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Does tranexamic acid reduce mortality in women with postpartum hemorrhage?
EVIDENCE SUMMARY
A 2017 double-blind RCT that included 20,060 women with PPH from 21 countries (the WOMAN trial) found that the risk of maternal mortality was significantly lower among women who received tranexamic acid as part of their PPH treatment compared with placebo (1.5% [N = 155] vs 1.9% [N = 191]; P = .045; relative risk [RR] = 0.81; 95% confidence interval [CI], 0.65-1; number needed to treat [NNT] = 250).1
Inclusion criteria were age 16 years or older, postpartum course complicated by hemorrhage of known or unknown etiology, and a case in which the clinician considered using tranexamic acid in addition to the standard of care. PPH was defined as > 500 mL blood loss after vaginal delivery, > 1000 mL blood loss after cesarean section, or blood loss sufficient to produce hemodynamic compromise.
Researchers randomized 10,051 women to the tranexamic acid group and 10,009 to the placebo group. Women in the experimental group received a 1-g IV injection of tranexamic acid over 10 to 20 minutes. A second dose was given if bleeding restarted after 30 minutes and within 24 hours of the first dose.
To reduce mortality give tranexamic acid promptly
Tranexamic acid reduced mortality most effectively compared with placebo when given within 3 hours of delivery (1.2% [N = 89] vs 1.7% [N = 127]; P = .008; RR = 0.69; 95% CI 0.52-0.91; NNT = 200). After 3 hours, no significant decrease in mortality occurred. No significant difference in effect was noted between vaginal and cesarean deliveries nor between uterine atony as the primary cause of hemorrhage and other causes.
Administering tranexamic acid didn’t reduce the composite primary endpoint of hysterectomy or death from all causes. Nor did it reduce the secondary endpoints of intrauterine tamponade, embolization, manual placental extraction, arterial ligation, blood transfusions, or number of units of packed red blood cells. The tranexamic acid group showed a significant decrease in cases of laparotomy for PPH (0.8% vs 1.3%; P = .002; RR = 0.64; 95% CI, 0.49-0.85; NNT = 200).
Women who received tranexamic acid vs placebo showed no significant difference in mortality from pulmonary embolism (0.1% [N = 10] vs 0.1% [N = 11]; P = .82; RR = .9; 95% CI, 0.38-2.13), organ failure ure (0.3% [N = 25] vs 0.2% [N = 18]; P = .29; RR = 1.38; 95% CI, 0.75-2.53), sepsis (0.2% [N = 15] vs 0.1% [N = 8]; P = .15; RR = 1.87; 95% CI, 0.79-4.4), eclampsia (0.02% [N = 2] vs 0.1% [N = 8]; P = .057; RR = .25; 95% CI, 0.05-1.17), or other causes (0.2% [N = 20] vs 0.2% [N = 20]; P = .99; RR = 0.99; 95% CI, 0.54-1.85).
Tranexamic acid doesn’t increase the risk of thromboembolism
A 2018 Cochrane review sought more broadly to determine the general effectiveness and safety of antifibrinolytic drugs in treating primary PPH.2 Of 15 RCTs identified, only 3 met the inclusion criteria for the review, 1 of which was the WOMAN trial (which contributed most of the data in the review). The other trials were a study conducted in France that recruited 152 women and a study of 200 women in Iran that contributed only 1 primary outcome—estimated blood loss—to the review. The former study didn’t report any maternal deaths, and the latter study didn’t look at maternal deaths. The Cochrane review concluded, based on data from the WOMAN trial, that IV tranexamic acid, if given as early as possible, reduced mortality from bleeding in women with primary PPH after both vaginal and cesarean delivery and didn’t increase the risk of thromboembolic events.2
Continue to: RECOMMENDATIONS
RECOMMENDATIONS
The newest practice guidelines on the management of postpartum hemorrhage published by the American College of Obstetricians and Gynecologists recommends considering tranexamic acid as an additional agent in managing PPH when initial standard-of-care treatments fail.3
Editor’s takeaway
The large international double-blind, randomized placebo-controlled trial provides convincing evidence that tranexamic acid should be administered readily in cases of PPH.
1. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–2116.
2. Shakur H, Beaumont D, Pavord S, et al. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2018;2:CD012964.
3. Committee on Practice Bulletins-Obstetrics (American College of Obstetricians and Gynecologists). Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017;130:e168-e186.
EVIDENCE SUMMARY
A 2017 double-blind RCT that included 20,060 women with PPH from 21 countries (the WOMAN trial) found that the risk of maternal mortality was significantly lower among women who received tranexamic acid as part of their PPH treatment compared with placebo (1.5% [N = 155] vs 1.9% [N = 191]; P = .045; relative risk [RR] = 0.81; 95% confidence interval [CI], 0.65-1; number needed to treat [NNT] = 250).1
Inclusion criteria were age 16 years or older, postpartum course complicated by hemorrhage of known or unknown etiology, and a case in which the clinician considered using tranexamic acid in addition to the standard of care. PPH was defined as > 500 mL blood loss after vaginal delivery, > 1000 mL blood loss after cesarean section, or blood loss sufficient to produce hemodynamic compromise.
Researchers randomized 10,051 women to the tranexamic acid group and 10,009 to the placebo group. Women in the experimental group received a 1-g IV injection of tranexamic acid over 10 to 20 minutes. A second dose was given if bleeding restarted after 30 minutes and within 24 hours of the first dose.
To reduce mortality give tranexamic acid promptly
Tranexamic acid reduced mortality most effectively compared with placebo when given within 3 hours of delivery (1.2% [N = 89] vs 1.7% [N = 127]; P = .008; RR = 0.69; 95% CI 0.52-0.91; NNT = 200). After 3 hours, no significant decrease in mortality occurred. No significant difference in effect was noted between vaginal and cesarean deliveries nor between uterine atony as the primary cause of hemorrhage and other causes.
Administering tranexamic acid didn’t reduce the composite primary endpoint of hysterectomy or death from all causes. Nor did it reduce the secondary endpoints of intrauterine tamponade, embolization, manual placental extraction, arterial ligation, blood transfusions, or number of units of packed red blood cells. The tranexamic acid group showed a significant decrease in cases of laparotomy for PPH (0.8% vs 1.3%; P = .002; RR = 0.64; 95% CI, 0.49-0.85; NNT = 200).
Women who received tranexamic acid vs placebo showed no significant difference in mortality from pulmonary embolism (0.1% [N = 10] vs 0.1% [N = 11]; P = .82; RR = .9; 95% CI, 0.38-2.13), organ failure ure (0.3% [N = 25] vs 0.2% [N = 18]; P = .29; RR = 1.38; 95% CI, 0.75-2.53), sepsis (0.2% [N = 15] vs 0.1% [N = 8]; P = .15; RR = 1.87; 95% CI, 0.79-4.4), eclampsia (0.02% [N = 2] vs 0.1% [N = 8]; P = .057; RR = .25; 95% CI, 0.05-1.17), or other causes (0.2% [N = 20] vs 0.2% [N = 20]; P = .99; RR = 0.99; 95% CI, 0.54-1.85).
Tranexamic acid doesn’t increase the risk of thromboembolism
A 2018 Cochrane review sought more broadly to determine the general effectiveness and safety of antifibrinolytic drugs in treating primary PPH.2 Of 15 RCTs identified, only 3 met the inclusion criteria for the review, 1 of which was the WOMAN trial (which contributed most of the data in the review). The other trials were a study conducted in France that recruited 152 women and a study of 200 women in Iran that contributed only 1 primary outcome—estimated blood loss—to the review. The former study didn’t report any maternal deaths, and the latter study didn’t look at maternal deaths. The Cochrane review concluded, based on data from the WOMAN trial, that IV tranexamic acid, if given as early as possible, reduced mortality from bleeding in women with primary PPH after both vaginal and cesarean delivery and didn’t increase the risk of thromboembolic events.2
Continue to: RECOMMENDATIONS
RECOMMENDATIONS
The newest practice guidelines on the management of postpartum hemorrhage published by the American College of Obstetricians and Gynecologists recommends considering tranexamic acid as an additional agent in managing PPH when initial standard-of-care treatments fail.3
Editor’s takeaway
The large international double-blind, randomized placebo-controlled trial provides convincing evidence that tranexamic acid should be administered readily in cases of PPH.
EVIDENCE SUMMARY
A 2017 double-blind RCT that included 20,060 women with PPH from 21 countries (the WOMAN trial) found that the risk of maternal mortality was significantly lower among women who received tranexamic acid as part of their PPH treatment compared with placebo (1.5% [N = 155] vs 1.9% [N = 191]; P = .045; relative risk [RR] = 0.81; 95% confidence interval [CI], 0.65-1; number needed to treat [NNT] = 250).1
Inclusion criteria were age 16 years or older, postpartum course complicated by hemorrhage of known or unknown etiology, and a case in which the clinician considered using tranexamic acid in addition to the standard of care. PPH was defined as > 500 mL blood loss after vaginal delivery, > 1000 mL blood loss after cesarean section, or blood loss sufficient to produce hemodynamic compromise.
Researchers randomized 10,051 women to the tranexamic acid group and 10,009 to the placebo group. Women in the experimental group received a 1-g IV injection of tranexamic acid over 10 to 20 minutes. A second dose was given if bleeding restarted after 30 minutes and within 24 hours of the first dose.
To reduce mortality give tranexamic acid promptly
Tranexamic acid reduced mortality most effectively compared with placebo when given within 3 hours of delivery (1.2% [N = 89] vs 1.7% [N = 127]; P = .008; RR = 0.69; 95% CI 0.52-0.91; NNT = 200). After 3 hours, no significant decrease in mortality occurred. No significant difference in effect was noted between vaginal and cesarean deliveries nor between uterine atony as the primary cause of hemorrhage and other causes.
Administering tranexamic acid didn’t reduce the composite primary endpoint of hysterectomy or death from all causes. Nor did it reduce the secondary endpoints of intrauterine tamponade, embolization, manual placental extraction, arterial ligation, blood transfusions, or number of units of packed red blood cells. The tranexamic acid group showed a significant decrease in cases of laparotomy for PPH (0.8% vs 1.3%; P = .002; RR = 0.64; 95% CI, 0.49-0.85; NNT = 200).
Women who received tranexamic acid vs placebo showed no significant difference in mortality from pulmonary embolism (0.1% [N = 10] vs 0.1% [N = 11]; P = .82; RR = .9; 95% CI, 0.38-2.13), organ failure ure (0.3% [N = 25] vs 0.2% [N = 18]; P = .29; RR = 1.38; 95% CI, 0.75-2.53), sepsis (0.2% [N = 15] vs 0.1% [N = 8]; P = .15; RR = 1.87; 95% CI, 0.79-4.4), eclampsia (0.02% [N = 2] vs 0.1% [N = 8]; P = .057; RR = .25; 95% CI, 0.05-1.17), or other causes (0.2% [N = 20] vs 0.2% [N = 20]; P = .99; RR = 0.99; 95% CI, 0.54-1.85).
Tranexamic acid doesn’t increase the risk of thromboembolism
A 2018 Cochrane review sought more broadly to determine the general effectiveness and safety of antifibrinolytic drugs in treating primary PPH.2 Of 15 RCTs identified, only 3 met the inclusion criteria for the review, 1 of which was the WOMAN trial (which contributed most of the data in the review). The other trials were a study conducted in France that recruited 152 women and a study of 200 women in Iran that contributed only 1 primary outcome—estimated blood loss—to the review. The former study didn’t report any maternal deaths, and the latter study didn’t look at maternal deaths. The Cochrane review concluded, based on data from the WOMAN trial, that IV tranexamic acid, if given as early as possible, reduced mortality from bleeding in women with primary PPH after both vaginal and cesarean delivery and didn’t increase the risk of thromboembolic events.2
Continue to: RECOMMENDATIONS
RECOMMENDATIONS
The newest practice guidelines on the management of postpartum hemorrhage published by the American College of Obstetricians and Gynecologists recommends considering tranexamic acid as an additional agent in managing PPH when initial standard-of-care treatments fail.3
Editor’s takeaway
The large international double-blind, randomized placebo-controlled trial provides convincing evidence that tranexamic acid should be administered readily in cases of PPH.
1. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–2116.
2. Shakur H, Beaumont D, Pavord S, et al. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2018;2:CD012964.
3. Committee on Practice Bulletins-Obstetrics (American College of Obstetricians and Gynecologists). Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017;130:e168-e186.
1. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–2116.
2. Shakur H, Beaumont D, Pavord S, et al. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database Syst Rev. 2018;2:CD012964.
3. Committee on Practice Bulletins-Obstetrics (American College of Obstetricians and Gynecologists). Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017;130:e168-e186.
EVIDENCE-BASED ANSWER:
Yes. When used in conjunction with the standard of care, 1 g intravenous (IV) tranexamic acid given 1 to 3 hours after delivery is associated with a significant reduction in maternal mortality from postpartum hemorrhage (PPH) (strength of recommendation: A, randomized controlled trial [RCT] and Cochrane review).
No known significant risks are associated with the use of tranexamic acid to treat PPH.
Multidisciplinary care could address fertility preservation in transgender youth
PHILADELPHIA – A multidisciplinary approach is needed to care for gender-diverse transgender adolescents interested in fertility preservation, Leena Nahata, MD, said at the annual meeting of the American Society for Reproductive Medicine.
especially in the absence of longitudinal data, said Dr. Nahata, medical director of the fertility and reproductive health program at Nationwide Children’s Hospital, Columbus, Ohio. “We’re trying to counsel these youth and their parents about long-term outcomes of hormone therapies. However, despite the lack of data, not treating them also is not a viable option.”
Another concern among transgender individuals, Dr. Nahata said, is a high risk of mental health issues. Approximately one-third of transgender individuals experience depression, and between one-third and one-half have suicidal ideation or attempted suicide.
“It’s important to realize that these risks are not inevitable,” she said. Support from parents, peers, and social groups; engaging with the health care system; and having access to puberty suppression, gender-affirming hormones, and surgery are protective outcomes for mental health concerns. “It’s because of this that so many of us feel obligated to move on with treatments even in a setting of a lack of data.”
According to 2017 guidelines from the Endocrine Society on gender-dysphoric and gender-incongruent persons, patients can begin gonadotropin-releasing hormone (GnRH) agonists at Tanner Stage 2 of puberty (J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658). Before starting treatment, a mental health provider should confirm gender dysphoria or incongruence, and determine whether the patient has “sufficient mental capacity” to understand the long-term consequences of treatment with gender-affirming hormones such as estrogen and testosterone because the effects are partially irreversible, including a potential loss of fertility. Most pediatric patients will have this ability by 16 years old, but some programs across the country begin treatment between 13.5 years and 14 years of age, said Dr. Nahata. One consideration of beginning GnRH agonists and then moving directly to gender-affirming hormone therapy, there may not be an opportunity to explore fertility preservation.
Dr. Nahata acknowledged the data for the long-term effects of testosterone and estrogen on fertility is “murky,” but despite a lack of data, the American Society for Reproductive Medicine released an ethics statement in 2015 affirming that transgender patients “have the same interests as other persons in having children and in accessing fertility services for fertility preservation and reproduction” and pediatric providers “should offer fertility preservation options to individuals before gender transition” (Fertil Steril. 2015 Sep 9. doi: 10.1016/j.fertnstert.2015.08.021).
There also is mixed evidence that transgender individuals take advantage of fertility preservation services, whether offered or not. Two studies from Belgium that surveyed transgender individuals on parenthood preferences found 54% of adult trans men had a desire for children and that 38% of adult trans men and 51% of adult trans women would consider fertility preservation if it was an option. However, Dr. Nahata said a retrospective study from her own group of 50 adolescent trans males and 23 adolescent trans females found 99% of the cohort was counseled on fertility preservation, but only 3% (2 patients) attempted fertility preservation, and both were trans females (J Adolesc Health. 2017 Jul. doi: 10.1016/j.jadohealth.2016.12.012).
Another study examining use of fertility preservation in trans females in the Netherlands by Brik et al. found a much higher use of fertility preservation, with 38% of patients attempting cryopreservation after counseling (J Adolesc Health. 2019 May. doi: 10.1016/j.jadohealth.2018.11.008). “It’s unclear whether this is a regional difference or whether things are actually shifting over a short period of time,” said Dr. Nahata.
Attitudes about fertility preservation among gender-diverse transgender youth also impact its use in this patient population. A survey of transgender youth found less than 40% preferred adoption to biological parenthood, but said their feelings might change as time passes. However, more than half wanted more information on their family-building options. For other transgender youth aged 12-19 years, having children was their “lowest life priority,” compared with having friends, their health, and other issues in their lives, said Dr. Nahata.
In a 24-item survey Dr. Nahata and her team administered to 44 trans nonbinary adolescents, the most common reasons for not seeking fertility preservation were feelings of being too young, not wanting to be a parent or have a biological child, not wanting to delay treatment, and not being able to afford the cost of fertility preservation.
“This just speaks to the complexities of counseling in this population, and the importance of having a multidisciplinary team to see these youth and families to do more comprehensive counseling,” she said.
Dr. Nahata reported no relevant conflicts of interest.
PHILADELPHIA – A multidisciplinary approach is needed to care for gender-diverse transgender adolescents interested in fertility preservation, Leena Nahata, MD, said at the annual meeting of the American Society for Reproductive Medicine.
especially in the absence of longitudinal data, said Dr. Nahata, medical director of the fertility and reproductive health program at Nationwide Children’s Hospital, Columbus, Ohio. “We’re trying to counsel these youth and their parents about long-term outcomes of hormone therapies. However, despite the lack of data, not treating them also is not a viable option.”
Another concern among transgender individuals, Dr. Nahata said, is a high risk of mental health issues. Approximately one-third of transgender individuals experience depression, and between one-third and one-half have suicidal ideation or attempted suicide.
“It’s important to realize that these risks are not inevitable,” she said. Support from parents, peers, and social groups; engaging with the health care system; and having access to puberty suppression, gender-affirming hormones, and surgery are protective outcomes for mental health concerns. “It’s because of this that so many of us feel obligated to move on with treatments even in a setting of a lack of data.”
According to 2017 guidelines from the Endocrine Society on gender-dysphoric and gender-incongruent persons, patients can begin gonadotropin-releasing hormone (GnRH) agonists at Tanner Stage 2 of puberty (J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658). Before starting treatment, a mental health provider should confirm gender dysphoria or incongruence, and determine whether the patient has “sufficient mental capacity” to understand the long-term consequences of treatment with gender-affirming hormones such as estrogen and testosterone because the effects are partially irreversible, including a potential loss of fertility. Most pediatric patients will have this ability by 16 years old, but some programs across the country begin treatment between 13.5 years and 14 years of age, said Dr. Nahata. One consideration of beginning GnRH agonists and then moving directly to gender-affirming hormone therapy, there may not be an opportunity to explore fertility preservation.
Dr. Nahata acknowledged the data for the long-term effects of testosterone and estrogen on fertility is “murky,” but despite a lack of data, the American Society for Reproductive Medicine released an ethics statement in 2015 affirming that transgender patients “have the same interests as other persons in having children and in accessing fertility services for fertility preservation and reproduction” and pediatric providers “should offer fertility preservation options to individuals before gender transition” (Fertil Steril. 2015 Sep 9. doi: 10.1016/j.fertnstert.2015.08.021).
There also is mixed evidence that transgender individuals take advantage of fertility preservation services, whether offered or not. Two studies from Belgium that surveyed transgender individuals on parenthood preferences found 54% of adult trans men had a desire for children and that 38% of adult trans men and 51% of adult trans women would consider fertility preservation if it was an option. However, Dr. Nahata said a retrospective study from her own group of 50 adolescent trans males and 23 adolescent trans females found 99% of the cohort was counseled on fertility preservation, but only 3% (2 patients) attempted fertility preservation, and both were trans females (J Adolesc Health. 2017 Jul. doi: 10.1016/j.jadohealth.2016.12.012).
Another study examining use of fertility preservation in trans females in the Netherlands by Brik et al. found a much higher use of fertility preservation, with 38% of patients attempting cryopreservation after counseling (J Adolesc Health. 2019 May. doi: 10.1016/j.jadohealth.2018.11.008). “It’s unclear whether this is a regional difference or whether things are actually shifting over a short period of time,” said Dr. Nahata.
Attitudes about fertility preservation among gender-diverse transgender youth also impact its use in this patient population. A survey of transgender youth found less than 40% preferred adoption to biological parenthood, but said their feelings might change as time passes. However, more than half wanted more information on their family-building options. For other transgender youth aged 12-19 years, having children was their “lowest life priority,” compared with having friends, their health, and other issues in their lives, said Dr. Nahata.
In a 24-item survey Dr. Nahata and her team administered to 44 trans nonbinary adolescents, the most common reasons for not seeking fertility preservation were feelings of being too young, not wanting to be a parent or have a biological child, not wanting to delay treatment, and not being able to afford the cost of fertility preservation.
“This just speaks to the complexities of counseling in this population, and the importance of having a multidisciplinary team to see these youth and families to do more comprehensive counseling,” she said.
Dr. Nahata reported no relevant conflicts of interest.
PHILADELPHIA – A multidisciplinary approach is needed to care for gender-diverse transgender adolescents interested in fertility preservation, Leena Nahata, MD, said at the annual meeting of the American Society for Reproductive Medicine.
especially in the absence of longitudinal data, said Dr. Nahata, medical director of the fertility and reproductive health program at Nationwide Children’s Hospital, Columbus, Ohio. “We’re trying to counsel these youth and their parents about long-term outcomes of hormone therapies. However, despite the lack of data, not treating them also is not a viable option.”
Another concern among transgender individuals, Dr. Nahata said, is a high risk of mental health issues. Approximately one-third of transgender individuals experience depression, and between one-third and one-half have suicidal ideation or attempted suicide.
“It’s important to realize that these risks are not inevitable,” she said. Support from parents, peers, and social groups; engaging with the health care system; and having access to puberty suppression, gender-affirming hormones, and surgery are protective outcomes for mental health concerns. “It’s because of this that so many of us feel obligated to move on with treatments even in a setting of a lack of data.”
According to 2017 guidelines from the Endocrine Society on gender-dysphoric and gender-incongruent persons, patients can begin gonadotropin-releasing hormone (GnRH) agonists at Tanner Stage 2 of puberty (J Clin Endocrinol Metab. 2017 Nov. doi: 10.1210/jc.2017-01658). Before starting treatment, a mental health provider should confirm gender dysphoria or incongruence, and determine whether the patient has “sufficient mental capacity” to understand the long-term consequences of treatment with gender-affirming hormones such as estrogen and testosterone because the effects are partially irreversible, including a potential loss of fertility. Most pediatric patients will have this ability by 16 years old, but some programs across the country begin treatment between 13.5 years and 14 years of age, said Dr. Nahata. One consideration of beginning GnRH agonists and then moving directly to gender-affirming hormone therapy, there may not be an opportunity to explore fertility preservation.
Dr. Nahata acknowledged the data for the long-term effects of testosterone and estrogen on fertility is “murky,” but despite a lack of data, the American Society for Reproductive Medicine released an ethics statement in 2015 affirming that transgender patients “have the same interests as other persons in having children and in accessing fertility services for fertility preservation and reproduction” and pediatric providers “should offer fertility preservation options to individuals before gender transition” (Fertil Steril. 2015 Sep 9. doi: 10.1016/j.fertnstert.2015.08.021).
There also is mixed evidence that transgender individuals take advantage of fertility preservation services, whether offered or not. Two studies from Belgium that surveyed transgender individuals on parenthood preferences found 54% of adult trans men had a desire for children and that 38% of adult trans men and 51% of adult trans women would consider fertility preservation if it was an option. However, Dr. Nahata said a retrospective study from her own group of 50 adolescent trans males and 23 adolescent trans females found 99% of the cohort was counseled on fertility preservation, but only 3% (2 patients) attempted fertility preservation, and both were trans females (J Adolesc Health. 2017 Jul. doi: 10.1016/j.jadohealth.2016.12.012).
Another study examining use of fertility preservation in trans females in the Netherlands by Brik et al. found a much higher use of fertility preservation, with 38% of patients attempting cryopreservation after counseling (J Adolesc Health. 2019 May. doi: 10.1016/j.jadohealth.2018.11.008). “It’s unclear whether this is a regional difference or whether things are actually shifting over a short period of time,” said Dr. Nahata.
Attitudes about fertility preservation among gender-diverse transgender youth also impact its use in this patient population. A survey of transgender youth found less than 40% preferred adoption to biological parenthood, but said their feelings might change as time passes. However, more than half wanted more information on their family-building options. For other transgender youth aged 12-19 years, having children was their “lowest life priority,” compared with having friends, their health, and other issues in their lives, said Dr. Nahata.
In a 24-item survey Dr. Nahata and her team administered to 44 trans nonbinary adolescents, the most common reasons for not seeking fertility preservation were feelings of being too young, not wanting to be a parent or have a biological child, not wanting to delay treatment, and not being able to afford the cost of fertility preservation.
“This just speaks to the complexities of counseling in this population, and the importance of having a multidisciplinary team to see these youth and families to do more comprehensive counseling,” she said.
Dr. Nahata reported no relevant conflicts of interest.
EXPERT ANALYSIS FROM ASRM 2019
Melanoma incidence continues to increase, yet mortality stabilizing
LAS VEGAS – The according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.
At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.
A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”
Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.
The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”
Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.
Early detection of thin nodular melanomas has the potential to significantly impact melanoma mortality, “but we want to keep in mind that the majority of ultimately fatal melanomas are superficial spreading melanomas,” Dr. Ferris said. “That is because they are so much more prevalent. As a dermatologist, I think a lot about screening and early detection. Periodic screening is a good strategy for a slower-growing superficial spreading melanoma, but it’s not necessarily a good strategy for a rapidly growing nodular melanoma. That’s going to require better education and better access to health care.”
Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”
Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”
Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).
“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”
Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.
SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.
LAS VEGAS – The according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.
At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.
A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”
Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.
The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”
Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.
Early detection of thin nodular melanomas has the potential to significantly impact melanoma mortality, “but we want to keep in mind that the majority of ultimately fatal melanomas are superficial spreading melanomas,” Dr. Ferris said. “That is because they are so much more prevalent. As a dermatologist, I think a lot about screening and early detection. Periodic screening is a good strategy for a slower-growing superficial spreading melanoma, but it’s not necessarily a good strategy for a rapidly growing nodular melanoma. That’s going to require better education and better access to health care.”
Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”
Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”
Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).
“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”
Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.
SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.
LAS VEGAS – The according to data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.
At the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar, Laura Korb Ferris, MD, PhD, said that SEER data project 96,480 new cases of melanoma in 2019, as well as 7,230 deaths from the disease. In 2016, SEER projected 10,130 deaths from melanoma, “so we’re actually projecting a reduction in melanoma deaths,” said Dr. Ferris, director of clinical trials at the University of Pittsburgh Medical Center’s department of dermatology. She added that the death rate from melanoma in 2016 was 2.17 per 100,000 population, a reduction from 2.69 per 100,000 population in 2011, “so it looks like melanoma mortality may be stable,” or even reduced, despite an increase in melanoma incidence.
A study of SEER data between 1989 and 2009 found that melanoma incidence is increasing across all lesion thicknesses (J Natl Cancer Inst. 2015 Nov 12. doi: 10.1093/jnci/djv294). Specifically, the incidence increased most among thin lesions, but there was a smaller increased incidence of thick melanoma. “This suggests that the overall burden of disease is truly increasing, but it is primarily stemming from an increase in T1/T2 disease,” Dr. Ferris said. “This could be due in part to increased early detection.”
Improvements in melanoma-specific survival, she continued, are likely a combination of improved management of T4 disease, a shift toward detection of thinner T1/T2 melanoma, and increased detection of T1/T2 disease.
The SEER data also showed that the incidence of fatal cases of melanoma has decreased since 1989, but only in thick melanomas. This trend may indicate a modest improvement in the management of T4 tumors. “Optimistically, I think increased detection efforts are improving survival by early detection of thin but ultimately fatal melanomas,” Dr. Ferris said. “Hopefully we are finding disease earlier and we are preventing patients from progressing to these fatal T4 melanomas.”
Disparities in melanoma-specific survival also come into play. Men have poorer survival compared with women, whites have the highest survival, and non-Hispanic whites have a better survival than Hispanic whites, Dr. Ferris said, while lower rates of survival are seen in blacks and nonblack minorities, as well as among those in high poverty and those who are separated/nonmarried. Lesion type also matters. The highest survival is seen in those with superficial spreading melanoma, while lower survival is observed in those with nodular melanoma, and acral lentiginous melanoma.
Early detection of thin nodular melanomas has the potential to significantly impact melanoma mortality, “but we want to keep in mind that the majority of ultimately fatal melanomas are superficial spreading melanomas,” Dr. Ferris said. “That is because they are so much more prevalent. As a dermatologist, I think a lot about screening and early detection. Periodic screening is a good strategy for a slower-growing superficial spreading melanoma, but it’s not necessarily a good strategy for a rapidly growing nodular melanoma. That’s going to require better education and better access to health care.”
Self-detection of melanoma is another strategy to consider. According to Dr. Ferris, results from multiple studies suggest that about 50% of all melanomas are detected by patients, but the ones they find tend to be thicker than the ones that clinicians detect during office visits. “It would be great if we can get that number higher than 50%,” Dr. Ferris said. “If patients really understood what melanoma is, what it looks like, and when they needed to seek medical attention, perhaps we could get that over 50% and see self-detection of thinner melanomas. That’s a very low-cost intervention.”
Targeted screening efforts that stratify by risk factors and by age “makes screening more efficient and more cost-effective,” she added. She cited one analysis, which found that clinicians need to screen 606 people and conduct 25 biopsies in order to find one melanoma. “That’s very resource intensive,” she said. “However, if you only screened people 50 or older or 65 or older, the number needed to screen goes down, and because your pretest probability is higher, your number need to biopsy goes down as well. If you factor in things like a history of atypical nevi or a personal history of melanoma, those patients are at a higher risk of developing melanoma.”
Dr. Ferris closed her presentation by noting that Australia leads other countries in melanoma prevention efforts. There, the combined incidence of skin cancer is higher than the incidence of any other type of cancer. Four decades ago, Australian health officials launched SunSmart, a series of initiatives intended to reduce skin cancer. These include implementation of policies for hat wearing and shade provision in schools and at work, availability of more effective sunscreens, inclusion of sun protection items as a tax-deductible expense for outdoor workers, increased availability since the 1980s of long-sleeved sun protective swimwear, a ban on the use of indoor tanning since 2014, provision of UV forecasts in weather, and a comprehensive program of grants for community shade structures (PLoSMed. 2019 Oct 8;16[10]:e1002932).
“One approach to melanoma prevention won’t fit all,” she concluded. “We need to focus on prevention, public education to improve knowledge and self-detection.”
Dr. Ferris disclosed that she is a consultant to and an investigator for DermTech and Scibase. She is also an investigator for Castle Biosciences.
SDEF and this news organization are owned by the same parent company. Dr. Ferris spoke during a forum on cutaneous malignancies at the meeting.
EXPERT ANALYSIS FROM THE SDEF LAS VEGAS DERMATOLOGY SEMINAR
Probiotics with Lactobacillus reduce loss in spine BMD for postmenopausal women
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
FROM THE LANCET RHEUMATOLOGY
Ask about vaping and e-cigarette use
When we studied the knowledge and practice of e-cigarette use among pregnant women in one of our outpatient practices, we found that 43% of more than 300 survey participants believed e-cigarettes are less harmful to a fetus than traditional cigarettes. Just over half – 57% – believed that e-cigarettes contain nicotine.
This study from 5 years ago demonstrated the need for more patient education.1 Today, we have even more clarity that, while there may be health benefits of switching to noncombustible forms of nicotine consumption outside of pregnancy, these potential benefits do not extend to pregnancy. Both human and animal studies have demonstrated that nicotine itself is harmful to the developing fetus; the Centers for Disease Control and Prevention warns against the use of e-cigarettes in pregnancy for this reason.
A 2018 literature review on the use of e-cigarettes in pregnancy and the effects on perinatal/neonatal outcomes reported that the amount of nicotine consumed by e-cigarette users is similar to that of cigarette smokers and that most animal studies suggest a potential danger to the fetus, primarily because of the nicotine.2 Effects on the immune system, neural development, lung function, and cardiac function were all noted in the review. Other research has shown that e-cigarette fluid can contain formaldehyde and other harmful substances.
A new analysis of data from the 2014-2017 National Health Interview Survey shows a significantly lower prevalence of conventional cigarette use among pregnant women than in nonpregnant women, and an almost identical prevalence of e-cigarette use among pregnant and nonpregnant women of reproductive age.3 This discrepancy again suggests that women may not be aware of the potential harms of e-cigarettes in pregnancy, which is not surprising considering that prenatal care clinicians often are not appropriately screening or counseling regarding e-cigarette use.4
and counsel women that the use of e-cigarettes is not a safer alternative to cigarette smoking. I urge patients who have switched to e-cigarettes as a means of smoking cessation or as a choice they perceive to be safer to work together with me to find another way to reduce potential harm to their baby.
References
1. J Addict Med. 2015 Jul-Aug;9(4):266-72.
2. Obstet Gynecol Surv. 2018 Sep;73(9):544-9.
3. JAMA Pediatr. 2019 Jun 1;173(6):600-2.
4. Am J Obstet Gynecol. 2014 Dec;211(6):695.e1-7.
When we studied the knowledge and practice of e-cigarette use among pregnant women in one of our outpatient practices, we found that 43% of more than 300 survey participants believed e-cigarettes are less harmful to a fetus than traditional cigarettes. Just over half – 57% – believed that e-cigarettes contain nicotine.
This study from 5 years ago demonstrated the need for more patient education.1 Today, we have even more clarity that, while there may be health benefits of switching to noncombustible forms of nicotine consumption outside of pregnancy, these potential benefits do not extend to pregnancy. Both human and animal studies have demonstrated that nicotine itself is harmful to the developing fetus; the Centers for Disease Control and Prevention warns against the use of e-cigarettes in pregnancy for this reason.
A 2018 literature review on the use of e-cigarettes in pregnancy and the effects on perinatal/neonatal outcomes reported that the amount of nicotine consumed by e-cigarette users is similar to that of cigarette smokers and that most animal studies suggest a potential danger to the fetus, primarily because of the nicotine.2 Effects on the immune system, neural development, lung function, and cardiac function were all noted in the review. Other research has shown that e-cigarette fluid can contain formaldehyde and other harmful substances.
A new analysis of data from the 2014-2017 National Health Interview Survey shows a significantly lower prevalence of conventional cigarette use among pregnant women than in nonpregnant women, and an almost identical prevalence of e-cigarette use among pregnant and nonpregnant women of reproductive age.3 This discrepancy again suggests that women may not be aware of the potential harms of e-cigarettes in pregnancy, which is not surprising considering that prenatal care clinicians often are not appropriately screening or counseling regarding e-cigarette use.4
and counsel women that the use of e-cigarettes is not a safer alternative to cigarette smoking. I urge patients who have switched to e-cigarettes as a means of smoking cessation or as a choice they perceive to be safer to work together with me to find another way to reduce potential harm to their baby.
References
1. J Addict Med. 2015 Jul-Aug;9(4):266-72.
2. Obstet Gynecol Surv. 2018 Sep;73(9):544-9.
3. JAMA Pediatr. 2019 Jun 1;173(6):600-2.
4. Am J Obstet Gynecol. 2014 Dec;211(6):695.e1-7.
When we studied the knowledge and practice of e-cigarette use among pregnant women in one of our outpatient practices, we found that 43% of more than 300 survey participants believed e-cigarettes are less harmful to a fetus than traditional cigarettes. Just over half – 57% – believed that e-cigarettes contain nicotine.
This study from 5 years ago demonstrated the need for more patient education.1 Today, we have even more clarity that, while there may be health benefits of switching to noncombustible forms of nicotine consumption outside of pregnancy, these potential benefits do not extend to pregnancy. Both human and animal studies have demonstrated that nicotine itself is harmful to the developing fetus; the Centers for Disease Control and Prevention warns against the use of e-cigarettes in pregnancy for this reason.
A 2018 literature review on the use of e-cigarettes in pregnancy and the effects on perinatal/neonatal outcomes reported that the amount of nicotine consumed by e-cigarette users is similar to that of cigarette smokers and that most animal studies suggest a potential danger to the fetus, primarily because of the nicotine.2 Effects on the immune system, neural development, lung function, and cardiac function were all noted in the review. Other research has shown that e-cigarette fluid can contain formaldehyde and other harmful substances.
A new analysis of data from the 2014-2017 National Health Interview Survey shows a significantly lower prevalence of conventional cigarette use among pregnant women than in nonpregnant women, and an almost identical prevalence of e-cigarette use among pregnant and nonpregnant women of reproductive age.3 This discrepancy again suggests that women may not be aware of the potential harms of e-cigarettes in pregnancy, which is not surprising considering that prenatal care clinicians often are not appropriately screening or counseling regarding e-cigarette use.4
and counsel women that the use of e-cigarettes is not a safer alternative to cigarette smoking. I urge patients who have switched to e-cigarettes as a means of smoking cessation or as a choice they perceive to be safer to work together with me to find another way to reduce potential harm to their baby.
References
1. J Addict Med. 2015 Jul-Aug;9(4):266-72.
2. Obstet Gynecol Surv. 2018 Sep;73(9):544-9.
3. JAMA Pediatr. 2019 Jun 1;173(6):600-2.
4. Am J Obstet Gynecol. 2014 Dec;211(6):695.e1-7.
Cannabis and prenatal care
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
We know that the environment significantly impacts our health. People who live in areas prone to industrial waste, poor air or water quality, and crime have higher risks for cardiovascular disease, severe asthma, and stress-induced illnesses. Children who grow up under these conditions can experience a failure to thrive.
As ob.gyns., we also recognize that the intrauterine environment plays a key role in influencing embryonic and fetal development. For this reason, we counsel our pregnant patients to eat well-balanced diets, drink healthy amounts of water, get plenty of rest, and incorporate physical activity into their daily routines. Indeed, the seminal work by Sir David Barker demonstrated that the roots of chronic diseases – including hypertension, stroke, and type 2 diabetes – begin in utero. We truly are where we live – from before birth up through adulthood.
Because the womb environment, where we spend the first critical 9 months of life, dramatically affects our lifelong health, we advise against the use of certain medications and other substances during pregnancy. Some of these recommendations seem clear-cut: Don’t smoke and significantly reduce or abstain from alcohol consumption; illicit drugs – such as cocaine or heroin – should never be used. However, gray areas exist. For example, although anticonvulsants carry higher risks for congenital malformations, patients who experience seizures may need to continue taking antiepileptic drugs during pregnancy, especially those with long safety records.
One of the newer challenges the medical community in general must face is the broadened use and wider societal acceptance of cannabis. Currently legal in 33 U.S. states and Washington, D.C., medical marijuana now is viewed as another legitimate tool in the health care arsenal, rather than the off-limits, off-label substance it was less than a generation ago.
Although proponents may tout the health benefits of cannabis and related products like cannabidiol, it remains unclear what the long-term effects of routine use may have on development, especially fetal development. However, how we as ob.gyns. navigate conversations with our patients around substance use remains crucial to our delivery of the best possible prenatal care.
We have invited Katrina S. Mark, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, to examine use of cannabis in pregnancy and the need for maintaining trust in the patient-practitioner relationship when discussing substance use during prenatal counseling.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
Counseling on cannabis use in pregnancy
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
A flurry of research papers published this year has simultaneously documented a rise in the use of cannabis during pregnancy and offered more data about its potential harms. This confluence of findings is concerning and highlights the importance of screening our patients for cannabis use and engaging with them in a way in which we can maintain their trust and their commitment to prenatal care.
A retrospective cohort study involving 661,617 women in Ontario found a significant association between self-reported cannabis use in pregnancy and an increased risk of preterm birth (relative risk, 1.41), as well as a greater likelihood of small-for-gestational-age babies (RR, 1.53), placental abruption (RR, 1.72), and transfer to neonatal intensive care (RR, 1.40).1 The study, reported in JAMA in July 2019, carefully matched users with nonusers who had the same characteristics – for example, tobacco use or not.
This new information builds upon other meta-analyses that have demonstrated a decrease in birth weight and greater admittance to the neonatal ICU associated with cannabis use in pregnancy – and it supplements what some research suggests about long-term neurologic development and a potentially increased risk of attention and behavioral problems. Other outcomes that have been noted in long-term neurologic studies of children who were exposed to cannabis in utero include impaired visual acuity, verbal reasoning and comprehension, and short-term memory.2
Increases in use were recently documented in two studies. One, an analysis of data from the National Survey on Drug Use and Health (NSDUH) published in JAMA in June 2019, showed that, between 2002-2003 and 2016-2017, the use of cannabis “in the past month” increased from 3.4% to 7.0% among pregnant women overall, and from 6% to 12% during the first trimester.3
The use of cannabis on a daily or near-daily basis, moreover, increased from 0.9% to 3% among pregnant women overall and from 2% to 5% during the first trimester. The data were collected during face-to-face interviews and were adjusted for age, race/ethnicity, and family income.
In the second study – a cross-sectional study of 367,403 pregnancies among women who filled out a questionnaire on cannabis use during standard prenatal care at Kaiser Permanente Northern California – the adjusted prevalence of use in the year before pregnancy increased from 7% in 2009 to 13% in 2017, and the adjusted prevalence during pregnancy increased from 2% to 3%.4
As in the NSDUH analysis, daily use increased most rapidly (compared with weekly or monthly) such that, by 2017, 25% of those who reported using cannabis in the year before pregnancy – and 21% of those who used cannabis during pregnancy – were daily users. It is notable that Kaiser’s population is diverse in all respects, and that the annual relative rates of increase in cannabis use before and during pregnancy (at each level of frequency) were consistent across racial/ethnic and household income groups.
It’s also worth noting that, in earlier research covering a similar time period (2009-2016), the investigators found significant increases in use via urine toxicology testing that occurs at the first prenatal visit at Kaiser. The increase found through questionnaires, therefore, reflects more than a greater willingness to self-report.
Choosing a screening tool
Universal prenatal substance use screening is recommended by the American College of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention, but we don’t have any specific recommendations on what this means. Who should be screening, and what should that screening look like? Should we use a biologic screen, a standardized screening tool, or simply ask patients whether they use illicit substances?
Screening tools seem advantageous in that they are low cost, noninvasive, potentially comprehensive, and not subject to false-positive results as biologic screens can be – but which tool or tools are best? There are several validated screening tools that can be used outside of pregnancy to determine an individual’s use of illicit substances and whether or not that use is problematic, but previous studies have not used biologic markers to validate substance use screeners in pregnancy. Nor have studies compared screeners in pregnancy.
In our prenatal population in Baltimore, we have not been getting the answers we want using various nonvalidated screening tools. Approximately 30% of patients are positive for cannabis by urine screen, but only half tell us about their use.
Through research in our two prenatal care practices (one serving mostly privately insured and the other serving primarily Medicaid-eligible patients), we assessed both the accuracy and the acceptability of three substance use screening tools that are brief and that have been validated (for the general population) by the World Health Organization for screening of multiple substances: the 4P’s Plus (Parents, Partner, Past, and Pregnancy), the National Institute on Drug Abuse Quick Screen–ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile–Pregnancy) scale.
In one study, published in May 2019 in Obstetrics & Gynecology, we recruited 500 pregnant women and administered these three tests to each of them.5 We then compared results with those of urine and hair drug testing, and checked the test-retest reliability of each test by readministering them (albeit by telephone) a week later. Although hair testing is not an indicator of current substance use, we used it to validate the screening tools on less-recent use.
The tests with the highest sensitivity and negative predictive values – the qualities we most want for screening – were the SURP-P and the 4P’s Plus (sensitivity of 92.4% and 90.2%, respectively). Overall they were highly sensitive screening tools across all trimesters, races, and age groups, making them more ideal screening tests than the NIDA Quick Screen–ASSIST.
Of the two tests, the 4P’s Plus screening tool was the one preferred by staff from both practices. In a companion qualitative study, we conducted focus-group discussions with 40 practice staff who were responsible for administering or overseeing patient screening.6 The staff, who were unaware of the sensitivity findings, were asked what they thought about the acceptability to patients of each of the three tools and their usability in practice.
Most of the participating staff preferred the 4P’s Plus screening tool for several reasons: It is easy to understand, is brief and to the point, and it has nonjudgmental language and tone. The screener first asks the patient about her parents’ and her partner’s use of alcohol and drugs, and then asks the patient about her own use of alcohol and tobacco. Affirmative responses to these questions lead to additional questions.
The premise is that one’s genetics, history, and current exposures – as well as one’s own use of tobacco and alcohol – are significantly associated with the use of illicit substances. If the patient reports no parental history or partner usage, and has never drank or smoked before, it’s extremely unlikely that she is using other drugs. The progression of questions does indeed seem less judgmental than immediately asking: “Do you use drugs?”
For us, the insight from this staff perception study combined with the findings on accuracy mean that the 4P’s Plus may be the most useful and acceptable screening tool for routine use in prenatal care.
Talking with our patients
The increase in the use of cannabis before and after pregnancy parallels the movement toward state legalization and decriminalization. Historically, clinicians often have relied on illegality as their main focus of counseling when giving recommendations for cessation and abstinence in pregnancy.2 This approach not only leads to punitive counseling, which can fracture the doctor-patient relationship, but increasingly it is no longer valid. In our changing legal climate, we need to provide medically based counseling and be very clear with our patients that legalization does not equate to safety.
It is important that we neither minimize nor overstate the risks. The evidence base for adverse birth outcomes of cannabis use in pregnancy is quite robust, but the associations can be subtle and are moderated by other behaviors and environmental factors that continue to challenge researchers.
As with alcohol, there likely are dose-or trimester-dependent differences in perinatal outcomes, and it’s quite possible that different cannabis products and routes of consumption have different effects. At this point, however, we don’t know the full story, nor do we know the extent to which the literature is biased toward positive correlations – the reporting of adverse effects – compared with negative findings. It is our job as medical care providers to be comfortable in that gray area and to still counsel patients on what we do know, providing the best-possible medical advice based on the information available to us.
In talking with patients, I explain that cannabis may cause a spectrum of problems and that there certainly are risks. I also tell them that we’re uncertain about the conditions and magnitude of that risk and that some babies who are exposed to cannabis in utero may have no perceivable consequences. Such honesty is important for maintaining trust, especially as some patients may see friends and relatives who also are cannabis users have normal pregnancy outcomes.
Much of my concern about cannabis in pregnancy centers on its effect on the developing brain and on long-term neurologic development. I share this with patients – I tell them that cannabis crosses the placenta and may well affect their baby’s brain as it is developing. I explain that I do not know whether this effect would be big or small, but that it’s not a chance I’m willing to take for their baby.
It is also important to educate patients that cannabis products are untested and unregulated and that they may be contaminated with heavy metals, pesticides, and other toxins that may be harmful to themselves and their babies. Patients also should know that the potency of cannabis has been dramatically increasing; research shows that the tetrahydrocannabinol – the psychoactive component – concentration has tripled over the past 2 decades.7
Research tells us that women who use illicit drugs and alcohol categorically engage in some form of harm reduction once they learn they are pregnant, and the same is true for cannabis. This is seen in dramatically different rates of first- and third-trimester use in the new analysis of NSDUH data; third-trimester use is approximately halved.
Some women will not be able to discontinue use, however, or they may try to quit and fail in their attempts. As we should with substance use more broadly, we must meet patients where they are, view cannabis use as a chronic medical problem, offer our assistance in helping them reduce harms of their use, and understand that quitting is a process.
Screening for mental health disorders and trauma is, of course, especially important in patients who use cannabis and other substances recreationally. In cases of medical marijuana usage, I recommend, as ACOG and other have done, that we discuss the risks and benefits of continuing cannabis versus shifting to alternative medications if options exist.
All patients should be welcomed, congratulated on their pregnancy and on coming for prenatal care, and engaged in the overall process of optimizing their health and the health of their baby. Like any other health issue during pregnancy, cannabis use needs to be screened for and treated in an evidence-based manner, but it does not define the trajectory or success of a woman’s pregnancy or her ability to be a successful parent.
Dr. Mark is associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.
References
1. JAMA. 2019 Jul 9;322(2):145-52.
2. Preventive Medicine 2017 May 18;104:46-9.
3. JAMA. 2019 Jul 9;322(2):167-9.
4. JAMA Netw Open. 2019 Jul 3;2(7):e196471.
5. Obstet Gynecol. 2019 May;133(5):952-61.
6. J. Addict Med. 2019 May 10. doi: 10.1097/ADM.0000000000000543.
7. Biol Psychiatry. 2016 Apr 1;79(7):613-9.
Experts address barriers to genetic screening
WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.
“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.
Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.
Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.
The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.
By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.
Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.
Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.
The presenters had no financial conflicts to disclose.
WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.
“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.
Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.
Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.
The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.
By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.
Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.
Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.
The presenters had no financial conflicts to disclose.
WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.
“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.
Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.
Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.
The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.
By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.
Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.
Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.
The presenters had no financial conflicts to disclose.
EXPERT ANALYSIS FROM NORD 2019
Click for Credit: Long-term antibiotics & stroke, CHD; Postvaccination seizures; more
Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Poor response to statins hikes risk of cardiovascular events
To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020
2. Postvaccination febrile seizures are no more severe than other febrile seizures
To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020
3. Hydroxychloroquine adherence in SLE: worse than you thought
To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020
4. Long-term antibiotic use may heighten stroke, CHD risk
To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020
5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large
To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020
Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Poor response to statins hikes risk of cardiovascular events
To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020
2. Postvaccination febrile seizures are no more severe than other febrile seizures
To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020
3. Hydroxychloroquine adherence in SLE: worse than you thought
To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020
4. Long-term antibiotic use may heighten stroke, CHD risk
To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020
5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large
To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020
Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Poor response to statins hikes risk of cardiovascular events
To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020
2. Postvaccination febrile seizures are no more severe than other febrile seizures
To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020
3. Hydroxychloroquine adherence in SLE: worse than you thought
To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020
4. Long-term antibiotic use may heighten stroke, CHD risk
To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020
5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large
To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020
Disparity in endometrial cancer outcomes: What can we do?
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. Gynecol Oncol. 2016 Oct;143(1):98-104.
2. Am J Obstet Gynecol. 2018 Dec;219(6):593.e1-14.
3. J Clin Oncol. 2012 Jun 1;30(16):1980-8.
4. Obstet Gynecol. 2016 Sep;128(3):526-34.
5. Am J Obstet Gynecol. 2018 Nov;219(5):459.e1-11.
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. Gynecol Oncol. 2016 Oct;143(1):98-104.
2. Am J Obstet Gynecol. 2018 Dec;219(6):593.e1-14.
3. J Clin Oncol. 2012 Jun 1;30(16):1980-8.
4. Obstet Gynecol. 2016 Sep;128(3):526-34.
5. Am J Obstet Gynecol. 2018 Nov;219(5):459.e1-11.
While the incidence of most cancers is falling, endometrial cancer rates continue to rise, in large part because of increasing life expectancy and obesity rates. However, what is even more alarming is the observation that there is a clear disparity in outcomes between black and white women with this disease. But there are things that all health care providers, including nononcologists, can do to help to overcome this disparity.
Black women are nearly twice as likely as non-Hispanic white women to die from the endometrial cancer. The 5-year survival for stage III and IV cancer is 43% for non-Hispanic white women, yet only 25% for black women.1 For a long time, this survival disparity was assumed to be a function of the more aggressive cancer histologies, such as serous, which are more commonly seen in black women. These high-grade cancers are more likely to present in advanced stages and with poorer responses to treatments; however, the predisposition to aggressive cancers tells only part of the story of racial disparities in endometrial cancer and their presentation at later stages. Indeed, fueling the problem are the findings that black women report symptoms less, experience more delays in diagnosis or more frequent deviations from guideline-directed diagnostics, undergo more morbid surgical approaches, receive less surgical staging, are enrolled less in clinical trials, have lower socioeconomic status and lower rates of health insurance, and receive less differential administration of adjuvant therapies, as well as have a background of higher all-cause mortality and comorbidities. While this array of contributing factors may seem overwhelming, it also can be considered a guide for health care providers because most of these factors, unlike histologic cell type, are modifiable, and it is important that we all consider what role we can play in dismantling them.
Black women are less likely to receive guideline-recommended care upon presentation. Research by Kemi M. Doll, MD, from the University of Washington, Seattle, demonstrated that, among women with endometrial cancers, black women were less likely to have documented histories of postmenopausal bleeding within 2 years of the diagnosis, presumably because of factors related to underreporting and inadequate ascertainment by medical professionals of whether or not they had experienced postmenopausal bleeding.2 Additionally, when postmenopausal bleeding was reported by these women, they were less likely to receive the appropriate diagnostic work-up as described by American College of Obstetricians and Gynecologists guidelines, and their bleeding was more likely to be ascribed to nonmalignant pathologies. Her work raises the important question about how black women view the health care profession and their willingness to engage early in good faith that their concerns will be met. These concerns are understandable given the documented different responsiveness of providers to black patients’ symptoms such as pain.3
both of which are considered the standard of care.1,4 Lower rates of minimally invasive surgery expose black women to increased morbidity and are deleterious to quality of life, return to work, and functionality. If surgical staging is omitted, which is more common for these women, clinicians are less able to appropriately prescribe adjuvant therapies which might prevent lethal recurrences from unrecognized advanced cancer or they may overtreat early-stage cancers with adjuvant therapy to make up for gaps in staging information.1,5 However, adjuvant therapy is not a benign intervention, and itself is associated with morbidity.
As mentioned earlier, black women are at a higher risk for developing more aggressive cancer subtypes, and this phenomenon may appear unmodifiable. However, important research is looking at the concept of epigenetics and how modifiable environmental factors may contribute to the development of more aggressive types of cancer through gene expression. Additionally, differences in the gene mutations and gene expression of cancers more frequently acquired by black women may negatively influence how these cancers respond to conventional therapies. In the GOG210 study, which evaluated the outcomes of women with comprehensively staged endometrial cancer, black women demonstrated worse survival from cancer, even though they were more likely to receive chemotherapy.5 One explanation for this finding is that these women’s cancers were less responsive to conventional chemotherapy agents.
This raises a critical issue of disparity in clinical trial inclusion. Black women are underrepresented in clinical trials in the United States. There is a dark history in medical research and minority populations, particularly African American populations, which continues to be remembered and felt. However, not all of this underrepresentation may be from unwillingness to participate: For black women, issues of lack of access to or being considered for clinical trials is also a factor. But without adequate representation in trials of novel agents, we will not know whether they are effective for all populations, and indeed it would appear that we should not assume they are equally effective based on the results to date.
So how can we all individually help to overcome these disparities in endometrial cancer outcomes? To begin with, it is important to acknowledge that black women commonly report negative experiences with reproductive health care. From early in their lives, we must sensitively engage all of our patients and ensure they all feel heard and valued. They should know that their symptoms, including pain or bleeding, are taken and treated seriously. If we can do better with this throughout a woman’s earlier reproductive health care experiences, perhaps later in her life, when she experiences postmenopausal bleeding, she will feel comfortable raising this issue with her health care provider who in turn must take this symptom seriously and expeditiously engage all of the appropriate diagnostic resources. Health care delivery is about more than simply offering the best treatment. We also are responsible for education and shared decision making to ensure that we can deliver the best treatment.
We also can support organizations such as ECANA (Endometrial Cancer Action Network for African Americans) which serves to inform black women in their communities about the threat that endometrial cancer plays and empowers them through education about its symptoms and the need to seek care.
Systematically we must ensure black women have access to the same standards in surgical and nonsurgical management of these cancers. This includes referral of all women with cancer, including minorities, to high-volume centers with oncology specialists and explaining to those who may be reluctant to travel that this is associated with improved outcomes in the short and long term. We also must actively consider our black patients for clinical trials, sensitively educate them about their benefits, and overcome barriers to access. One simple way to do this is to explain that the treatments that we have developed for endometrial cancer have mostly been tested on white women, which may explain in part why they do not work so well for nonwhite women.
The racial disparity in endometrial cancer outcomes cannot entirely be attributed to the passive phenomenon of patient and tumor genetics, particularly with consideration that race is a social construct rather than a biological phenomenon. We can all make a difference through advocacy, access, education, and heightened awareness to combat this inequity and overcome these disparate outcomes.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. Gynecol Oncol. 2016 Oct;143(1):98-104.
2. Am J Obstet Gynecol. 2018 Dec;219(6):593.e1-14.
3. J Clin Oncol. 2012 Jun 1;30(16):1980-8.
4. Obstet Gynecol. 2016 Sep;128(3):526-34.
5. Am J Obstet Gynecol. 2018 Nov;219(5):459.e1-11.