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Click for Credit: Alcohol use while breastfeeding; cigarette smoking in HCV; more
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
USPSTF releases its first perinatal depression draft recommendations
It has given this draft recommendation a B grade, which means that there is moderate certainty of at least moderate net benefit. This is the first time the USPSTF has reviewed this topic.
It’s estimated that one in seven women are affected by perinatal depression, which can have negative effects on both the mothers affected and their children. In its review of evidence, the USPSTF found convincing evidence that counseling, particularly cognitive-behavioral and interpersonal therapies, can prevent perinatal depression.
The draft recommendation affects women who are pregnant or 1 year post partum; specifically, these women will not have a current diagnosis of depression but are at increased risk for it nonetheless. At this time, there is no accurate screening tool available to determine whether women have perinatal depression or are at increased risk. However, certain risk factors have been associated with it, including current stressful life events, personal or family history of depression, history of physical or sexual abuse, pregestational or gestational diabetes, complications during pregnancy such as hyperemesis or premature contractions, adolescent pregnancy, lack of social or financial support, and low socioeconomic status.
The USPSTF reviewed 50 trials considered to be of good or fair quality, with a mean participant age of 29 years; 26 included pregnant women, 22 included women post partum, and 2 included both. Counseling interventions were the most widely studied and “reduced the likelihood of the onset of perinatal depression by 39%” for a pooled risk ratio of 0.61 (95% confidence interval, 0.47-0.78), compared with control conditions. Two kinds of therapies stood out as especially effective: cognitive-behavioral and interpersonal. Cognitive-behavioral therapy focuses on negative thoughts, moods, behaviors, and attitudes and seeks to increase positive events and activities. Interpersonal therapy focuses on how interpersonal interactions and patterns can contribute to the development and maintenance of psychological issues and distress.
The comment period for these draft recommendations will continue through Sept. 24 at www.uspreventiveservicestaskforce.org/tfcomment.htm.
This article was updated 8/28/18.
It has given this draft recommendation a B grade, which means that there is moderate certainty of at least moderate net benefit. This is the first time the USPSTF has reviewed this topic.
It’s estimated that one in seven women are affected by perinatal depression, which can have negative effects on both the mothers affected and their children. In its review of evidence, the USPSTF found convincing evidence that counseling, particularly cognitive-behavioral and interpersonal therapies, can prevent perinatal depression.
The draft recommendation affects women who are pregnant or 1 year post partum; specifically, these women will not have a current diagnosis of depression but are at increased risk for it nonetheless. At this time, there is no accurate screening tool available to determine whether women have perinatal depression or are at increased risk. However, certain risk factors have been associated with it, including current stressful life events, personal or family history of depression, history of physical or sexual abuse, pregestational or gestational diabetes, complications during pregnancy such as hyperemesis or premature contractions, adolescent pregnancy, lack of social or financial support, and low socioeconomic status.
The USPSTF reviewed 50 trials considered to be of good or fair quality, with a mean participant age of 29 years; 26 included pregnant women, 22 included women post partum, and 2 included both. Counseling interventions were the most widely studied and “reduced the likelihood of the onset of perinatal depression by 39%” for a pooled risk ratio of 0.61 (95% confidence interval, 0.47-0.78), compared with control conditions. Two kinds of therapies stood out as especially effective: cognitive-behavioral and interpersonal. Cognitive-behavioral therapy focuses on negative thoughts, moods, behaviors, and attitudes and seeks to increase positive events and activities. Interpersonal therapy focuses on how interpersonal interactions and patterns can contribute to the development and maintenance of psychological issues and distress.
The comment period for these draft recommendations will continue through Sept. 24 at www.uspreventiveservicestaskforce.org/tfcomment.htm.
This article was updated 8/28/18.
It has given this draft recommendation a B grade, which means that there is moderate certainty of at least moderate net benefit. This is the first time the USPSTF has reviewed this topic.
It’s estimated that one in seven women are affected by perinatal depression, which can have negative effects on both the mothers affected and their children. In its review of evidence, the USPSTF found convincing evidence that counseling, particularly cognitive-behavioral and interpersonal therapies, can prevent perinatal depression.
The draft recommendation affects women who are pregnant or 1 year post partum; specifically, these women will not have a current diagnosis of depression but are at increased risk for it nonetheless. At this time, there is no accurate screening tool available to determine whether women have perinatal depression or are at increased risk. However, certain risk factors have been associated with it, including current stressful life events, personal or family history of depression, history of physical or sexual abuse, pregestational or gestational diabetes, complications during pregnancy such as hyperemesis or premature contractions, adolescent pregnancy, lack of social or financial support, and low socioeconomic status.
The USPSTF reviewed 50 trials considered to be of good or fair quality, with a mean participant age of 29 years; 26 included pregnant women, 22 included women post partum, and 2 included both. Counseling interventions were the most widely studied and “reduced the likelihood of the onset of perinatal depression by 39%” for a pooled risk ratio of 0.61 (95% confidence interval, 0.47-0.78), compared with control conditions. Two kinds of therapies stood out as especially effective: cognitive-behavioral and interpersonal. Cognitive-behavioral therapy focuses on negative thoughts, moods, behaviors, and attitudes and seeks to increase positive events and activities. Interpersonal therapy focuses on how interpersonal interactions and patterns can contribute to the development and maintenance of psychological issues and distress.
The comment period for these draft recommendations will continue through Sept. 24 at www.uspreventiveservicestaskforce.org/tfcomment.htm.
This article was updated 8/28/18.
RA, JIA may raise risk of preterm delivery
according to a study examining autoimmune disease in pregnancy. Corticosteroid use in any trimester increased that risk from 100%-400%, regardless of how active the arthritis was.
The study found that women with RA had more than double the risk for preterm delivery, compared with a cohort without autoimmune disease (relative risk, 2.09; 95% confidence interval, 1.50-2.91). For women with juvenile idiopathic arthritis (JIA), the relative risk was 1.81 for preterm delivery (95% CI, 1.14-2.89).
The prospective cohort study, part of the Organization of Teratology Information Specialists Autoimmune Disease in Pregnancy Project, enrolled 657 women with RA and 170 women with JIA. The study also included a comparison group of 564 women without autoimmune disease. All of those included in the study were enrolled before 19 weeks’ gestation and delivered live-born infants during 2004-2017.
The study adds to a clinically important area of research that has yielded sometimes conflicting results; clarity has also been impeded by a variety of methodologies. Though several analyses have shown higher risk of preterm delivery in women with RA, not all studies have adjusted for medication use and disease activity, Chelsey F. Smith, MD, and her coauthors wrote in Arthritis Care & Research. Further, how women with JIA fare in pregnancy has not been well studied, they said.
Dr. Smith, a rheumatologist at the University of California, San Diego, and her colleagues included many baseline covariates in their analysis of pregnancy outcomes; these included maternal age and race, socioeconomic status, body mass index, previous adverse pregnancy outcomes, and comorbidities, including autoimmune disease. Adverse pregnancy outcomes during the studied pregnancy were also included as covariates, and deliveries were considered preterm if labor began before 37 weeks’ gestation.
For women with RA, a higher active disease score at any point during pregnancy was associated with a significantly higher risk of preterm delivery, even after adjustment for other potential risk factors, including first-trimester corticosteroid use (adjusted risk ratio, 1.52; 95% CI, 1.06-2.18). The persistence of this association, wrote Dr. Smith and her colleagues, implies “that active disease in RA may contribute to [preterm delivery] independent of medications,” perhaps through the action of proinflammatory cytokines that may stimulate prostaglandins and provoke uterine contractions.
The researchers found, though, that this association between disease activity and risk for preterm birth did not hold true for women with JIA, leaving part of the mystery unsolved.
However, women with both RA and JIA who used corticosteroids in any trimester were more likely to have a preterm delivery, as were women with JIA who used NSAIDs in the first trimester of pregnancy. The use of disease-modifying antirheumatic drugs (DMARDs) and biologics in any trimester did not confer increased risk for preterm delivery in women with either disease state.
There were other differences between the groups: Women with JIA were overall younger, but had more prepregnancy hypertension, which “may have contributed to the elevated incidence of preeclampsia seen in this group,” the investigators wrote. Fever was more common in women with JIA, and had an independent association with preterm delivery, as did first trimester NSAID use in this group alone.
Dr. Smith and her colleagues hypothesized that the relative heterogeneity of the JIA group may mean that disease activity still influenced outcomes.
Among other comorbidities, gestational diabetes (GDM) was more common in the RA group than in the JIA group or the comparison cohort, and was associated with a significantly higher risk for preterm delivery in women with RA, even after accounting for preeclampsia and hypertension in a multivariate analysis.
Dr. Smith and her colleagues pointed out that it was difficult to account for physician behavior in managing pregnancy in these high-risk women. “Additionally, given that women with both RA and GDM are at a particularly high risk for perinatal complications, we can speculate that the obstetricians in this group were perhaps more aggressive about inducing at an earlier gestational age than in other groups, but this information was not available in the dataset.”
Through phone interviews, investigators obtained information about prescription and nonprescription medication use during pregnancy; women were also asked about use of other substances and occupational exposures, infections, and prenatal testing and other medical procedures. Another telephone interview conducted soon after delivery asked about birth outcomes. Abstracted medical record data were used to verify and supplement the interview information.
When looking at treatments used, Dr. Smith and her colleagues grouped autoimmune disease medications into DMARDs, non-DMARD biologic medications, corticosteroids, and NSAIDs.
Disease activity assessment, conducted at intake and at 32 weeks’ gestation, used the Health Assessment Questionnaire, pain scores, and patient global disease activity to calculate a Patient Activity Scale score ranging from 0 to 10. Patients with a score over 3.7 were classified as having high disease activity.
Dr. Smith and her colleagues said that the study’s strengths included its prospective design and robust statistical schema. Also, using data about corticosteroid use and disease activity earlier in pregnancy avoided the inclusion of a reverse causation effect, where systemic inflammatory changes associated with preterm delivery might provoke more disease activity and a consequent boost in corticosteroid use.
However, the researchers said, the overall numbers of participants with preterm delivery was relatively small, and the JIA cohort was small as well.
“Further analyses are necessary to look at other categories of arthritis affecting women of childbearing age, racial disparities in these populations, as well as the influence of disease activity in the later stages of pregnancy on other perinatal factors” that can contribute to preterm delivery, said Dr. Smith and her colleagues.
The collaborative research group that collected data for the study receives research funding from several pharmaceutical companies. None of the authors reported any personal conflicts of interest.
SOURCE: Smith CF et al. Arthritis Care Res. 2018 Aug 21. doi: 10.1002/acr.23730.
according to a study examining autoimmune disease in pregnancy. Corticosteroid use in any trimester increased that risk from 100%-400%, regardless of how active the arthritis was.
The study found that women with RA had more than double the risk for preterm delivery, compared with a cohort without autoimmune disease (relative risk, 2.09; 95% confidence interval, 1.50-2.91). For women with juvenile idiopathic arthritis (JIA), the relative risk was 1.81 for preterm delivery (95% CI, 1.14-2.89).
The prospective cohort study, part of the Organization of Teratology Information Specialists Autoimmune Disease in Pregnancy Project, enrolled 657 women with RA and 170 women with JIA. The study also included a comparison group of 564 women without autoimmune disease. All of those included in the study were enrolled before 19 weeks’ gestation and delivered live-born infants during 2004-2017.
The study adds to a clinically important area of research that has yielded sometimes conflicting results; clarity has also been impeded by a variety of methodologies. Though several analyses have shown higher risk of preterm delivery in women with RA, not all studies have adjusted for medication use and disease activity, Chelsey F. Smith, MD, and her coauthors wrote in Arthritis Care & Research. Further, how women with JIA fare in pregnancy has not been well studied, they said.
Dr. Smith, a rheumatologist at the University of California, San Diego, and her colleagues included many baseline covariates in their analysis of pregnancy outcomes; these included maternal age and race, socioeconomic status, body mass index, previous adverse pregnancy outcomes, and comorbidities, including autoimmune disease. Adverse pregnancy outcomes during the studied pregnancy were also included as covariates, and deliveries were considered preterm if labor began before 37 weeks’ gestation.
For women with RA, a higher active disease score at any point during pregnancy was associated with a significantly higher risk of preterm delivery, even after adjustment for other potential risk factors, including first-trimester corticosteroid use (adjusted risk ratio, 1.52; 95% CI, 1.06-2.18). The persistence of this association, wrote Dr. Smith and her colleagues, implies “that active disease in RA may contribute to [preterm delivery] independent of medications,” perhaps through the action of proinflammatory cytokines that may stimulate prostaglandins and provoke uterine contractions.
The researchers found, though, that this association between disease activity and risk for preterm birth did not hold true for women with JIA, leaving part of the mystery unsolved.
However, women with both RA and JIA who used corticosteroids in any trimester were more likely to have a preterm delivery, as were women with JIA who used NSAIDs in the first trimester of pregnancy. The use of disease-modifying antirheumatic drugs (DMARDs) and biologics in any trimester did not confer increased risk for preterm delivery in women with either disease state.
There were other differences between the groups: Women with JIA were overall younger, but had more prepregnancy hypertension, which “may have contributed to the elevated incidence of preeclampsia seen in this group,” the investigators wrote. Fever was more common in women with JIA, and had an independent association with preterm delivery, as did first trimester NSAID use in this group alone.
Dr. Smith and her colleagues hypothesized that the relative heterogeneity of the JIA group may mean that disease activity still influenced outcomes.
Among other comorbidities, gestational diabetes (GDM) was more common in the RA group than in the JIA group or the comparison cohort, and was associated with a significantly higher risk for preterm delivery in women with RA, even after accounting for preeclampsia and hypertension in a multivariate analysis.
Dr. Smith and her colleagues pointed out that it was difficult to account for physician behavior in managing pregnancy in these high-risk women. “Additionally, given that women with both RA and GDM are at a particularly high risk for perinatal complications, we can speculate that the obstetricians in this group were perhaps more aggressive about inducing at an earlier gestational age than in other groups, but this information was not available in the dataset.”
Through phone interviews, investigators obtained information about prescription and nonprescription medication use during pregnancy; women were also asked about use of other substances and occupational exposures, infections, and prenatal testing and other medical procedures. Another telephone interview conducted soon after delivery asked about birth outcomes. Abstracted medical record data were used to verify and supplement the interview information.
When looking at treatments used, Dr. Smith and her colleagues grouped autoimmune disease medications into DMARDs, non-DMARD biologic medications, corticosteroids, and NSAIDs.
Disease activity assessment, conducted at intake and at 32 weeks’ gestation, used the Health Assessment Questionnaire, pain scores, and patient global disease activity to calculate a Patient Activity Scale score ranging from 0 to 10. Patients with a score over 3.7 were classified as having high disease activity.
Dr. Smith and her colleagues said that the study’s strengths included its prospective design and robust statistical schema. Also, using data about corticosteroid use and disease activity earlier in pregnancy avoided the inclusion of a reverse causation effect, where systemic inflammatory changes associated with preterm delivery might provoke more disease activity and a consequent boost in corticosteroid use.
However, the researchers said, the overall numbers of participants with preterm delivery was relatively small, and the JIA cohort was small as well.
“Further analyses are necessary to look at other categories of arthritis affecting women of childbearing age, racial disparities in these populations, as well as the influence of disease activity in the later stages of pregnancy on other perinatal factors” that can contribute to preterm delivery, said Dr. Smith and her colleagues.
The collaborative research group that collected data for the study receives research funding from several pharmaceutical companies. None of the authors reported any personal conflicts of interest.
SOURCE: Smith CF et al. Arthritis Care Res. 2018 Aug 21. doi: 10.1002/acr.23730.
according to a study examining autoimmune disease in pregnancy. Corticosteroid use in any trimester increased that risk from 100%-400%, regardless of how active the arthritis was.
The study found that women with RA had more than double the risk for preterm delivery, compared with a cohort without autoimmune disease (relative risk, 2.09; 95% confidence interval, 1.50-2.91). For women with juvenile idiopathic arthritis (JIA), the relative risk was 1.81 for preterm delivery (95% CI, 1.14-2.89).
The prospective cohort study, part of the Organization of Teratology Information Specialists Autoimmune Disease in Pregnancy Project, enrolled 657 women with RA and 170 women with JIA. The study also included a comparison group of 564 women without autoimmune disease. All of those included in the study were enrolled before 19 weeks’ gestation and delivered live-born infants during 2004-2017.
The study adds to a clinically important area of research that has yielded sometimes conflicting results; clarity has also been impeded by a variety of methodologies. Though several analyses have shown higher risk of preterm delivery in women with RA, not all studies have adjusted for medication use and disease activity, Chelsey F. Smith, MD, and her coauthors wrote in Arthritis Care & Research. Further, how women with JIA fare in pregnancy has not been well studied, they said.
Dr. Smith, a rheumatologist at the University of California, San Diego, and her colleagues included many baseline covariates in their analysis of pregnancy outcomes; these included maternal age and race, socioeconomic status, body mass index, previous adverse pregnancy outcomes, and comorbidities, including autoimmune disease. Adverse pregnancy outcomes during the studied pregnancy were also included as covariates, and deliveries were considered preterm if labor began before 37 weeks’ gestation.
For women with RA, a higher active disease score at any point during pregnancy was associated with a significantly higher risk of preterm delivery, even after adjustment for other potential risk factors, including first-trimester corticosteroid use (adjusted risk ratio, 1.52; 95% CI, 1.06-2.18). The persistence of this association, wrote Dr. Smith and her colleagues, implies “that active disease in RA may contribute to [preterm delivery] independent of medications,” perhaps through the action of proinflammatory cytokines that may stimulate prostaglandins and provoke uterine contractions.
The researchers found, though, that this association between disease activity and risk for preterm birth did not hold true for women with JIA, leaving part of the mystery unsolved.
However, women with both RA and JIA who used corticosteroids in any trimester were more likely to have a preterm delivery, as were women with JIA who used NSAIDs in the first trimester of pregnancy. The use of disease-modifying antirheumatic drugs (DMARDs) and biologics in any trimester did not confer increased risk for preterm delivery in women with either disease state.
There were other differences between the groups: Women with JIA were overall younger, but had more prepregnancy hypertension, which “may have contributed to the elevated incidence of preeclampsia seen in this group,” the investigators wrote. Fever was more common in women with JIA, and had an independent association with preterm delivery, as did first trimester NSAID use in this group alone.
Dr. Smith and her colleagues hypothesized that the relative heterogeneity of the JIA group may mean that disease activity still influenced outcomes.
Among other comorbidities, gestational diabetes (GDM) was more common in the RA group than in the JIA group or the comparison cohort, and was associated with a significantly higher risk for preterm delivery in women with RA, even after accounting for preeclampsia and hypertension in a multivariate analysis.
Dr. Smith and her colleagues pointed out that it was difficult to account for physician behavior in managing pregnancy in these high-risk women. “Additionally, given that women with both RA and GDM are at a particularly high risk for perinatal complications, we can speculate that the obstetricians in this group were perhaps more aggressive about inducing at an earlier gestational age than in other groups, but this information was not available in the dataset.”
Through phone interviews, investigators obtained information about prescription and nonprescription medication use during pregnancy; women were also asked about use of other substances and occupational exposures, infections, and prenatal testing and other medical procedures. Another telephone interview conducted soon after delivery asked about birth outcomes. Abstracted medical record data were used to verify and supplement the interview information.
When looking at treatments used, Dr. Smith and her colleagues grouped autoimmune disease medications into DMARDs, non-DMARD biologic medications, corticosteroids, and NSAIDs.
Disease activity assessment, conducted at intake and at 32 weeks’ gestation, used the Health Assessment Questionnaire, pain scores, and patient global disease activity to calculate a Patient Activity Scale score ranging from 0 to 10. Patients with a score over 3.7 were classified as having high disease activity.
Dr. Smith and her colleagues said that the study’s strengths included its prospective design and robust statistical schema. Also, using data about corticosteroid use and disease activity earlier in pregnancy avoided the inclusion of a reverse causation effect, where systemic inflammatory changes associated with preterm delivery might provoke more disease activity and a consequent boost in corticosteroid use.
However, the researchers said, the overall numbers of participants with preterm delivery was relatively small, and the JIA cohort was small as well.
“Further analyses are necessary to look at other categories of arthritis affecting women of childbearing age, racial disparities in these populations, as well as the influence of disease activity in the later stages of pregnancy on other perinatal factors” that can contribute to preterm delivery, said Dr. Smith and her colleagues.
The collaborative research group that collected data for the study receives research funding from several pharmaceutical companies. None of the authors reported any personal conflicts of interest.
SOURCE: Smith CF et al. Arthritis Care Res. 2018 Aug 21. doi: 10.1002/acr.23730.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point: The risk of preterm delivery was increased in women with RA and juvenile idiopathic arthritis.
Major finding: The risk ratio for preterm delivery in women with RA was 2.09.
Study details: A prospective cohort study of 657 women with RA, 170 women with juvenile idiopathic arthritis, and 564 women without autoimmune disease.
Disclosures: The study was part of the Organization of Teratology Information Specialists Autoimmune Disease in Pregnancy Project, which receives research funding from several pharmaceutical companies. None of the authors reported any personal conflicts of interest.
Source: Smith CF et al. Arthritis Care Res. 2018 Aug 21. doi: 10.1002/acr.23730.
AAP cautions against marijuana use during pregnancy, breastfeeding
, according to a recent clinical report published in the journal Pediatrics.
“The fact that marijuana is legal in many states may give the impression the drug is harmless during pregnancy, especially with stories swirling on social media about using it for nausea with morning sickness,” Sheryl A. Ryan, MD, FAAP, Chair of the American Academy of Pediatrics (AAP) Committee on Substance Use and Prevention, stated in a press release. “But in fact, this is still a big question. We do not have good safety data on prenatal exposure to marijuana. Based on the limited data that do exist, as pediatricians, we believe there is cause to be concerned about how the drug will impact the long-term development of children.”
The rate of marijuana use is increasing among pregnant women 18 years to 44 years old is increasing, the committee said, with 3.84% of women in 2014 within that age range using marijuana within the past month compared with 2.37% in 2002. Among women who were between 18 years and 25 years old, the rate of marijuana use within the past month was 7.47% in 2014.
The committee also noted research has shown cannabidiol exposure in the short term may impact placental permeability to “pharmacologic agents and recreational substances, potentially placing the fetus at risk from these agents or drugs.” A more well-known substance in marijuana, delta-9-tetrahydrocannabinol (THC) crosses the placental barrier and can appear in fetal blood. Studies have reported any level of marijuana use among pregnant women put the mothers at risk of anemia, while their newborns had an increased risk of low-birth weight and neonatal intensive care unit (NICU) use. Further research has shown impaired mental development, executive function deficits, increased impulsivity and hyperactivity, behavioral problems, depressive symptoms, and greater rates of substance abuse among children exposed to marijuana.
“Many of these effects may not show up right away, but they can impact how well a child can maneuver in the world,” Dr. Ryan stated in the release. “Children’s and teens’ cognitive ability to manage their time and school work might be harmed down the line from marijuana use during their mother’s pregnancy.”
In a related study, Kerri A. Bertrand, MPH, from the department of pediatrics at the University of California in San Diego, Calif., and her colleagues studied cannabinoid concentrations in breastmilk donated to a human milk biorepository. The investigators analyzed 54 samples donated by 50 women who used marijuana while breastfeeding between 2014 and 2017 and determined whether substances such as delta-9-THC, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), cannabidiol, and cannabinol were present in breastmilk by performing liquid chromatography mass spectrometry electrospray ionization on the samples.
They found 34 of 54 samples (64%) had detectable delta-9-THC approximately 6 days after marijuana use (median concentration, 9.47 ng/mL; range, 1.01-323 ng/mL), while 5 of 54 samples (9%) had measurable concentrations of 11-OH-THC (range, 1.33-12.80 ng/mL) and 5 of 54 samples (9%) contained measurable cannabidiol (range, 1.32-8.56 ng/mL). Predictors of log delta-9-THC concentrations included number of hours since last use (-0.03; 95% confidence interval, -0.04 to -0.01; P equals .005), the number of times per day marijuana was used (0.51; 95% CI, 0.03-0.99; P equals .039), and the amount of time between sample donation and analysis (0.08; 95% CI, 0.00-0.15; P equals .038), researchers said.
“Because marijuana is the most commonly used recreational drug among breastfeeding women, information regarding risks to breastfeeding infants is urgently needed,” Dr. Bertrand and colleagues wrote in their study.
The authors of the AAP clinical report acknowledge no relevant conflicts of interest. The study by Bertrand and colleagues was supported by the University of California San Diego Center for Better Beginnings, a grant from the National Institutes of Health, and the Gerber Foundation.
SOURCE: Bertrand KA et al. Pediatrics. 2018 Aug 27;doi:10.1542/peds.2018-1076.
The study by Bertrand and colleagues should be commended for being among the first to analyze cannabinoids in breast milk, but there are still very important questions to be answered about marijuana use among women who breast-feed, Sheryl A. Ryan, MD, FAAP, wrote in a related editorial.
Questions remain about why one-third of participants in the study had no detectable cannabinoids in their breast milk, and a frame of reference is needed for the levels that did appear in the study, Dr. Ryan said. Data are also needed on how the cannabinoids “accumulate in the infant, how the infant metabolizes these substances, how quickly they are excreted, whether they accumulate, and thus how long these metabolites remain in the infant,” she said.
Dr. Ryan also questioned what to tell mothers who use marijuana but want to breastfeed their newborns, and noted guidelines from the AAP and the American College of Obstetricians currently recommend avoiding marijuana use entirely while breastfeeding.
“With their study, Bertrand et al. have provided additional and valuable support for those current recommendations. But the picture is incomplete without our understanding of what is happening at the level of those infants exposed to cannabinoid–containing breast milk,” Dr. Ryan said. “Hopefully, the calls for research to answer these important questions will not go unheeded.”
Dr. Ryan is from the Division of Adolescent Medicine and Department of Pediatrics at Penn State Health Children’s Hospital in Hershey, Penn. These comments summarize her editorial in response to Bertrand and colleagues. She reports no relevant conflicts of interest (Ryan SA. Pediatrics. 2018;142[3]:e20181921).
The study by Bertrand and colleagues should be commended for being among the first to analyze cannabinoids in breast milk, but there are still very important questions to be answered about marijuana use among women who breast-feed, Sheryl A. Ryan, MD, FAAP, wrote in a related editorial.
Questions remain about why one-third of participants in the study had no detectable cannabinoids in their breast milk, and a frame of reference is needed for the levels that did appear in the study, Dr. Ryan said. Data are also needed on how the cannabinoids “accumulate in the infant, how the infant metabolizes these substances, how quickly they are excreted, whether they accumulate, and thus how long these metabolites remain in the infant,” she said.
Dr. Ryan also questioned what to tell mothers who use marijuana but want to breastfeed their newborns, and noted guidelines from the AAP and the American College of Obstetricians currently recommend avoiding marijuana use entirely while breastfeeding.
“With their study, Bertrand et al. have provided additional and valuable support for those current recommendations. But the picture is incomplete without our understanding of what is happening at the level of those infants exposed to cannabinoid–containing breast milk,” Dr. Ryan said. “Hopefully, the calls for research to answer these important questions will not go unheeded.”
Dr. Ryan is from the Division of Adolescent Medicine and Department of Pediatrics at Penn State Health Children’s Hospital in Hershey, Penn. These comments summarize her editorial in response to Bertrand and colleagues. She reports no relevant conflicts of interest (Ryan SA. Pediatrics. 2018;142[3]:e20181921).
The study by Bertrand and colleagues should be commended for being among the first to analyze cannabinoids in breast milk, but there are still very important questions to be answered about marijuana use among women who breast-feed, Sheryl A. Ryan, MD, FAAP, wrote in a related editorial.
Questions remain about why one-third of participants in the study had no detectable cannabinoids in their breast milk, and a frame of reference is needed for the levels that did appear in the study, Dr. Ryan said. Data are also needed on how the cannabinoids “accumulate in the infant, how the infant metabolizes these substances, how quickly they are excreted, whether they accumulate, and thus how long these metabolites remain in the infant,” she said.
Dr. Ryan also questioned what to tell mothers who use marijuana but want to breastfeed their newborns, and noted guidelines from the AAP and the American College of Obstetricians currently recommend avoiding marijuana use entirely while breastfeeding.
“With their study, Bertrand et al. have provided additional and valuable support for those current recommendations. But the picture is incomplete without our understanding of what is happening at the level of those infants exposed to cannabinoid–containing breast milk,” Dr. Ryan said. “Hopefully, the calls for research to answer these important questions will not go unheeded.”
Dr. Ryan is from the Division of Adolescent Medicine and Department of Pediatrics at Penn State Health Children’s Hospital in Hershey, Penn. These comments summarize her editorial in response to Bertrand and colleagues. She reports no relevant conflicts of interest (Ryan SA. Pediatrics. 2018;142[3]:e20181921).
, according to a recent clinical report published in the journal Pediatrics.
“The fact that marijuana is legal in many states may give the impression the drug is harmless during pregnancy, especially with stories swirling on social media about using it for nausea with morning sickness,” Sheryl A. Ryan, MD, FAAP, Chair of the American Academy of Pediatrics (AAP) Committee on Substance Use and Prevention, stated in a press release. “But in fact, this is still a big question. We do not have good safety data on prenatal exposure to marijuana. Based on the limited data that do exist, as pediatricians, we believe there is cause to be concerned about how the drug will impact the long-term development of children.”
The rate of marijuana use is increasing among pregnant women 18 years to 44 years old is increasing, the committee said, with 3.84% of women in 2014 within that age range using marijuana within the past month compared with 2.37% in 2002. Among women who were between 18 years and 25 years old, the rate of marijuana use within the past month was 7.47% in 2014.
The committee also noted research has shown cannabidiol exposure in the short term may impact placental permeability to “pharmacologic agents and recreational substances, potentially placing the fetus at risk from these agents or drugs.” A more well-known substance in marijuana, delta-9-tetrahydrocannabinol (THC) crosses the placental barrier and can appear in fetal blood. Studies have reported any level of marijuana use among pregnant women put the mothers at risk of anemia, while their newborns had an increased risk of low-birth weight and neonatal intensive care unit (NICU) use. Further research has shown impaired mental development, executive function deficits, increased impulsivity and hyperactivity, behavioral problems, depressive symptoms, and greater rates of substance abuse among children exposed to marijuana.
“Many of these effects may not show up right away, but they can impact how well a child can maneuver in the world,” Dr. Ryan stated in the release. “Children’s and teens’ cognitive ability to manage their time and school work might be harmed down the line from marijuana use during their mother’s pregnancy.”
In a related study, Kerri A. Bertrand, MPH, from the department of pediatrics at the University of California in San Diego, Calif., and her colleagues studied cannabinoid concentrations in breastmilk donated to a human milk biorepository. The investigators analyzed 54 samples donated by 50 women who used marijuana while breastfeeding between 2014 and 2017 and determined whether substances such as delta-9-THC, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), cannabidiol, and cannabinol were present in breastmilk by performing liquid chromatography mass spectrometry electrospray ionization on the samples.
They found 34 of 54 samples (64%) had detectable delta-9-THC approximately 6 days after marijuana use (median concentration, 9.47 ng/mL; range, 1.01-323 ng/mL), while 5 of 54 samples (9%) had measurable concentrations of 11-OH-THC (range, 1.33-12.80 ng/mL) and 5 of 54 samples (9%) contained measurable cannabidiol (range, 1.32-8.56 ng/mL). Predictors of log delta-9-THC concentrations included number of hours since last use (-0.03; 95% confidence interval, -0.04 to -0.01; P equals .005), the number of times per day marijuana was used (0.51; 95% CI, 0.03-0.99; P equals .039), and the amount of time between sample donation and analysis (0.08; 95% CI, 0.00-0.15; P equals .038), researchers said.
“Because marijuana is the most commonly used recreational drug among breastfeeding women, information regarding risks to breastfeeding infants is urgently needed,” Dr. Bertrand and colleagues wrote in their study.
The authors of the AAP clinical report acknowledge no relevant conflicts of interest. The study by Bertrand and colleagues was supported by the University of California San Diego Center for Better Beginnings, a grant from the National Institutes of Health, and the Gerber Foundation.
SOURCE: Bertrand KA et al. Pediatrics. 2018 Aug 27;doi:10.1542/peds.2018-1076.
, according to a recent clinical report published in the journal Pediatrics.
“The fact that marijuana is legal in many states may give the impression the drug is harmless during pregnancy, especially with stories swirling on social media about using it for nausea with morning sickness,” Sheryl A. Ryan, MD, FAAP, Chair of the American Academy of Pediatrics (AAP) Committee on Substance Use and Prevention, stated in a press release. “But in fact, this is still a big question. We do not have good safety data on prenatal exposure to marijuana. Based on the limited data that do exist, as pediatricians, we believe there is cause to be concerned about how the drug will impact the long-term development of children.”
The rate of marijuana use is increasing among pregnant women 18 years to 44 years old is increasing, the committee said, with 3.84% of women in 2014 within that age range using marijuana within the past month compared with 2.37% in 2002. Among women who were between 18 years and 25 years old, the rate of marijuana use within the past month was 7.47% in 2014.
The committee also noted research has shown cannabidiol exposure in the short term may impact placental permeability to “pharmacologic agents and recreational substances, potentially placing the fetus at risk from these agents or drugs.” A more well-known substance in marijuana, delta-9-tetrahydrocannabinol (THC) crosses the placental barrier and can appear in fetal blood. Studies have reported any level of marijuana use among pregnant women put the mothers at risk of anemia, while their newborns had an increased risk of low-birth weight and neonatal intensive care unit (NICU) use. Further research has shown impaired mental development, executive function deficits, increased impulsivity and hyperactivity, behavioral problems, depressive symptoms, and greater rates of substance abuse among children exposed to marijuana.
“Many of these effects may not show up right away, but they can impact how well a child can maneuver in the world,” Dr. Ryan stated in the release. “Children’s and teens’ cognitive ability to manage their time and school work might be harmed down the line from marijuana use during their mother’s pregnancy.”
In a related study, Kerri A. Bertrand, MPH, from the department of pediatrics at the University of California in San Diego, Calif., and her colleagues studied cannabinoid concentrations in breastmilk donated to a human milk biorepository. The investigators analyzed 54 samples donated by 50 women who used marijuana while breastfeeding between 2014 and 2017 and determined whether substances such as delta-9-THC, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), cannabidiol, and cannabinol were present in breastmilk by performing liquid chromatography mass spectrometry electrospray ionization on the samples.
They found 34 of 54 samples (64%) had detectable delta-9-THC approximately 6 days after marijuana use (median concentration, 9.47 ng/mL; range, 1.01-323 ng/mL), while 5 of 54 samples (9%) had measurable concentrations of 11-OH-THC (range, 1.33-12.80 ng/mL) and 5 of 54 samples (9%) contained measurable cannabidiol (range, 1.32-8.56 ng/mL). Predictors of log delta-9-THC concentrations included number of hours since last use (-0.03; 95% confidence interval, -0.04 to -0.01; P equals .005), the number of times per day marijuana was used (0.51; 95% CI, 0.03-0.99; P equals .039), and the amount of time between sample donation and analysis (0.08; 95% CI, 0.00-0.15; P equals .038), researchers said.
“Because marijuana is the most commonly used recreational drug among breastfeeding women, information regarding risks to breastfeeding infants is urgently needed,” Dr. Bertrand and colleagues wrote in their study.
The authors of the AAP clinical report acknowledge no relevant conflicts of interest. The study by Bertrand and colleagues was supported by the University of California San Diego Center for Better Beginnings, a grant from the National Institutes of Health, and the Gerber Foundation.
SOURCE: Bertrand KA et al. Pediatrics. 2018 Aug 27;doi:10.1542/peds.2018-1076.
PEDIATRICS
Key clinical point: More studies are needed to analyze the long-term effects marijuana has on mother and child during pregnancy and while breastfeeding.
Major finding: Of women between 18 years and 44 years old, 3.84% used marijuana during pregnancy in 2014 compared with 2.37% in 2002; 64% of samples in Bertrand and colleagues’ study had THC traceable in breastmilk approximately 6 days after marijuana use.
Study details:A clinical report on marijuana use during pregnancy and while breastfeeding, and a study of 50 women who used marijuana while breastfeeding and donated samples to a human milk biorepository.
Disclosures:The authors of the AAP clinical report no relevant conflicts of interest. The study by Bertrand and colleagues was supported by the University of California San Diego Center for Better Beginnings, a grant from the National Institutes of Health, and the Gerber Foundation.
Source: Ryan SA et al. Pediatrics. 2018 Aug 27;doi:10.1542/peds.2018-1889. Bertrand KA et al. Pediatrics. 2018 Aug 27;doi:10.1542/peds.2018-1076.
In geriatric urinary incontinence, think DIAPERS mnemonic
NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.
Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.
“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.
He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.
“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.
The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.
“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”
He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.
The scope of the problem
More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.
“The morbidity is huge and the costs are astonishing,” the geriatrician declared.
Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.
Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
The lowdown on DIAPERS
- Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
- Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
- “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
- Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
- “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
- Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
- They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
- “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
- Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
- Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
- Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
- In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.
Dr. Resnick reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.
Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.
“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.
He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.
“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.
The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.
“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”
He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.
The scope of the problem
More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.
“The morbidity is huge and the costs are astonishing,” the geriatrician declared.
Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.
Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
The lowdown on DIAPERS
- Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
- Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
- “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
- Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
- “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
- Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
- They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
- “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
- Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
- Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
- Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
- In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.
Dr. Resnick reported having no financial conflicts of interest regarding his presentation.
NEW ORLEANS – Neil M. Resnick, MD, has devoted more than 30 years of his career to refining the diagnosis and management of geriatric urinary incontinence. He has found it to be a deeply rewarding area of his medical practice. And he wants primary care physicians to share the joy.
Once you get the hang of it, you’re going to love it,” he promised at the annual meeting of the American College of Physicians.
“There is so much you have to offer, and it’s going to make you one happy, fulfilled, non–burned-out physician,” added Dr. Resnick, professor of medicine and chief of the division of geriatric medicine at the University of Pittsburgh.
He insisted that geriatric urinary incontinence belongs squarely in the province of primary care physicians, not just urologic surgeons. That’s because the condition is typically caused or exacerbated by medical diseases and drugs.
“These are things for which we are the experts, because they are conditions outside the bladder that our surgical colleagues aren’t always expert in,” the internist emphasized.
The seven reversible causes of geriatric urinary incontinence, which are categorized as transient urinary incontinence, can easily be remembered by busy primary care practitioners with the aid of a mnemonic of Dr. Resnick’s own devising: DIAPERS. It stands for Delirium, Infection, Atrophic urethritis/vaginitis, Pharmaceuticals, Excess urine output, Restricted mobility, and Stool impaction.
“Treatable causes of urinary incontinence are much more common in older people than in the young,” Dr. Resnick said. “If you just pay attention to these, and you can’t even spell ‘bladder,’ you can cure one-third of older patients. It’s pretty dramatic. And it improves the incontinence in all of the people in whom it’s still persistent, and that means improved responsiveness to further treatment addressing the urinary tract, improvement of other problems related to the incontinence, better quality of life, and it just makes patients better overall. This is really the joy and glory of geriatrics.”
He emphasized that urinary incontinence is never normal, no matter how advanced the patient’s age. The basic geriatric principle is that aging reduces resilience. Bladder sensation and contractility decrease with age. The prostate enlarges. Sphincter strength and urethral length decrease in older women. Involuntary bladder contractions occur in half of all elderly individuals. Nocturnal urine excretion increases. Postvoid urine volume creeps up to 50-100 mL. These are normal changes, but they predispose to tipping over into urinary incontinence in the setting of any additional challenges created by DIAPERS.
The scope of the problem
More than one-third of elderly individuals experience urinary incontinence with daily to weekly frequency. The associated morbidity includes cellulitis, perineal rashes, pressure ulcers, falls, fractures, anxiety, depression, and sexual dysfunction. The economic cost of geriatric urinary incontinence is believed to exceed that of coronary artery bypass surgery and renal dialysis combined.
“The morbidity is huge and the costs are astonishing,” the geriatrician declared.
Fewer than one-fifth and perhaps as few as one-tenth of affected patients actually require surgery.
Less than 20% of elderly patients with urinary incontinence volunteer that information to their primary care physician because of the stigma involved. So, it’s important to ask about it, he noted.
The lowdown on DIAPERS
- Delirium. “The last thing you want to do is refer a patient with urinary incontinence and delirium to a urologist for cystoscopy or urodynamic testing,” according to Dr. Resnick. “It misses the point: The problem is their brain is not working. If you address the causes of delirium, once the delirium subsides, the incontinence will abate.” However, addressing the cause of the acute confusional state can be challenging, he conceded, because delirium can result from virtually any drug or disease anywhere in the body.
- Infection. Acute urinary tract infection (UTI) is the cause of about only 3% of geriatric urinary incontinence. But when present, it’s simple enough to diagnosis and treat. Far more common is asymptomatic bacteriuria, which is present in about 20% of elderly men and 40% of elderly women but does not cause incontinence.
- “The key symptom is dysuria: If the patient [with bacteriuria] has new-onset urinary incontinence or worsened urinary incontinence that’s happened for only the last couple days, that’s an acute UTI that needs to be treated,” Dr. Resnick advised. “Other than that, don’t treat. All you’ll do is select for more virulent organisms, so when the patient does get an acute UTI, it’s tougher to treat.”
- Atrophic vaginitis/urethritis. A common condition when endogenous estrogen goes down. It is characterized by vaginal and urethral erosions and tissue friability. When an affected woman urinates, the acid urine gains exposure to the underlying subendothelial tissue, causing inflammation and irritation that prevent the urethra from closing properly. This condition, frequently mistaken for a UTI, responds well to low-dose topical estrogen in the form of either an easily implantable ring that lasts for 3 months or a topical estrogen cream applied once daily, after establishing the absence of breast or uterine cancer.
- “It takes weeks to months for this condition to remit,” he said. “So, if they’re doing cream, they do it every day for a month. Then every month, they pull back by one day. Eventually, they get to the point where they can be maintained with once- or twice-weekly application.”
- Pharmaceuticals. The list of potential offenders is lengthy. Dr. Resnick focused on six types of medications that are most often linked to increased risk of geriatric urinary incontinence. Those six include long-acting sedative hypnotics, including diazepam (Valium); loop diuretics; and anticholinergic agents, including sedating antihistamines, antipsychotics, tricyclic antidepressants, and tiotropium bromide (Spiriva).
- They also include adrenergic agents, with alpha-adrenergic blockers causing or contributing to urinary incontinence in women and alpha-adrenergic agonists – present in a vast number of OTC cold, sleep, and cough medications – being responsible for problems in men; drugs causing fluid accumulation, including the dihydropyridine calcium channel blockers, NSAIDs, some Parkinson’s agents, and gabapentin/pregabalin; and ACE inhibitors because of their side effect of cough.
- “The most common problem drugs in my practice are calcium channel blockers and gabapentin or pregabalin,” according to the geriatrician.
- Excess urine output. Older people have smaller bladders. Dr. Resnick loathes the popular advice to drink 8 glasses of water per day. Every time that so-called health tip appears in the mass media, he sees a flurry of patients with new-onset geriatric urinary incontinence. Other causes of excess urine output include alcohol, caffeine, metabolic disorders including hyperglycemia, and peripheral edema attributable to heart failure or venous insufficiency.
- Restricted mobility. This often results from overlooked correctable conditions that bedevil older people, including poorly fitting shoes, calluses, bunions, and deformed toenails, as well as readily treatable disorders including depression, orthostatic or postprandial hypotension, and arthritis pain.
- Stool impaction. “The clinical key is new onset of double incontinence associated with bladder distension. One gloved finger will disimpact and cure both,” Dr. Resnick said.
- In patients whose urinary incontinence persists after systematic attention to the DIAPERS details, there are only four possible mechanisms, according to Dr. Resnick: an overactive detrusor or stress incontinence, which can be categorized as storage problems, or an underactive detrusor or a urethral obstruction, which can be considered emptying problems.
Dr. Resnick reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM ACP INTERNAL MEDICINE
Early HbA1c levels may predict gestational diabetes
according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.
Women who went on to develop GDM had higher HbA1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.
A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).
HbA1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA1c levels and GDM in population-based samples.
Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.
GDM cases had higher HbA1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.
In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).
A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).
When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA1c levels at enrollment increased from 0.59 to 0.65.
Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA1c in a better way than we’ve ever looked at it before.”
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.
SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.
“I don’t think clinically this particular finding can make a change right off the bat. What it shows us is we need to understand, at a deeper level, what mechanistic processes might be going on. What underlying process is going on in the woman that looks apparently normal but has a slightly elevated HbA1c. What are the factors that are making this woman become at (greater) risk?”
Suchi Chandrasekaran, MD, MSCE, is an assistant professor of obstetrics and gynecology in the division of maternal fetal medicine at the University of Washington, Yakima. She had no relevant financial disclosures. She was not associated with the study.
“I don’t think clinically this particular finding can make a change right off the bat. What it shows us is we need to understand, at a deeper level, what mechanistic processes might be going on. What underlying process is going on in the woman that looks apparently normal but has a slightly elevated HbA1c. What are the factors that are making this woman become at (greater) risk?”
Suchi Chandrasekaran, MD, MSCE, is an assistant professor of obstetrics and gynecology in the division of maternal fetal medicine at the University of Washington, Yakima. She had no relevant financial disclosures. She was not associated with the study.
“I don’t think clinically this particular finding can make a change right off the bat. What it shows us is we need to understand, at a deeper level, what mechanistic processes might be going on. What underlying process is going on in the woman that looks apparently normal but has a slightly elevated HbA1c. What are the factors that are making this woman become at (greater) risk?”
Suchi Chandrasekaran, MD, MSCE, is an assistant professor of obstetrics and gynecology in the division of maternal fetal medicine at the University of Washington, Yakima. She had no relevant financial disclosures. She was not associated with the study.
according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.
Women who went on to develop GDM had higher HbA1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.
A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).
HbA1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA1c levels and GDM in population-based samples.
Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.
GDM cases had higher HbA1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.
In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).
A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).
When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA1c levels at enrollment increased from 0.59 to 0.65.
Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA1c in a better way than we’ve ever looked at it before.”
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.
SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.
according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.
Women who went on to develop GDM had higher HbA1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.
A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).
HbA1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA1c levels and GDM in population-based samples.
Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.
GDM cases had higher HbA1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.
In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).
A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).
When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA1c levels at enrollment increased from 0.59 to 0.65.
Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA1c in a better way than we’ve ever looked at it before.”
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.
SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.
FROM SCIENTIFIC REPORTS
Key clinical point: First trimester HbA1c levels could improve early diagnosis.
Major finding: HbA1c levels of 5.1% predicted later gestational diabetes with a sensitivity of 47% and a specificity of 79%
Study details: Nested case-control study of 107 gestational diabetes cases and 214 controls.
Disclosures: The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by the American Recovery and Reinvestment Act funding. .
Source: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.
Options for treatment of bipolar disorder during pregnancy
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extract database found an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics (2016;73[9]:938-46).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population (2018 Aug 16. doi: 10.1176/appi.ajp.2018.18010098).
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (2017;376:2245-54). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry (2018 Aug;5[8]:644-52), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email him at [email protected].
Breastfeeding lowered later stroke risk in WHI
Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.
“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.
Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.
There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.
The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.
“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”
They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.
“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”
“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.
Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.
“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”
Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.
“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”
This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.
SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.
This is an important study for pediatricians who counsel breastfeeding mothers and families on the benefits of breastfeeding for mothers and their families.
The current study is important because of its large scale and the fact that it shows an association between any breastfeeding longer than 1 month and protection against stroke, especially for the non-Hispanic black population. These women face higher risks of cardiovascular disease, including hypertension and heart disease, and also higher risks from obesity and hypertension. Longer duration of breastfeeding showed an association with decreased risk of stroke for both non-Hispanic white women and non-Hispanic black women in this study.
On the basis of this study, pediatricians can include potential protection against strokes, as part of the list of protective effects when counseling mothers, either prenatally or in the postpartum setting. Women of childbearing age are not at high risk for stroke, but breastfeeding is a healthy life choice that has significant benefits not just during the period of direct breastfeeding but for years afterward. This study also emphasizes that the benefits of breastfeeding are often dose related. In other words, the longer the mother breastfeeds, the greater the health benefits are for her and for her child.
It would be helpful to have further long-term prospective studies that collect information about breastfeeding at the time that the mother is breastfeeding and then throughout her lifespan. That way, the risk of stroke as well as other cardiovascular risks and cancer risks could be more precisely delineated without the potential for recall bias.
Joan Younger Meek, MD, is chair of the American Academy of Pediatrics Section on Breastfeeding and associate dean for graduate medical education at Florida State University, Orlando. These comments were excerpted from an email interview. She has no relevant conflicts of interest.
This is an important study for pediatricians who counsel breastfeeding mothers and families on the benefits of breastfeeding for mothers and their families.
The current study is important because of its large scale and the fact that it shows an association between any breastfeeding longer than 1 month and protection against stroke, especially for the non-Hispanic black population. These women face higher risks of cardiovascular disease, including hypertension and heart disease, and also higher risks from obesity and hypertension. Longer duration of breastfeeding showed an association with decreased risk of stroke for both non-Hispanic white women and non-Hispanic black women in this study.
On the basis of this study, pediatricians can include potential protection against strokes, as part of the list of protective effects when counseling mothers, either prenatally or in the postpartum setting. Women of childbearing age are not at high risk for stroke, but breastfeeding is a healthy life choice that has significant benefits not just during the period of direct breastfeeding but for years afterward. This study also emphasizes that the benefits of breastfeeding are often dose related. In other words, the longer the mother breastfeeds, the greater the health benefits are for her and for her child.
It would be helpful to have further long-term prospective studies that collect information about breastfeeding at the time that the mother is breastfeeding and then throughout her lifespan. That way, the risk of stroke as well as other cardiovascular risks and cancer risks could be more precisely delineated without the potential for recall bias.
Joan Younger Meek, MD, is chair of the American Academy of Pediatrics Section on Breastfeeding and associate dean for graduate medical education at Florida State University, Orlando. These comments were excerpted from an email interview. She has no relevant conflicts of interest.
This is an important study for pediatricians who counsel breastfeeding mothers and families on the benefits of breastfeeding for mothers and their families.
The current study is important because of its large scale and the fact that it shows an association between any breastfeeding longer than 1 month and protection against stroke, especially for the non-Hispanic black population. These women face higher risks of cardiovascular disease, including hypertension and heart disease, and also higher risks from obesity and hypertension. Longer duration of breastfeeding showed an association with decreased risk of stroke for both non-Hispanic white women and non-Hispanic black women in this study.
On the basis of this study, pediatricians can include potential protection against strokes, as part of the list of protective effects when counseling mothers, either prenatally or in the postpartum setting. Women of childbearing age are not at high risk for stroke, but breastfeeding is a healthy life choice that has significant benefits not just during the period of direct breastfeeding but for years afterward. This study also emphasizes that the benefits of breastfeeding are often dose related. In other words, the longer the mother breastfeeds, the greater the health benefits are for her and for her child.
It would be helpful to have further long-term prospective studies that collect information about breastfeeding at the time that the mother is breastfeeding and then throughout her lifespan. That way, the risk of stroke as well as other cardiovascular risks and cancer risks could be more precisely delineated without the potential for recall bias.
Joan Younger Meek, MD, is chair of the American Academy of Pediatrics Section on Breastfeeding and associate dean for graduate medical education at Florida State University, Orlando. These comments were excerpted from an email interview. She has no relevant conflicts of interest.
Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.
“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.
Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.
There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.
The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.
“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”
They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.
“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”
“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.
Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.
“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”
Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.
“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”
This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.
SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.
Postmenopausal women who breastfed their children had a lower risk of stroke compared with women who had children but never breastfed, with non-Hispanic black women showing a significantly stronger association between breastfeeding and lower stroke risk, according to results from the prospective Women’s Health Initiative Observational Study.
“Some studies have reported that breastfeeding may reduce the rates of breast cancer, ovarian cancer and risk of developing type 2 diabetes in mothers. Recent findings point to the benefits of breastfeeding on heart disease and other specific cardiovascular risk factors,” Lisette T. Jacobson, PhD, of the department of preventive medicine and public health at the University of Kansas, Wichita, said in a statement.
Dr. Jacobson and her colleagues evaluated 80,191 women from the Women’s Health Initiative (WHI) Observational Study who were aged 50-79 at baseline. The average age was 64 years, and 83% were white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were another race or ethnicity. Of the women observed, 58% had breastfed and 3.4% had a stroke within an average of 13 years of follow-up. The investigators used three adjusted regression models to analyze stroke risk: Model 1 was minimally adjusted, model 2 was adjusted for nonmodifiable potential confounders, and model 3 was adjusted for modifiable lifestyle factors.
There was a 23% lower risk of stroke among all postmenopausal women who breastfed compared with those who never breastfed, with women who breastfed between 1 month and 6 months carrying a 19% lower risk of stroke. In the minimally adjusted model, non-Hispanic white women who breastfed carried a 21% lower risk, Hispanic women had an adjusted 32% lower risk, and women of other races and ethnicity had a 24% lower risk of stroke. However, women who were non-Hispanic black had a stronger association with breastfeeding and stroke reduction, with a 48% lower risk, and non-Hispanic white and non-Hispanic black women showed a stronger association between longer duration of breastfeeding and lower stroke risk when results were minimally adjusted, the investigators said. All differences were statistically significant.
The investigators noted the study’s observational nature and said they were not able to determine what caused breastfeeding’s association with lower stroke risk, with other factors potentially affecting results.
“Breastfeeding is only one of many factors that could potentially protect against stroke,” Dr. Jacobson said in the report, published online in the Journal of the American Heart Association. “Others include getting adequate exercise, choosing healthy foods, not smoking, and seeking treatment if needed to keep your blood pressure, cholesterol, and blood sugar in the normal range.”
They also noted potential limitations in the study: the WHI cohort’s low number of strokes in follow-up, lack of classification of stroke, recall bias due to the women self-reporting strokes, average age at baseline, and lack of data on pregnancy.
“Our study did not address whether racial/ethnic differences in breastfeeding contribute to disparities in stroke risk,” Dr. Jacobson said. “Additional research should consider the degree to which breastfeeding might alter racial/ethnic differences in stroke risk.”
“This is an observational, prospective cohort study that was performed very carefully, but it is important to not conclude causality in that breastfeeding results in a reduction in late life stroke,” Larry B. Goldstein, MD, said in an email interview.
Dr. Goldstein, a neurologist who has published several guidelines on primary prevention and early management of stroke with the American Heart Association, noted that although the authors addressed many confounders, studies of this type are still open to residual confounding. He said one of the factors the authors could not measure was eclampsia and preeclampsia, which inhibits breastfeeding.
“The possibility of unmeasured confounding despite how well the study was done is still there. But having said that, the recommendations for breastfeeding are strong from the American Academy of Pediatrics and from the World Health Organization,” and other studies have found an association with a reduction in later life cardiovascular disease, said Dr. Goldstein, the Ruth L. Works professor and chairman in the department of neurology at the University of Kentucky, Lexington. “But just in terms of the benefits to the mother and to the child from breastfeeding, this is another potential plus [in that] even if it doesn’t pan out, it doesn’t really change the recommendation for breastfeeding.”
Dr. Goldstein noted that finding these results in a different prospective cohort would strengthen the recommendations, as would examining whether factors such as lifestyle affected stroke risk for women.
“Showing causality is always going to be difficult,” he stressed. “There is no particular causal mechanism that’s been espoused for how this might decrease stroke risk in later life.”
This study is funded by Frontiers: The Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The WHI program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. The authors reported having no conflicts of interest.
SOURCE: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi:10.1161/JAHA.118.008739.
FROM JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point:
Major finding: Women who had ever breastfed had a 23% decreased risk of stroke, while breastfeeding between 1 month and 6 months carried a 19% lower risk of stroke.
Study details: A longitudinal national health study of 80,191 postmenopausal women in the Women’s Health Initiative.
Disclosures: This study is funded by the Heartland Institute for Clinical and Translational Research and the Wichita Center for Graduate Medical Education–Kansas Bioscience Authority. The authors reported having no conflicts of interest.
Source: Jacobson LT et al. J Am Heart Assoc. 2018 Aug 22. doi: 10.1161/JAHA.118.008739.
Neural-tube defect signal from dolutegravir HIV treatment raises concerns
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.
The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).
Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.
One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.
Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.
The NTD data
The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.
A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).
When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.
During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.
Modeling the risks and benefits
Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.
The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.
Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”
“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.
The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.
Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”
Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
REPORTING FROM AIDS 2018
Cervical cancer screening recommendations vary by age and risk
Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .
The statement, accompanying evidence report, and a modeling study were published online in JAMA.
Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.
The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.
To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.
In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.
Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.
In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”
The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.
The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.
Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.
In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.
However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.
The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.
“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.
“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.
The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.
SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
In 2016, the Society for Gynecologic Oncology (SGO) recommended screening with the newly approved hrHPV test for women aged 25 years and older, with rescreening 3 years later if the test was negative, George F. Sawaya, MD, wrote in an accompanying editorial published in JAMA Internal Medicine. The new recommendations from the U.S. Preventive Services Task Force do not endorse a single triage strategy, and do not consider costs, he said.
“Although the USPSTF sets the standard for evidence-based recommendations and acknowledges the critical value of high-quality evidence in making recommendations, it might reasonably be asked, where is the evidence of value in cervical cancer screening?” Dr. Sawaya wrote.
The updated USPSTF recommendations differ from the SGO recommendation by changing the starting age for hrHPV testing to 30 years from 25, and rescreening at 5-year intervals.
“The USPSTF recommendation that HPV testing not begin until age 30 years seems prudent,” Dr. Sawaya said, in light of the evidence report and modeling analysis of harms and benefits. He noted that the evidence reviewed by the task force showed that HPV testing and cotesting resulting in a small amount of life-years gained compared with no testing, but with the trade-off of more follow-up tests and colposcopies.
“From the perspective of society, it has been proposed that cost-effectiveness analyses be an essential part of the guideline process,” Dr. Sawaya noted. “To assist in policy decisions that many professional societies will soon face, a study that I am leading is seeking to use cost-effectiveness analyses to determine the range of reasonable options for cervical cancer screening. Such analyses may inform future screening recommendations.”
Dr. Sawaya is affiliated with the University of California, San Francisco. These comments are taken from an editorial accompanying USPSTF recommendations on cervical cancer screening (JAMA Intern Med. 2018 Aug 21. doi: 10.1001/jamainternmed.2018.4282). He disclosed serving as the principal investigator of a National Cancer Institute study on cost-effectiveness analyses to determine reasonable options for cervical cancer screening. He also served as a member of the U.S. Preventive Services Task Force from 2004 to 2008.
In 2016, the Society for Gynecologic Oncology (SGO) recommended screening with the newly approved hrHPV test for women aged 25 years and older, with rescreening 3 years later if the test was negative, George F. Sawaya, MD, wrote in an accompanying editorial published in JAMA Internal Medicine. The new recommendations from the U.S. Preventive Services Task Force do not endorse a single triage strategy, and do not consider costs, he said.
“Although the USPSTF sets the standard for evidence-based recommendations and acknowledges the critical value of high-quality evidence in making recommendations, it might reasonably be asked, where is the evidence of value in cervical cancer screening?” Dr. Sawaya wrote.
The updated USPSTF recommendations differ from the SGO recommendation by changing the starting age for hrHPV testing to 30 years from 25, and rescreening at 5-year intervals.
“The USPSTF recommendation that HPV testing not begin until age 30 years seems prudent,” Dr. Sawaya said, in light of the evidence report and modeling analysis of harms and benefits. He noted that the evidence reviewed by the task force showed that HPV testing and cotesting resulting in a small amount of life-years gained compared with no testing, but with the trade-off of more follow-up tests and colposcopies.
“From the perspective of society, it has been proposed that cost-effectiveness analyses be an essential part of the guideline process,” Dr. Sawaya noted. “To assist in policy decisions that many professional societies will soon face, a study that I am leading is seeking to use cost-effectiveness analyses to determine the range of reasonable options for cervical cancer screening. Such analyses may inform future screening recommendations.”
Dr. Sawaya is affiliated with the University of California, San Francisco. These comments are taken from an editorial accompanying USPSTF recommendations on cervical cancer screening (JAMA Intern Med. 2018 Aug 21. doi: 10.1001/jamainternmed.2018.4282). He disclosed serving as the principal investigator of a National Cancer Institute study on cost-effectiveness analyses to determine reasonable options for cervical cancer screening. He also served as a member of the U.S. Preventive Services Task Force from 2004 to 2008.
In 2016, the Society for Gynecologic Oncology (SGO) recommended screening with the newly approved hrHPV test for women aged 25 years and older, with rescreening 3 years later if the test was negative, George F. Sawaya, MD, wrote in an accompanying editorial published in JAMA Internal Medicine. The new recommendations from the U.S. Preventive Services Task Force do not endorse a single triage strategy, and do not consider costs, he said.
“Although the USPSTF sets the standard for evidence-based recommendations and acknowledges the critical value of high-quality evidence in making recommendations, it might reasonably be asked, where is the evidence of value in cervical cancer screening?” Dr. Sawaya wrote.
The updated USPSTF recommendations differ from the SGO recommendation by changing the starting age for hrHPV testing to 30 years from 25, and rescreening at 5-year intervals.
“The USPSTF recommendation that HPV testing not begin until age 30 years seems prudent,” Dr. Sawaya said, in light of the evidence report and modeling analysis of harms and benefits. He noted that the evidence reviewed by the task force showed that HPV testing and cotesting resulting in a small amount of life-years gained compared with no testing, but with the trade-off of more follow-up tests and colposcopies.
“From the perspective of society, it has been proposed that cost-effectiveness analyses be an essential part of the guideline process,” Dr. Sawaya noted. “To assist in policy decisions that many professional societies will soon face, a study that I am leading is seeking to use cost-effectiveness analyses to determine the range of reasonable options for cervical cancer screening. Such analyses may inform future screening recommendations.”
Dr. Sawaya is affiliated with the University of California, San Francisco. These comments are taken from an editorial accompanying USPSTF recommendations on cervical cancer screening (JAMA Intern Med. 2018 Aug 21. doi: 10.1001/jamainternmed.2018.4282). He disclosed serving as the principal investigator of a National Cancer Institute study on cost-effectiveness analyses to determine reasonable options for cervical cancer screening. He also served as a member of the U.S. Preventive Services Task Force from 2004 to 2008.
Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .
The statement, accompanying evidence report, and a modeling study were published online in JAMA.
Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.
The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.
To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.
In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.
Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.
In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”
The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.
The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.
Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.
In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.
However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.
The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.
“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.
“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.
The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.
SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
Screen women for cervical cancer with basic cytology starting at age 21 years, and consider adding high-risk human papillomavirus (hrHPV) testing alone or with cytology for women aged 30 years and older, the U.S. Preventive Services Task Force recommended in an updated statement on cervical cancer screening .
The statement, accompanying evidence report, and a modeling study were published online in JAMA.
Cervical cancer deaths in the United States have declined from 2.8 deaths per 100,000 women in 2000 to 2.3 deaths per 100,000 women in 2015 because of the adoption of widespread screening, according to Susan J. Curry, PhD., of the University of Iowa, Iowa City, and her colleagues in the USPSTF (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
Based on the latest evidence and the modeling study, the USPSTF gives an A recommendation to screening women aged 21-29 years for cervical cancer every 3 years with cervical cytology alone. The task force also gives an A to screening women aged 30-65 years every 5 years with either hrHPV testing alone or in combination with cytology.
The task force recommends against screening (D recommendation) for women younger than 21 years, older than 65 years with a history of screening and low cervical cancer risk, and women who have had hysterectomies with removal of the cervix and no history of cervical cancer risk.
To update the previous recommendations issued in 2012, the task force reviewed the latest evidence and commissioned a modeling study to help determine the best screening strategies in terms of age, screening intervals, and risks vs. benefits.
In the model, researchers assessed 19 strategies for cervical cancer screening based on a hypothetical cohort of women who began screening at 21 years of age.
Overall, the different strategies were similar in effectiveness, but primary hrHPV testing and alternative cotesting were slightly more effective: Cervical cancer deaths ranged from 0.23 to 0.29 deaths per 1,000 women in strategies involving hrHPV testing or cotesting, vs. 0.30 to 0.76 deaths per 1,000 women for strategies based on the current guidelines.
In addition, switching the age of hrHPV testing from 25 years to 30 years and using a 5-year screening interval showed the most effectiveness in terms of risks vs. harms, wrote Jane K. Kim, PhD, of Harvard University, Boston, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872). “Switching from cytology to 5-year primary hrHPV testing at age 30 years (strategy 14) was associated with a ratio of 640 colposcopies per cancer case averted; earlier switch ages required a greater number of colposcopies per cancer case averted.”
The recommendations also were supported by an evidence report including eight randomized, controlled trials of 410,556 women, five cohort studies of 402,615 women, and a meta-analysis of individual participant data including 176,464 women.
The evidence report sought to address the benefits and harms of cervical cancer screening using hrHPV screening alone as the primary screening method or paired with cytology (cotesting), compared with primary screening using cytology alone.
Overall, both hrHPV and hrHPV plus cytology were associated with higher rates of false-positives and colposcopy compared with cytology alone, “which could lead to more treatments with potential harms,” wrote Joy Melnikow, MD, of the University of California, Davis, and her colleagues (JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400.
In addition, hrHPV testing yielded higher rates of positive cervical intraepithelial neoplasia, compared with cytology alone as initial screening.
However, further research is needed to address the impact of any cervical cancer screening strategies in populations with limited access to health care and screening, the researchers noted.
The updated USPSTF recommendations are largely in line with those issued by leading women’s health organizations including the American College of Obstetricians and Gynecologists, ASCCP, and the Society for Gynecologic Oncology, according to a joint statement.
“With a number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” according to the statement, “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in the country are not. It’s also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.
“We hope the USPSTF recommendations foster more discussions between patients and providers about cervical cancer screening, promote opportunities for patient education on the benefits and safety of HPV vaccination for cervical cancer prevention and encourage providers to offer HPV vaccines in their offices,” the statement noted.
The USPSTF research was funded by the Agency for Healthcare Research and Quality. The researchers for the modeling report were supported in part by a National Cancer Institute grant. The researchers had no relevant financial conflicts to disclose.
SOURCES: Kim J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2017.19872; Melnikow J et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10400; Curry S et al. JAMA. 2018 Aug 21. doi: 10.1001/jama.2018.10897.
FROM JAMA