online rating review, he added.

Don’t say ‘just lose weight’

When asked what type of counseling works best, many said that nonspecific recommendations such as “you need to lose weight” or “exercise more” were the least helpful. Targeted advice such as “avoid eating at night and take walks every day,” works more effectively. “Any kind of referral to a bariatrics team or weight loss program was seen as helpful by patients,” said Dr. O’Neill.

Suggestions that considered the difficulty of this process, such as seeking therapy, were also helpful. “Patients appreciated empathy, compassion, and encouragement” from their physicians, she said.
 

The role of physicians in weight loss

Physicians can make a difference. Studies show that patients who received weight loss counseling were more likely to attempt weight loss and report clinically significant weight loss.

The American College of Obstetricians and Gynecologists and ASRM recommend counseling patients with overweight and obesity to lose weight before getting pregnant. A modest weight loss of 10% is associated with improved ovulatory function and higher pregnancy rates, said Dr. O’Neill.

“Appropriately, the infertility specialist should strongly recommend [that women who are obese] obtain a more optimal BMI prior to fertility treatment. While there is no guarantee of decreased infertility and decreased pregnancy complications following weight loss, a lower BMI improves outcomes,” said Dr. Trolice.

Future research should address the fertility outcomes of women who have been counseled by their providers to lose weight and the most effective method of counseling, noted Dr. O’Neill. “We have to find the best ways to address this at each fertility institution.”

The study had limited generalizability because of its narrow patient population and regional differences in access to insurance and weight loss specialists. COVID-19 also reduced the sample size, said Dr. O’Neill. She noted that patient perceptions might not equate with actual counseling delivered.

Dr. O’Neill and Dr. Trolice had no disclosures.

Physicians could be doing a better job of counseling patients with obesity and overweight on weight loss and fertility. A study of 48 women seeking infertility care at a large academic center found that less than half received advice on weight loss from their primary ob.gyn. prior to referral for infertility treatment.

Patients are thinking about this – many attempt to lose weight independently of support from their health care providers, said lead study author Margaret R. O’Neill, MD, a resident at the University of Massachusetts Medical Center in Worcester. Dr. O’Neill discussed these results at the American Society of Reproductive Medicine’s 2021 meeting.

Nearly half of all U.S. women of reproductive age have overweight or obesity, with a body mass index of >25 kg/m². Menstrual irregularity, ovulatory dysfunction, reduced fecundity, and lower efficacy of infertility treatment are some of the consequences of obesity on fertility, said Dr. O’Neill. Obesity also affects the health of expectant mothers and fetuses, increasing the likelihood of gestational diabetes, preterm delivery, and preeclampsia, and increased incidence of fetal anomalies.

“Unfortunately, even though the prevalence of obesity has been increasing substantially in our country, there’s not excellent rates of this being addressed by physicians,” said Dr. O’Neill. BMI is often left out of documentation and rates of referrals to weight loss specialists are also low.

Conversations have been taking place about IVF centers instituting different BMI cutoffs for certain types of assisted reproductive technology, she noted.

Dr. O’Neill and her colleagues undertook a survey to see what advice community providers were dispensing about weight management on fertility.
 

Infertility specialists offer the most guidance

The prospective study included 48 nonpregnant women of reproductive age women presenting for IVF who needed an anesthesia consultation because of elevated BMI (> 35) prior to initiation of IVF. Mean age was 36 years and mean BMI was 38.5. More than 70% of the patients were White and they were predominantly English speakers.

All participants had attempted weight loss, including an attempt in the last year, and 93.8% reported trying to lose weight in the last year. On average, patients weighed about 20 pounds less than their heaviest adult weight. Nineteen percent of the participants were at their heaviest adult weight.

While 60% said they’d received weight loss/infertility counseling by any health care provider, just 41.7% reported that their primary ob.gyn. counseled them about weight loss before referring them for treatment. Infertility specialists seem to provide the most assistance: Nearly 70% of the respondents said they’ve been counseled by these providers.

Women with a higher-than-average BMI (39) were more likely to report a referral to weight loss counseling compared with women not referred (37.9, P = .2). 

Investigators also asked patients about their knowledge of obesity and its relationship to other health conditions. About 90% understood that infertility and excess weight were related. Overall, they were less sure about the link between obesity and still birth, breast cancer, and birth defects. Only 37% were able to identify a normal BMI range.
 

Avoiding a touchy subject

BMI is a highly sensitive area for many women, despite its detrimental effect on fertility, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“By the time their journey has led them to an infertility specialist, most women are very anxious to begin treatment,” said Dr. Trolice, who was not involved in the survey. These patients, however, could interpret any medical advice to achieve a more optimal BMI and healthier lifestyle as a negative judgment that could delay their goal of having a healthy child, he said.

Physicians in turn may avoid these conversations because they don’t want to encourage the ire of patients and/or risk a negative online rating review, he added.

Don’t say ‘just lose weight’

When asked what type of counseling works best, many said that nonspecific recommendations such as “you need to lose weight” or “exercise more” were the least helpful. Targeted advice such as “avoid eating at night and take walks every day,” works more effectively. “Any kind of referral to a bariatrics team or weight loss program was seen as helpful by patients,” said Dr. O’Neill.

Suggestions that considered the difficulty of this process, such as seeking therapy, were also helpful. “Patients appreciated empathy, compassion, and encouragement” from their physicians, she said.
 

The role of physicians in weight loss

Physicians can make a difference. Studies show that patients who received weight loss counseling were more likely to attempt weight loss and report clinically significant weight loss.

The American College of Obstetricians and Gynecologists and ASRM recommend counseling patients with overweight and obesity to lose weight before getting pregnant. A modest weight loss of 10% is associated with improved ovulatory function and higher pregnancy rates, said Dr. O’Neill.

“Appropriately, the infertility specialist should strongly recommend [that women who are obese] obtain a more optimal BMI prior to fertility treatment. While there is no guarantee of decreased infertility and decreased pregnancy complications following weight loss, a lower BMI improves outcomes,” said Dr. Trolice.

Future research should address the fertility outcomes of women who have been counseled by their providers to lose weight and the most effective method of counseling, noted Dr. O’Neill. “We have to find the best ways to address this at each fertility institution.”

The study had limited generalizability because of its narrow patient population and regional differences in access to insurance and weight loss specialists. COVID-19 also reduced the sample size, said Dr. O’Neill. She noted that patient perceptions might not equate with actual counseling delivered.

Dr. O’Neill and Dr. Trolice had no disclosures.

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

In the first study of its kind, women with a breast cancer diagnosis who recalled eating nuts were found to have a significantly better disease-free survival over a 10-year study period, compared with those who said they had not eaten nuts.

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There was also an improvement in overall survival, but this was not statistically significant.

The finding comes from a study of more than 3,000 patients conducted in China, published online in the International Journal of Cancer. Patients were queried about nut consumption on only one occasion, 5 years after their breast cancer diagnosis. 

The investigators report a dose-response pattern between nut eating and the risk of both breast cancer recurrence and overall mortality, with those consuming the largest amounts having the lowest risks.

“Nuts are important components of healthy diets. Promoting this modifiable lifestyle factor should be emphasized in breast cancer survivor guidelines,” conclude Xiao-Ou Shu, MD, PhD, of Vanderbilt University, Nashville, Tenn., and colleagues in the study.

“The association for disease-free survival is quite strong and robust,” Dr. Shu told this news organization.

However, as with all observational studies, this report shows an association and not causation.

“Based upon this study alone, the evidence is weak,” said Wendy Chen, MD, MPH, a breast oncologist at Dana-Farber Cancer Institute in Boston, who was approached for comment.  

The people who consumed nuts generally had more education, higher income, lower body mass index, earlier-stage cancers, and more physically active lives – all factors associated with better breast cancer survival, she observed. “The authors tried to control for these factors,” Dr. Chen acknowledged. But it’s hard to know whether nut consumption was “truly” the difference maker, she said.

Furthermore, the study population is also “a bit unusual” because people had to survive 5 years after diagnosis to be included in the analysis – and thus is not representative of breast cancer survivors, she noted.

Erin Van Blarigan, PhD, an epidemiologist at the University of California, San Francisco, described the overall evidence of the beneficial relationship between nut eating and breast cancer – including this study – as “limited.” She previously led a study that observed benefits of nut intake for patients with colon cancer.

Dr. Van Blarigan also noted that nut intake in this study was “very low” – with the median intake less than one serving per week.

She also offered some general advice about eating nuts.  

“Nuts are an energy-dense food, so portion sizes should be kept small,” she said, explaining a portion should be about 1 ounce or 1/4 cup of nuts or 1-2 tablespoons of nut butter.

A little may go a long way, she suggested, as research to date “suggests only small amounts may be needed to gain potential benefits.”

The level of nut consumption was low in the Chinese study population (median = 17.3 grams/week) compared with the 42.5 grams/week recommended by the American Heart Association, the study authors acknowledge.

“Nuts, particularly tree nuts, are expensive in China. Traditionally, nut consumption level has been low among Chinese, particularly in the old generation,” commented Dr. Shu.
 

Study authors did an adjusted analysis

The new study was conducted among 3,449 participants of the Shanghai Breast Cancer Survival Study.

Nut consumption (including peanuts and tree nuts such as walnuts) was assessed with a food questionnaire at 5 years post-diagnosis.

An analysis was conducted at 10 years post-diagnosis (and 5 years after the diet questionnaire). At this 10-year mark, there were 252 breast cancer-specific deaths. Among 3,274 survivors without previous recurrence at the dietary assessment, 209 went on to develop breast cancer-specific events – either recurrence, metastasis, or breast cancer mortality.

Nut consumers had higher overall survival (93.7% vs. 89%; P = .003) and disease-free survival (94.1% vs. 86.2%; P <.001) rates than nonconsumers.

However, the two groups had many differences, as noted by the authors and outside experts.

The consumers had a younger age at diagnosis, lower BMI, higher total energy intake, higher diet quality score, and higher soy food intake. In addition, nut consumers were more likely to have a higher education, personal income, and physical activity level (≥7.5 metabolic equivalent of task-hour/week) as well as to have received immunotherapy.

So the investigators adjusted for many of those variables and found that nut consumption was associated with significantly better disease-free survival (hazard ratio, 0.52; 95% confidence interval, 0.35-0.75), but a nonsignificantly improved overall survival (HR, 0.90; 95% CI, 0.66-1.23), as noted above.

Analyses by amount of nut intake showed a dose-response relationship for both overall survival (P trend = .022) and disease-free survival (P trend = .003).

The authors say that “there has been no strong evidence to support individual food items in favor of breast cancer survival,” citing a 2018 report entitled “Diet, Nutrition, Physical Activity and Breast Cancer Survivors” from the World Cancer Research Fund/American Institute for Cancer Research.

The new study provides evidence that nuts may be such a food, they say, while also calling for studies to confirm their findings.

Study limitations include that fact that the statuses of recurrence and metastasis were self-reported. Misclassification, particularly regarding the event date, is likely, the team says.

The study authors and Dr. Van Blarigan and Dr. Chen have disclosed no relevant financial relationships.

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

In the first study of its kind, women with a breast cancer diagnosis who recalled eating nuts were found to have a significantly better disease-free survival over a 10-year study period, compared with those who said they had not eaten nuts.

PxHere

There was also an improvement in overall survival, but this was not statistically significant.

The finding comes from a study of more than 3,000 patients conducted in China, published online in the International Journal of Cancer. Patients were queried about nut consumption on only one occasion, 5 years after their breast cancer diagnosis. 

The investigators report a dose-response pattern between nut eating and the risk of both breast cancer recurrence and overall mortality, with those consuming the largest amounts having the lowest risks.

“Nuts are important components of healthy diets. Promoting this modifiable lifestyle factor should be emphasized in breast cancer survivor guidelines,” conclude Xiao-Ou Shu, MD, PhD, of Vanderbilt University, Nashville, Tenn., and colleagues in the study.

“The association for disease-free survival is quite strong and robust,” Dr. Shu told this news organization.

However, as with all observational studies, this report shows an association and not causation.

“Based upon this study alone, the evidence is weak,” said Wendy Chen, MD, MPH, a breast oncologist at Dana-Farber Cancer Institute in Boston, who was approached for comment.  

The people who consumed nuts generally had more education, higher income, lower body mass index, earlier-stage cancers, and more physically active lives – all factors associated with better breast cancer survival, she observed. “The authors tried to control for these factors,” Dr. Chen acknowledged. But it’s hard to know whether nut consumption was “truly” the difference maker, she said.

Furthermore, the study population is also “a bit unusual” because people had to survive 5 years after diagnosis to be included in the analysis – and thus is not representative of breast cancer survivors, she noted.

Erin Van Blarigan, PhD, an epidemiologist at the University of California, San Francisco, described the overall evidence of the beneficial relationship between nut eating and breast cancer – including this study – as “limited.” She previously led a study that observed benefits of nut intake for patients with colon cancer.

Dr. Van Blarigan also noted that nut intake in this study was “very low” – with the median intake less than one serving per week.

She also offered some general advice about eating nuts.  

“Nuts are an energy-dense food, so portion sizes should be kept small,” she said, explaining a portion should be about 1 ounce or 1/4 cup of nuts or 1-2 tablespoons of nut butter.

A little may go a long way, she suggested, as research to date “suggests only small amounts may be needed to gain potential benefits.”

The level of nut consumption was low in the Chinese study population (median = 17.3 grams/week) compared with the 42.5 grams/week recommended by the American Heart Association, the study authors acknowledge.

“Nuts, particularly tree nuts, are expensive in China. Traditionally, nut consumption level has been low among Chinese, particularly in the old generation,” commented Dr. Shu.
 

Study authors did an adjusted analysis

The new study was conducted among 3,449 participants of the Shanghai Breast Cancer Survival Study.

Nut consumption (including peanuts and tree nuts such as walnuts) was assessed with a food questionnaire at 5 years post-diagnosis.

An analysis was conducted at 10 years post-diagnosis (and 5 years after the diet questionnaire). At this 10-year mark, there were 252 breast cancer-specific deaths. Among 3,274 survivors without previous recurrence at the dietary assessment, 209 went on to develop breast cancer-specific events – either recurrence, metastasis, or breast cancer mortality.

Nut consumers had higher overall survival (93.7% vs. 89%; P = .003) and disease-free survival (94.1% vs. 86.2%; P <.001) rates than nonconsumers.

However, the two groups had many differences, as noted by the authors and outside experts.

The consumers had a younger age at diagnosis, lower BMI, higher total energy intake, higher diet quality score, and higher soy food intake. In addition, nut consumers were more likely to have a higher education, personal income, and physical activity level (≥7.5 metabolic equivalent of task-hour/week) as well as to have received immunotherapy.

So the investigators adjusted for many of those variables and found that nut consumption was associated with significantly better disease-free survival (hazard ratio, 0.52; 95% confidence interval, 0.35-0.75), but a nonsignificantly improved overall survival (HR, 0.90; 95% CI, 0.66-1.23), as noted above.

Analyses by amount of nut intake showed a dose-response relationship for both overall survival (P trend = .022) and disease-free survival (P trend = .003).

The authors say that “there has been no strong evidence to support individual food items in favor of breast cancer survival,” citing a 2018 report entitled “Diet, Nutrition, Physical Activity and Breast Cancer Survivors” from the World Cancer Research Fund/American Institute for Cancer Research.

The new study provides evidence that nuts may be such a food, they say, while also calling for studies to confirm their findings.

Study limitations include that fact that the statuses of recurrence and metastasis were self-reported. Misclassification, particularly regarding the event date, is likely, the team says.

The study authors and Dr. Van Blarigan and Dr. Chen have disclosed no relevant financial relationships.

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

In the first study of its kind, women with a breast cancer diagnosis who recalled eating nuts were found to have a significantly better disease-free survival over a 10-year study period, compared with those who said they had not eaten nuts.

PxHere

There was also an improvement in overall survival, but this was not statistically significant.

The finding comes from a study of more than 3,000 patients conducted in China, published online in the International Journal of Cancer. Patients were queried about nut consumption on only one occasion, 5 years after their breast cancer diagnosis. 

The investigators report a dose-response pattern between nut eating and the risk of both breast cancer recurrence and overall mortality, with those consuming the largest amounts having the lowest risks.

“Nuts are important components of healthy diets. Promoting this modifiable lifestyle factor should be emphasized in breast cancer survivor guidelines,” conclude Xiao-Ou Shu, MD, PhD, of Vanderbilt University, Nashville, Tenn., and colleagues in the study.

“The association for disease-free survival is quite strong and robust,” Dr. Shu told this news organization.

However, as with all observational studies, this report shows an association and not causation.

“Based upon this study alone, the evidence is weak,” said Wendy Chen, MD, MPH, a breast oncologist at Dana-Farber Cancer Institute in Boston, who was approached for comment.  

The people who consumed nuts generally had more education, higher income, lower body mass index, earlier-stage cancers, and more physically active lives – all factors associated with better breast cancer survival, she observed. “The authors tried to control for these factors,” Dr. Chen acknowledged. But it’s hard to know whether nut consumption was “truly” the difference maker, she said.

Furthermore, the study population is also “a bit unusual” because people had to survive 5 years after diagnosis to be included in the analysis – and thus is not representative of breast cancer survivors, she noted.

Erin Van Blarigan, PhD, an epidemiologist at the University of California, San Francisco, described the overall evidence of the beneficial relationship between nut eating and breast cancer – including this study – as “limited.” She previously led a study that observed benefits of nut intake for patients with colon cancer.

Dr. Van Blarigan also noted that nut intake in this study was “very low” – with the median intake less than one serving per week.

She also offered some general advice about eating nuts.  

“Nuts are an energy-dense food, so portion sizes should be kept small,” she said, explaining a portion should be about 1 ounce or 1/4 cup of nuts or 1-2 tablespoons of nut butter.

A little may go a long way, she suggested, as research to date “suggests only small amounts may be needed to gain potential benefits.”

The level of nut consumption was low in the Chinese study population (median = 17.3 grams/week) compared with the 42.5 grams/week recommended by the American Heart Association, the study authors acknowledge.

“Nuts, particularly tree nuts, are expensive in China. Traditionally, nut consumption level has been low among Chinese, particularly in the old generation,” commented Dr. Shu.
 

Study authors did an adjusted analysis

The new study was conducted among 3,449 participants of the Shanghai Breast Cancer Survival Study.

Nut consumption (including peanuts and tree nuts such as walnuts) was assessed with a food questionnaire at 5 years post-diagnosis.

An analysis was conducted at 10 years post-diagnosis (and 5 years after the diet questionnaire). At this 10-year mark, there were 252 breast cancer-specific deaths. Among 3,274 survivors without previous recurrence at the dietary assessment, 209 went on to develop breast cancer-specific events – either recurrence, metastasis, or breast cancer mortality.

Nut consumers had higher overall survival (93.7% vs. 89%; P = .003) and disease-free survival (94.1% vs. 86.2%; P <.001) rates than nonconsumers.

However, the two groups had many differences, as noted by the authors and outside experts.

The consumers had a younger age at diagnosis, lower BMI, higher total energy intake, higher diet quality score, and higher soy food intake. In addition, nut consumers were more likely to have a higher education, personal income, and physical activity level (≥7.5 metabolic equivalent of task-hour/week) as well as to have received immunotherapy.

So the investigators adjusted for many of those variables and found that nut consumption was associated with significantly better disease-free survival (hazard ratio, 0.52; 95% confidence interval, 0.35-0.75), but a nonsignificantly improved overall survival (HR, 0.90; 95% CI, 0.66-1.23), as noted above.

Analyses by amount of nut intake showed a dose-response relationship for both overall survival (P trend = .022) and disease-free survival (P trend = .003).

The authors say that “there has been no strong evidence to support individual food items in favor of breast cancer survival,” citing a 2018 report entitled “Diet, Nutrition, Physical Activity and Breast Cancer Survivors” from the World Cancer Research Fund/American Institute for Cancer Research.

The new study provides evidence that nuts may be such a food, they say, while also calling for studies to confirm their findings.

Study limitations include that fact that the statuses of recurrence and metastasis were self-reported. Misclassification, particularly regarding the event date, is likely, the team says.

The study authors and Dr. Van Blarigan and Dr. Chen have disclosed no relevant financial relationships.

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

Side effects from relugolix combination therapy (Myfembree) in premenopausal women treated for uterine fibroids and endometriosis are minimal, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The Food and Drug Administration approved relugolix, a daily oral gonadotropin-releasing hormone antagonist medication, earlier this year to treat heavy menstrual bleeding associated with uterine fibroids. It has not received Food and Drug Administration approval to treat endometriosis yet.

“It was a good kind of vindication about the safety of relugolix combination therapy,” Ayman Al-Hendy, MD, PhD, gynecologist and endoscopic surgeon at the University of Chicago, said in an interview.

Researchers led by Dr. Al-Hendy analyzed the results from two 24-week clinical trials that examined the effects of relugolix on premenopausal women between the ages of 18 and 50 suffering from uterine fibroids and endometriosis, both of which found that the treatment was well tolerated. With 1,344 patients in total, researchers found that the most common side effects of the treatment were headache, which occurred in 24.3% of participants, and hot flush, which affected 10.6%.

However, the prevalence of adverse reactions was similar to that of the placebo group in which 21.4% of participants experienced headaches and 6.4% experienced hot flushes, which, according to Dr. Al-Hendy, means that there is “really no increased risk” of experiencing an adverse event while taking relugolix.

“If we follow a large number of patients [with uterine fibroids or endometriosis], they will have some of these symptoms like headache or hot flushes or fatigue and so on. Either because it just happens in women for no known reason or because maybe the disease itself is causing some of these symptoms. The question is does the treatment in this case increase the frequency of these events?” Dr. Al-Hendy said.

“As long as it’s similar, fairly similar, or close between the [treatment and placebo group], then we know it’s not because of the medication,” Dr. Al-Hendy added.

Other adverse reactions that occurred while taking relugolix were “relatively rare” Dr. Al-Hendy said during his presentation. About 5.5% of those who took relugolix had uterine bleeding, 3.4% had decreased libido, 1.9% suffered from hyperhidrosis, 1.2% experienced night sweats, and 1.3% suffered from vaginal dryness.

The study shows that the risk profile of relugolix combination therapy is favorable and the side effects are relatively mild compared with past treatment options used to treat fibroids or endometriosis, said J. Ricardo Loret de Mola, MD, FACOG, FACS, who was not involved in the study.

However, Dr. Loret de Mola emphasized that this treatment isn’t for women who are seeking fertility or to get pregnant so it’s important for physicians to ask patients about their goals for treatment. Relugolix treatment could be a way for fibroid patients in their reproductive age to buy time and reduce the number of surgeries needed to get them to “the point where they would be ready to become mothers.”

He said surgery could be the right option for endometriosis patients who want to have children in the near future.

“This is an additional tool that we have available now that’s effective,” Dr. Loret de Mola said. “It is not going to cure either one of the two conditions, but could buy enough time for patients to be able to reach their goals, which is not having symptoms of endometriosis and fibroids after menopause or for people who just want to buy time.”

Dr. Al-Hendy said he hopes his findings reassure and encourage health care providers to discuss with patients different options for treating fibroids, and not just counsel them about surgery.

“So more awareness of these nonsurgical options hopefully will offer our patients a wide range of options when they seek help with fibroids and then against endometriosis [if or when] it’s [FDA]-approved,” Dr. Al-Hendy said.

None of the experts interviewed had conflicts of interest.

Side effects from relugolix combination therapy (Myfembree) in premenopausal women treated for uterine fibroids and endometriosis are minimal, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The Food and Drug Administration approved relugolix, a daily oral gonadotropin-releasing hormone antagonist medication, earlier this year to treat heavy menstrual bleeding associated with uterine fibroids. It has not received Food and Drug Administration approval to treat endometriosis yet.

“It was a good kind of vindication about the safety of relugolix combination therapy,” Ayman Al-Hendy, MD, PhD, gynecologist and endoscopic surgeon at the University of Chicago, said in an interview.

Researchers led by Dr. Al-Hendy analyzed the results from two 24-week clinical trials that examined the effects of relugolix on premenopausal women between the ages of 18 and 50 suffering from uterine fibroids and endometriosis, both of which found that the treatment was well tolerated. With 1,344 patients in total, researchers found that the most common side effects of the treatment were headache, which occurred in 24.3% of participants, and hot flush, which affected 10.6%.

However, the prevalence of adverse reactions was similar to that of the placebo group in which 21.4% of participants experienced headaches and 6.4% experienced hot flushes, which, according to Dr. Al-Hendy, means that there is “really no increased risk” of experiencing an adverse event while taking relugolix.

“If we follow a large number of patients [with uterine fibroids or endometriosis], they will have some of these symptoms like headache or hot flushes or fatigue and so on. Either because it just happens in women for no known reason or because maybe the disease itself is causing some of these symptoms. The question is does the treatment in this case increase the frequency of these events?” Dr. Al-Hendy said.

“As long as it’s similar, fairly similar, or close between the [treatment and placebo group], then we know it’s not because of the medication,” Dr. Al-Hendy added.

Other adverse reactions that occurred while taking relugolix were “relatively rare” Dr. Al-Hendy said during his presentation. About 5.5% of those who took relugolix had uterine bleeding, 3.4% had decreased libido, 1.9% suffered from hyperhidrosis, 1.2% experienced night sweats, and 1.3% suffered from vaginal dryness.

The study shows that the risk profile of relugolix combination therapy is favorable and the side effects are relatively mild compared with past treatment options used to treat fibroids or endometriosis, said J. Ricardo Loret de Mola, MD, FACOG, FACS, who was not involved in the study.

However, Dr. Loret de Mola emphasized that this treatment isn’t for women who are seeking fertility or to get pregnant so it’s important for physicians to ask patients about their goals for treatment. Relugolix treatment could be a way for fibroid patients in their reproductive age to buy time and reduce the number of surgeries needed to get them to “the point where they would be ready to become mothers.”

He said surgery could be the right option for endometriosis patients who want to have children in the near future.

“This is an additional tool that we have available now that’s effective,” Dr. Loret de Mola said. “It is not going to cure either one of the two conditions, but could buy enough time for patients to be able to reach their goals, which is not having symptoms of endometriosis and fibroids after menopause or for people who just want to buy time.”

Dr. Al-Hendy said he hopes his findings reassure and encourage health care providers to discuss with patients different options for treating fibroids, and not just counsel them about surgery.

“So more awareness of these nonsurgical options hopefully will offer our patients a wide range of options when they seek help with fibroids and then against endometriosis [if or when] it’s [FDA]-approved,” Dr. Al-Hendy said.

None of the experts interviewed had conflicts of interest.

Side effects from relugolix combination therapy (Myfembree) in premenopausal women treated for uterine fibroids and endometriosis are minimal, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The Food and Drug Administration approved relugolix, a daily oral gonadotropin-releasing hormone antagonist medication, earlier this year to treat heavy menstrual bleeding associated with uterine fibroids. It has not received Food and Drug Administration approval to treat endometriosis yet.

“It was a good kind of vindication about the safety of relugolix combination therapy,” Ayman Al-Hendy, MD, PhD, gynecologist and endoscopic surgeon at the University of Chicago, said in an interview.

Researchers led by Dr. Al-Hendy analyzed the results from two 24-week clinical trials that examined the effects of relugolix on premenopausal women between the ages of 18 and 50 suffering from uterine fibroids and endometriosis, both of which found that the treatment was well tolerated. With 1,344 patients in total, researchers found that the most common side effects of the treatment were headache, which occurred in 24.3% of participants, and hot flush, which affected 10.6%.

However, the prevalence of adverse reactions was similar to that of the placebo group in which 21.4% of participants experienced headaches and 6.4% experienced hot flushes, which, according to Dr. Al-Hendy, means that there is “really no increased risk” of experiencing an adverse event while taking relugolix.

“If we follow a large number of patients [with uterine fibroids or endometriosis], they will have some of these symptoms like headache or hot flushes or fatigue and so on. Either because it just happens in women for no known reason or because maybe the disease itself is causing some of these symptoms. The question is does the treatment in this case increase the frequency of these events?” Dr. Al-Hendy said.

“As long as it’s similar, fairly similar, or close between the [treatment and placebo group], then we know it’s not because of the medication,” Dr. Al-Hendy added.

Other adverse reactions that occurred while taking relugolix were “relatively rare” Dr. Al-Hendy said during his presentation. About 5.5% of those who took relugolix had uterine bleeding, 3.4% had decreased libido, 1.9% suffered from hyperhidrosis, 1.2% experienced night sweats, and 1.3% suffered from vaginal dryness.

The study shows that the risk profile of relugolix combination therapy is favorable and the side effects are relatively mild compared with past treatment options used to treat fibroids or endometriosis, said J. Ricardo Loret de Mola, MD, FACOG, FACS, who was not involved in the study.

However, Dr. Loret de Mola emphasized that this treatment isn’t for women who are seeking fertility or to get pregnant so it’s important for physicians to ask patients about their goals for treatment. Relugolix treatment could be a way for fibroid patients in their reproductive age to buy time and reduce the number of surgeries needed to get them to “the point where they would be ready to become mothers.”

He said surgery could be the right option for endometriosis patients who want to have children in the near future.

“This is an additional tool that we have available now that’s effective,” Dr. Loret de Mola said. “It is not going to cure either one of the two conditions, but could buy enough time for patients to be able to reach their goals, which is not having symptoms of endometriosis and fibroids after menopause or for people who just want to buy time.”

Dr. Al-Hendy said he hopes his findings reassure and encourage health care providers to discuss with patients different options for treating fibroids, and not just counsel them about surgery.

“So more awareness of these nonsurgical options hopefully will offer our patients a wide range of options when they seek help with fibroids and then against endometriosis [if or when] it’s [FDA]-approved,” Dr. Al-Hendy said.

None of the experts interviewed had conflicts of interest.

Black and Latina women are more likely to have an open surgery compared with a minimally invasive procedure to treat ectopic pregnancy, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The researchers found that Black and Latina women had 50% lesser odds of undergoing laparoscopic surgery, a minimally invasive procedure, compared to their White peers.

“We see these disparities in minority populations, [especially in] women with regard to so many other aspects of [gynecologic] surgery,” study author Alexandra Huttler, MD, said in an interview. “The fact that these disparities exist [in the treatment of tubal pregnancies] was unfortunately not surprising to us.”

Dr. Huttler and her team analyzed data from the American College of Surgeons’ National Surgical Quality Improvement Program, which followed more than 9,000 patients who had undergone surgical management of a tubal ectopic pregnancy between 2010 and 2019. Of the group, 85% underwent laparoscopic surgery while 14% had open surgery, which requires a longer recovery time.

The proportion of cases performed laparoscopically increased from 81% in 2010 to 91% in 2019. However, a disproportionate number of Black and Latina women underwent open surgery to treat ectopic pregnancies during this time. Because they are more invasive, open surgeries are associated with longer operative times, hospital stays, and increased complications, Dr. Huttler said. They are typically associated with more pain and patients are more likely to be admitted to the hospital for postoperative care.

On the other hand, minimally invasive surgeries are associated with decreased operative time, “less recovery and less pain,” Dr. Huttler explained.

The researchers also looked at trends of the related surgical procedure salpingectomy, which is surgical removal of one or both fallopian tubes versus salpingostomy, a surgical unblocking of the tube. Of the group, 91% underwent salpingectomy and 9% underwent salpingostomy.

Researchers found that Black and Latina women had 78% and 54% greater odds, respectively, of receiving a salpingectomy. However, the clinical significance of these findings are unclear because there are “many factors” that are patient and case specific, Dr. Huttler said.

The study is important and adds to a litany of studies that have shown that women of color do not receive optimal care, said Ruben Alvero, MD, who was not involved in the study.

“Women of color in general have seen compromises in their care at many levels in the system,” Dr. Alvero, professor of obstetrics and gynecology at Stanford (Calif.) University, said in an interview. “We really have to do a massive overhaul of how we treat women of color so they get the same level of treatment that all other populations receive.”

While the factors contributing to these health disparities can be complicated, Dr. Alvero said that one reason for this multivariate discrepancy could be that Black and Latina women tend to seek care at, or only have access to, underresourced hospitals.

Dr. Huttler said she hopes her findings prompt further discussion of these disparities.

“There really are disparities at all levels of care here and figuring out what the root of this is certainly requires further research,” Dr. Huttler said.

The experts interviewed disclosed no conflicts on interests.

Black and Latina women are more likely to have an open surgery compared with a minimally invasive procedure to treat ectopic pregnancy, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The researchers found that Black and Latina women had 50% lesser odds of undergoing laparoscopic surgery, a minimally invasive procedure, compared to their White peers.

“We see these disparities in minority populations, [especially in] women with regard to so many other aspects of [gynecologic] surgery,” study author Alexandra Huttler, MD, said in an interview. “The fact that these disparities exist [in the treatment of tubal pregnancies] was unfortunately not surprising to us.”

Dr. Huttler and her team analyzed data from the American College of Surgeons’ National Surgical Quality Improvement Program, which followed more than 9,000 patients who had undergone surgical management of a tubal ectopic pregnancy between 2010 and 2019. Of the group, 85% underwent laparoscopic surgery while 14% had open surgery, which requires a longer recovery time.

The proportion of cases performed laparoscopically increased from 81% in 2010 to 91% in 2019. However, a disproportionate number of Black and Latina women underwent open surgery to treat ectopic pregnancies during this time. Because they are more invasive, open surgeries are associated with longer operative times, hospital stays, and increased complications, Dr. Huttler said. They are typically associated with more pain and patients are more likely to be admitted to the hospital for postoperative care.

On the other hand, minimally invasive surgeries are associated with decreased operative time, “less recovery and less pain,” Dr. Huttler explained.

The researchers also looked at trends of the related surgical procedure salpingectomy, which is surgical removal of one or both fallopian tubes versus salpingostomy, a surgical unblocking of the tube. Of the group, 91% underwent salpingectomy and 9% underwent salpingostomy.

Researchers found that Black and Latina women had 78% and 54% greater odds, respectively, of receiving a salpingectomy. However, the clinical significance of these findings are unclear because there are “many factors” that are patient and case specific, Dr. Huttler said.

The study is important and adds to a litany of studies that have shown that women of color do not receive optimal care, said Ruben Alvero, MD, who was not involved in the study.

“Women of color in general have seen compromises in their care at many levels in the system,” Dr. Alvero, professor of obstetrics and gynecology at Stanford (Calif.) University, said in an interview. “We really have to do a massive overhaul of how we treat women of color so they get the same level of treatment that all other populations receive.”

While the factors contributing to these health disparities can be complicated, Dr. Alvero said that one reason for this multivariate discrepancy could be that Black and Latina women tend to seek care at, or only have access to, underresourced hospitals.

Dr. Huttler said she hopes her findings prompt further discussion of these disparities.

“There really are disparities at all levels of care here and figuring out what the root of this is certainly requires further research,” Dr. Huttler said.

The experts interviewed disclosed no conflicts on interests.

Black and Latina women are more likely to have an open surgery compared with a minimally invasive procedure to treat ectopic pregnancy, according to research presented at the American Society for Reproductive Medicine’s 2021 meeting.

The researchers found that Black and Latina women had 50% lesser odds of undergoing laparoscopic surgery, a minimally invasive procedure, compared to their White peers.

“We see these disparities in minority populations, [especially in] women with regard to so many other aspects of [gynecologic] surgery,” study author Alexandra Huttler, MD, said in an interview. “The fact that these disparities exist [in the treatment of tubal pregnancies] was unfortunately not surprising to us.”

Dr. Huttler and her team analyzed data from the American College of Surgeons’ National Surgical Quality Improvement Program, which followed more than 9,000 patients who had undergone surgical management of a tubal ectopic pregnancy between 2010 and 2019. Of the group, 85% underwent laparoscopic surgery while 14% had open surgery, which requires a longer recovery time.

The proportion of cases performed laparoscopically increased from 81% in 2010 to 91% in 2019. However, a disproportionate number of Black and Latina women underwent open surgery to treat ectopic pregnancies during this time. Because they are more invasive, open surgeries are associated with longer operative times, hospital stays, and increased complications, Dr. Huttler said. They are typically associated with more pain and patients are more likely to be admitted to the hospital for postoperative care.

On the other hand, minimally invasive surgeries are associated with decreased operative time, “less recovery and less pain,” Dr. Huttler explained.

The researchers also looked at trends of the related surgical procedure salpingectomy, which is surgical removal of one or both fallopian tubes versus salpingostomy, a surgical unblocking of the tube. Of the group, 91% underwent salpingectomy and 9% underwent salpingostomy.

Researchers found that Black and Latina women had 78% and 54% greater odds, respectively, of receiving a salpingectomy. However, the clinical significance of these findings are unclear because there are “many factors” that are patient and case specific, Dr. Huttler said.

The study is important and adds to a litany of studies that have shown that women of color do not receive optimal care, said Ruben Alvero, MD, who was not involved in the study.

“Women of color in general have seen compromises in their care at many levels in the system,” Dr. Alvero, professor of obstetrics and gynecology at Stanford (Calif.) University, said in an interview. “We really have to do a massive overhaul of how we treat women of color so they get the same level of treatment that all other populations receive.”

While the factors contributing to these health disparities can be complicated, Dr. Alvero said that one reason for this multivariate discrepancy could be that Black and Latina women tend to seek care at, or only have access to, underresourced hospitals.

Dr. Huttler said she hopes her findings prompt further discussion of these disparities.

“There really are disparities at all levels of care here and figuring out what the root of this is certainly requires further research,” Dr. Huttler said.

The experts interviewed disclosed no conflicts on interests.

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

 

 

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

 

 

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

 

 

ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

 

 

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

 

 

MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

 

 

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

 

 

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

 

 

ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

 

 

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

 

 

MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

 

 

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

 

 

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

 

 

ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

 

 

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

 

 

MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

FROM JAMA ONCOLOGY

Cancer centers with a high use of neoadjuvant chemotherapy in patients with advanced-stage epithelial ovarian cancer show similar improvements in median overall survival and larger declines in short-term mortality than in centers with low use of this treatment. This is according to a study published in JAMA Oncology, suggesting that neoadjuvant chemotherapy may be a suitable first-line treatment approach for many patients with advanced-stage ovarian cancer.

“There is considerable variation in practice. Some centers administer neoadjuvant chemotherapy to 75% of patients with advanced ovarian cancers, others use the approach very infrequently,” said Alexander Melamed, MD, MPH, of Columbia University, New York.

“I hope that those clinicians who have been worried about the negative impacts of too frequent administration of neoadjuvant chemotherapy may be reassured by this study and may come to use this good treatment more often.”

Research has shown that, compared with primary cytoreductive surgery, the use of neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes in patients with ovarian cancer. While the use of neoadjuvant chemotherapy has increased, many experts continue to recommend upfront surgery as the preferred treatment for these patients. 

“In part, these recommendations are based on flawed interpretations of real-world data. Specifically, many observational studies have concluded that upfront surgery results in better survival than neoadjuvant chemotherapy, based on study designs that ignored the fact that patients who receive neoadjuvant chemotherapy in the real word are sicker and have more extensive cancer than those who receive upfront surgery,” Dr. Melamed said.

In this difference-in-differences comparative effectiveness analysis, researchers asked if the difference in adoption of neoadjuvant chemotherapy by U.S. cancer centers for advanced-stage epithelial ovarian cancer was associated with differences in median overall survival and 1-year all-cause mortality.

“By assessing how this divergence in practice impacted patient outcomes we were able to infer how frequent use of neoadjuvant impacts survival in ovarian cancer patients. This study design allowed us to sidestep the problem of selection bias that has plagued many other observational studies in this space,” Dr. Melamed explained.

This observational study included 39,299 women with stage IIIC and IV epithelial ovarian cancer, diagnosed between 2004 and 2015 who were followed to the end of 2018, and treated at one of 664 cancer programs. Patients treated in programs that increased neoadjuvant chemotherapy administration had greater improvements in 1-year mortality (difference-in-differences, −2.1%; 95% confidence interval, −3.7 to −0.5) and equivalent gains in median overall survival  (difference-in-differences, 0.9 months; 95% CI, −1.9 to 3.7 months), compared with those treated in programs that used the treatment infrequently.

“For a long time, experts have suggested that the apparent discordance between randomized controlled trials and real-world studies that compare neoadjuvant chemotherapy to upfront surgery for ovarian cancer might mean that the randomized trials are not applicable to real-world practice. What is significant about our findings, is that, when more appropriate study methods are used to analyze the real-world data, the apparent contradiction between real-world and randomized studies is resolved.

“We found that, just as one would guess based on the findings of randomized trials, patients treated in the centers that increased the use of neoadjuvant chemotherapy did not have any decrement in long-term survival, but that short-term mortality did improve more in these centers than in centers that administered neoadjuvant chemotherapy rarely,” she said.

Dr. Melamed said that the findings should “spur a reappraisal” of what clinicians consider the default treatment for women with stage IIIC and IV ovarian cancer.

Taken together with randomized controlled trials, “the evidence may be at a point where it is now time to consider neoadjuvant chemotherapy as the default approach to patients with bulky carcinomatosis, and that primary surgery may be a reasonable alternative for a select group of healthy, young patients with low-volume metastasis.

“Other factors like the route of adjuvant chemotherapy may also need to be considered. However, I believe the belief that aggressive primary debulking is beneficial for most women with advanced ovarian cancer is outdated,” Dr. Melamed said.

No relevant conflicts of interest were reported for this research.

FROM JAMA ONCOLOGY

Cancer centers with a high use of neoadjuvant chemotherapy in patients with advanced-stage epithelial ovarian cancer show similar improvements in median overall survival and larger declines in short-term mortality than in centers with low use of this treatment. This is according to a study published in JAMA Oncology, suggesting that neoadjuvant chemotherapy may be a suitable first-line treatment approach for many patients with advanced-stage ovarian cancer.

“There is considerable variation in practice. Some centers administer neoadjuvant chemotherapy to 75% of patients with advanced ovarian cancers, others use the approach very infrequently,” said Alexander Melamed, MD, MPH, of Columbia University, New York.

“I hope that those clinicians who have been worried about the negative impacts of too frequent administration of neoadjuvant chemotherapy may be reassured by this study and may come to use this good treatment more often.”

Research has shown that, compared with primary cytoreductive surgery, the use of neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes in patients with ovarian cancer. While the use of neoadjuvant chemotherapy has increased, many experts continue to recommend upfront surgery as the preferred treatment for these patients. 

“In part, these recommendations are based on flawed interpretations of real-world data. Specifically, many observational studies have concluded that upfront surgery results in better survival than neoadjuvant chemotherapy, based on study designs that ignored the fact that patients who receive neoadjuvant chemotherapy in the real word are sicker and have more extensive cancer than those who receive upfront surgery,” Dr. Melamed said.

In this difference-in-differences comparative effectiveness analysis, researchers asked if the difference in adoption of neoadjuvant chemotherapy by U.S. cancer centers for advanced-stage epithelial ovarian cancer was associated with differences in median overall survival and 1-year all-cause mortality.

“By assessing how this divergence in practice impacted patient outcomes we were able to infer how frequent use of neoadjuvant impacts survival in ovarian cancer patients. This study design allowed us to sidestep the problem of selection bias that has plagued many other observational studies in this space,” Dr. Melamed explained.

This observational study included 39,299 women with stage IIIC and IV epithelial ovarian cancer, diagnosed between 2004 and 2015 who were followed to the end of 2018, and treated at one of 664 cancer programs. Patients treated in programs that increased neoadjuvant chemotherapy administration had greater improvements in 1-year mortality (difference-in-differences, −2.1%; 95% confidence interval, −3.7 to −0.5) and equivalent gains in median overall survival  (difference-in-differences, 0.9 months; 95% CI, −1.9 to 3.7 months), compared with those treated in programs that used the treatment infrequently.

“For a long time, experts have suggested that the apparent discordance between randomized controlled trials and real-world studies that compare neoadjuvant chemotherapy to upfront surgery for ovarian cancer might mean that the randomized trials are not applicable to real-world practice. What is significant about our findings, is that, when more appropriate study methods are used to analyze the real-world data, the apparent contradiction between real-world and randomized studies is resolved.

“We found that, just as one would guess based on the findings of randomized trials, patients treated in the centers that increased the use of neoadjuvant chemotherapy did not have any decrement in long-term survival, but that short-term mortality did improve more in these centers than in centers that administered neoadjuvant chemotherapy rarely,” she said.

Dr. Melamed said that the findings should “spur a reappraisal” of what clinicians consider the default treatment for women with stage IIIC and IV ovarian cancer.

Taken together with randomized controlled trials, “the evidence may be at a point where it is now time to consider neoadjuvant chemotherapy as the default approach to patients with bulky carcinomatosis, and that primary surgery may be a reasonable alternative for a select group of healthy, young patients with low-volume metastasis.

“Other factors like the route of adjuvant chemotherapy may also need to be considered. However, I believe the belief that aggressive primary debulking is beneficial for most women with advanced ovarian cancer is outdated,” Dr. Melamed said.

No relevant conflicts of interest were reported for this research.

FROM JAMA ONCOLOGY

Cancer centers with a high use of neoadjuvant chemotherapy in patients with advanced-stage epithelial ovarian cancer show similar improvements in median overall survival and larger declines in short-term mortality than in centers with low use of this treatment. This is according to a study published in JAMA Oncology, suggesting that neoadjuvant chemotherapy may be a suitable first-line treatment approach for many patients with advanced-stage ovarian cancer.

“There is considerable variation in practice. Some centers administer neoadjuvant chemotherapy to 75% of patients with advanced ovarian cancers, others use the approach very infrequently,” said Alexander Melamed, MD, MPH, of Columbia University, New York.

“I hope that those clinicians who have been worried about the negative impacts of too frequent administration of neoadjuvant chemotherapy may be reassured by this study and may come to use this good treatment more often.”

Research has shown that, compared with primary cytoreductive surgery, the use of neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes in patients with ovarian cancer. While the use of neoadjuvant chemotherapy has increased, many experts continue to recommend upfront surgery as the preferred treatment for these patients. 

“In part, these recommendations are based on flawed interpretations of real-world data. Specifically, many observational studies have concluded that upfront surgery results in better survival than neoadjuvant chemotherapy, based on study designs that ignored the fact that patients who receive neoadjuvant chemotherapy in the real word are sicker and have more extensive cancer than those who receive upfront surgery,” Dr. Melamed said.

In this difference-in-differences comparative effectiveness analysis, researchers asked if the difference in adoption of neoadjuvant chemotherapy by U.S. cancer centers for advanced-stage epithelial ovarian cancer was associated with differences in median overall survival and 1-year all-cause mortality.

“By assessing how this divergence in practice impacted patient outcomes we were able to infer how frequent use of neoadjuvant impacts survival in ovarian cancer patients. This study design allowed us to sidestep the problem of selection bias that has plagued many other observational studies in this space,” Dr. Melamed explained.

This observational study included 39,299 women with stage IIIC and IV epithelial ovarian cancer, diagnosed between 2004 and 2015 who were followed to the end of 2018, and treated at one of 664 cancer programs. Patients treated in programs that increased neoadjuvant chemotherapy administration had greater improvements in 1-year mortality (difference-in-differences, −2.1%; 95% confidence interval, −3.7 to −0.5) and equivalent gains in median overall survival  (difference-in-differences, 0.9 months; 95% CI, −1.9 to 3.7 months), compared with those treated in programs that used the treatment infrequently.

“For a long time, experts have suggested that the apparent discordance between randomized controlled trials and real-world studies that compare neoadjuvant chemotherapy to upfront surgery for ovarian cancer might mean that the randomized trials are not applicable to real-world practice. What is significant about our findings, is that, when more appropriate study methods are used to analyze the real-world data, the apparent contradiction between real-world and randomized studies is resolved.

“We found that, just as one would guess based on the findings of randomized trials, patients treated in the centers that increased the use of neoadjuvant chemotherapy did not have any decrement in long-term survival, but that short-term mortality did improve more in these centers than in centers that administered neoadjuvant chemotherapy rarely,” she said.

Dr. Melamed said that the findings should “spur a reappraisal” of what clinicians consider the default treatment for women with stage IIIC and IV ovarian cancer.

Taken together with randomized controlled trials, “the evidence may be at a point where it is now time to consider neoadjuvant chemotherapy as the default approach to patients with bulky carcinomatosis, and that primary surgery may be a reasonable alternative for a select group of healthy, young patients with low-volume metastasis.

“Other factors like the route of adjuvant chemotherapy may also need to be considered. However, I believe the belief that aggressive primary debulking is beneficial for most women with advanced ovarian cancer is outdated,” Dr. Melamed said.

No relevant conflicts of interest were reported for this research.

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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

For women with breast cancer who undergo mastectomy and opt for implant-based breast reconstruction (IBBR), the use of a mesh device does not appear to offer any advantage over conventional techniques.

A European study involving 155 women found that the use of acellular dermal matrix (ADM) did not lead to fewer reoperations, nor was it superior in terms of health-related quality of life or patient-reported cosmetic outcomes.

“We feel that women considering implant-based reconstructions for breast cancer should be informed about the lack of evidence supporting its advantage,” said lead author Fredrik Lohmander MD, department of breast and endocrine surgery, section of breast urgery, Karolinska University Hospital, Stockholm.

It is difficult to say generally whether ADM should be used in IBBR, he noted. “We can only conclude from our trial that there is no hard evidence that ADM is beneficial when performing breast reconstructions with implants,” he said in an interview. “In selected patients, ADM might be indicated.”

The study was conducted in Sweden and the United Kingdom. “Mostly because of high costs, ADM in implant-based breast reconstructions in Sweden is not frequently used,” Dr. Lohmander said. “It is slightly more common in the U.K., but much more common in the U.S.A.”

Although biological meshes have received regulatory approval by the U.S. Food and Drug Administration for reconstructive purposes, ADM has not been approved for use in breast reconstruction surgery, and its use in this setting is off label.

The study was published online October 1 in JAMA Network Open.
 

Any advantage to using mesh device?

Previous studies of ADMs suggested that the mesh device conferred several benefits, including superior cosmetic results, less need for tissue expanders, fewer elective reoperations, and less capsular contracture. The use of a mesh device also enlarges the subpectoral pocket, which allows for larger fixed-volume implants, the authors note.

However, these suggested advantages have not been universally accepted, and the authors note that there have been reports of associated harm, such as higher rates of infection and implant loss.

The new study included 135 women from five centers in Sweden and the United Kingdom. The patients had breast cancer and had planned to undergo mastectomy and immediate IBBR between 2014 and May 2017.

The primary endpoint was the number of repeat surgeries at 2 years.

At the 2-year follow-up, 31 patients (48%) in the ADM group had undergone at least one reoperation on the ipsilateral side, vs 35 (54%) in the control group (P = .54). Results were similar for the contralateral side: 34 (53%) vs 31 (48%).

Two patients in the ADM group and three patients in the control group underwent a risk-reducing mastectomy on the contralateral side. These five surgeries were included in the final analysis.

For nine patients (14%) in the ADM arm, the implant was removed. Four of the removals took place within 6 months after early surgical complications. In the control group, seven patients (11%) underwent implant removal; four were removed within 6 months, owing to early surgical complications.

The secondary endpoint was postoperative health-related quality of life, including perception of body image and satisfaction with cosmetic outcome. There were no significant differences between the two groups.

Some questions remain

Approached for comment on the study, Sameer A. Patel, MD, FACS, chief of plastic and reconstructive surgery at Fox Chase Cancer Center, Philadelphia, noted that the practice of using AMD for breast reconstruction is quite common in the United States, so these data are informative and add to the current understanding of the value of ADM in breast reconstruction. “The study hypothesized that the use of ADM would reduce the number of reoperations within the first 24 months, which it did not,” he said. “This is despite the fact that the ADM group had a significantly higher number of direct-to-implant reconstructions.”

Importantly, the study showed that patient-reported outcomes, as opposed to surgeon’s evaluation of outcomes, were also not different for the most part between the two groups, Dr. Patel pointed out. “The only exception of small favorable advantage in the ADM group was for fitting bras,” he said.

However, there were limitations to the study’s endpoint. “I would add that there are some purported advantages of using ADM, such as reduction in postoperative pain and reduction in length of hospital stay, which are not evaluated by this study,” Patel explained. “Also, I am not certain that they can conclude from this study that capsular contracture is not reduced, because it is not designed to evaluate that.”

But the biggest limitation is one that study authors point out in their discussion at the end of the article, he added. “The use of prepectoral reconstruction is rapidly replacing the dual plane reconstruction that this paper used in the ADM group,” Dr. Patel said. “The role of ADM in prepectoral reconstruction is somewhat different than in the dual plane reconstruction, and so these results may not necessarily be extrapolated to prepectoral reconstruction.”

The study was funded with grants from the Swedish Breast Cancer Association and Stockholm City Council. The trial was initiated by Karolinska University Hospital and Karolinska Institutet. Acelity (an Allergan company) supplied the study with acellular dermal matrix meshes. Dr. Lohmander and Dr. Patel have disclosed no relevant financial relationships.

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

For women with breast cancer who undergo mastectomy and opt for implant-based breast reconstruction (IBBR), the use of a mesh device does not appear to offer any advantage over conventional techniques.

A European study involving 155 women found that the use of acellular dermal matrix (ADM) did not lead to fewer reoperations, nor was it superior in terms of health-related quality of life or patient-reported cosmetic outcomes.

“We feel that women considering implant-based reconstructions for breast cancer should be informed about the lack of evidence supporting its advantage,” said lead author Fredrik Lohmander MD, department of breast and endocrine surgery, section of breast urgery, Karolinska University Hospital, Stockholm.

It is difficult to say generally whether ADM should be used in IBBR, he noted. “We can only conclude from our trial that there is no hard evidence that ADM is beneficial when performing breast reconstructions with implants,” he said in an interview. “In selected patients, ADM might be indicated.”

The study was conducted in Sweden and the United Kingdom. “Mostly because of high costs, ADM in implant-based breast reconstructions in Sweden is not frequently used,” Dr. Lohmander said. “It is slightly more common in the U.K., but much more common in the U.S.A.”

Although biological meshes have received regulatory approval by the U.S. Food and Drug Administration for reconstructive purposes, ADM has not been approved for use in breast reconstruction surgery, and its use in this setting is off label.

The study was published online October 1 in JAMA Network Open.
 

Any advantage to using mesh device?

Previous studies of ADMs suggested that the mesh device conferred several benefits, including superior cosmetic results, less need for tissue expanders, fewer elective reoperations, and less capsular contracture. The use of a mesh device also enlarges the subpectoral pocket, which allows for larger fixed-volume implants, the authors note.

However, these suggested advantages have not been universally accepted, and the authors note that there have been reports of associated harm, such as higher rates of infection and implant loss.

The new study included 135 women from five centers in Sweden and the United Kingdom. The patients had breast cancer and had planned to undergo mastectomy and immediate IBBR between 2014 and May 2017.

The primary endpoint was the number of repeat surgeries at 2 years.

At the 2-year follow-up, 31 patients (48%) in the ADM group had undergone at least one reoperation on the ipsilateral side, vs 35 (54%) in the control group (P = .54). Results were similar for the contralateral side: 34 (53%) vs 31 (48%).

Two patients in the ADM group and three patients in the control group underwent a risk-reducing mastectomy on the contralateral side. These five surgeries were included in the final analysis.

For nine patients (14%) in the ADM arm, the implant was removed. Four of the removals took place within 6 months after early surgical complications. In the control group, seven patients (11%) underwent implant removal; four were removed within 6 months, owing to early surgical complications.

The secondary endpoint was postoperative health-related quality of life, including perception of body image and satisfaction with cosmetic outcome. There were no significant differences between the two groups.

Some questions remain

Approached for comment on the study, Sameer A. Patel, MD, FACS, chief of plastic and reconstructive surgery at Fox Chase Cancer Center, Philadelphia, noted that the practice of using AMD for breast reconstruction is quite common in the United States, so these data are informative and add to the current understanding of the value of ADM in breast reconstruction. “The study hypothesized that the use of ADM would reduce the number of reoperations within the first 24 months, which it did not,” he said. “This is despite the fact that the ADM group had a significantly higher number of direct-to-implant reconstructions.”

Importantly, the study showed that patient-reported outcomes, as opposed to surgeon’s evaluation of outcomes, were also not different for the most part between the two groups, Dr. Patel pointed out. “The only exception of small favorable advantage in the ADM group was for fitting bras,” he said.

However, there were limitations to the study’s endpoint. “I would add that there are some purported advantages of using ADM, such as reduction in postoperative pain and reduction in length of hospital stay, which are not evaluated by this study,” Patel explained. “Also, I am not certain that they can conclude from this study that capsular contracture is not reduced, because it is not designed to evaluate that.”

But the biggest limitation is one that study authors point out in their discussion at the end of the article, he added. “The use of prepectoral reconstruction is rapidly replacing the dual plane reconstruction that this paper used in the ADM group,” Dr. Patel said. “The role of ADM in prepectoral reconstruction is somewhat different than in the dual plane reconstruction, and so these results may not necessarily be extrapolated to prepectoral reconstruction.”

The study was funded with grants from the Swedish Breast Cancer Association and Stockholm City Council. The trial was initiated by Karolinska University Hospital and Karolinska Institutet. Acelity (an Allergan company) supplied the study with acellular dermal matrix meshes. Dr. Lohmander and Dr. Patel have disclosed no relevant financial relationships.

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

For women with breast cancer who undergo mastectomy and opt for implant-based breast reconstruction (IBBR), the use of a mesh device does not appear to offer any advantage over conventional techniques.

A European study involving 155 women found that the use of acellular dermal matrix (ADM) did not lead to fewer reoperations, nor was it superior in terms of health-related quality of life or patient-reported cosmetic outcomes.

“We feel that women considering implant-based reconstructions for breast cancer should be informed about the lack of evidence supporting its advantage,” said lead author Fredrik Lohmander MD, department of breast and endocrine surgery, section of breast urgery, Karolinska University Hospital, Stockholm.

It is difficult to say generally whether ADM should be used in IBBR, he noted. “We can only conclude from our trial that there is no hard evidence that ADM is beneficial when performing breast reconstructions with implants,” he said in an interview. “In selected patients, ADM might be indicated.”

The study was conducted in Sweden and the United Kingdom. “Mostly because of high costs, ADM in implant-based breast reconstructions in Sweden is not frequently used,” Dr. Lohmander said. “It is slightly more common in the U.K., but much more common in the U.S.A.”

Although biological meshes have received regulatory approval by the U.S. Food and Drug Administration for reconstructive purposes, ADM has not been approved for use in breast reconstruction surgery, and its use in this setting is off label.

The study was published online October 1 in JAMA Network Open.
 

Any advantage to using mesh device?

Previous studies of ADMs suggested that the mesh device conferred several benefits, including superior cosmetic results, less need for tissue expanders, fewer elective reoperations, and less capsular contracture. The use of a mesh device also enlarges the subpectoral pocket, which allows for larger fixed-volume implants, the authors note.

However, these suggested advantages have not been universally accepted, and the authors note that there have been reports of associated harm, such as higher rates of infection and implant loss.

The new study included 135 women from five centers in Sweden and the United Kingdom. The patients had breast cancer and had planned to undergo mastectomy and immediate IBBR between 2014 and May 2017.

The primary endpoint was the number of repeat surgeries at 2 years.

At the 2-year follow-up, 31 patients (48%) in the ADM group had undergone at least one reoperation on the ipsilateral side, vs 35 (54%) in the control group (P = .54). Results were similar for the contralateral side: 34 (53%) vs 31 (48%).

Two patients in the ADM group and three patients in the control group underwent a risk-reducing mastectomy on the contralateral side. These five surgeries were included in the final analysis.

For nine patients (14%) in the ADM arm, the implant was removed. Four of the removals took place within 6 months after early surgical complications. In the control group, seven patients (11%) underwent implant removal; four were removed within 6 months, owing to early surgical complications.

The secondary endpoint was postoperative health-related quality of life, including perception of body image and satisfaction with cosmetic outcome. There were no significant differences between the two groups.

Some questions remain

Approached for comment on the study, Sameer A. Patel, MD, FACS, chief of plastic and reconstructive surgery at Fox Chase Cancer Center, Philadelphia, noted that the practice of using AMD for breast reconstruction is quite common in the United States, so these data are informative and add to the current understanding of the value of ADM in breast reconstruction. “The study hypothesized that the use of ADM would reduce the number of reoperations within the first 24 months, which it did not,” he said. “This is despite the fact that the ADM group had a significantly higher number of direct-to-implant reconstructions.”

Importantly, the study showed that patient-reported outcomes, as opposed to surgeon’s evaluation of outcomes, were also not different for the most part between the two groups, Dr. Patel pointed out. “The only exception of small favorable advantage in the ADM group was for fitting bras,” he said.

However, there were limitations to the study’s endpoint. “I would add that there are some purported advantages of using ADM, such as reduction in postoperative pain and reduction in length of hospital stay, which are not evaluated by this study,” Patel explained. “Also, I am not certain that they can conclude from this study that capsular contracture is not reduced, because it is not designed to evaluate that.”

But the biggest limitation is one that study authors point out in their discussion at the end of the article, he added. “The use of prepectoral reconstruction is rapidly replacing the dual plane reconstruction that this paper used in the ADM group,” Dr. Patel said. “The role of ADM in prepectoral reconstruction is somewhat different than in the dual plane reconstruction, and so these results may not necessarily be extrapolated to prepectoral reconstruction.”

The study was funded with grants from the Swedish Breast Cancer Association and Stockholm City Council. The trial was initiated by Karolinska University Hospital and Karolinska Institutet. Acelity (an Allergan company) supplied the study with acellular dermal matrix meshes. Dr. Lohmander and Dr. Patel have disclosed no relevant financial relationships.

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