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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.
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].
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
In the U.S., breastfeeding starts out strong, but drops off fast
More than half the infants born in the United States in 2015 (57.6%) were still breastfeeding at 6 months old – an improvement over 2014 survey results, and another step toward the 61% goal set forth in Healthy People 2020.
The CDC Breastfeeding Report Card for 2018 found that about 83% of infants born in 2015 started to breastfeed at birth. Further, five of eight Healthy People 2020 breastfeeding goals were met in 2015.
Yet, the numbers also paint a picture familiar to many clinicians and families: By 1 year, only 36% of infants were still breastfeeding, and just 25% of infants were exclusively breastfed through 6 months, as the American Academy of Pediatrics recommends. This puts the U.S. on the lower end of the global breastfeeding scale, with most countries reporting rates of 30% and higher, according to World Health Organization data. Globally, 41% of mothers breastfeed exclusively through 6 months, according to the latest UNICEF data.
The report concludes that U.S. mothers may not be getting the support they need from health care providers, family members, and employers to meet their breastfeeding goals.
“High breastfeeding initiation rates show that most mothers in the United States want to breastfeed and start out doing so,” the report states. “However, despite the recommendation to breastfeed exclusively for about the first 6 months, less than 50% of infants were exclusively breastfed through 3 months and about 25% were exclusively breastfed through 6 months.”
The CDC Breastfeeding Report Card provides national- and state-level data to help clinicians, child care providers, and families promote breastfeeding and support the women who choose it. In addition to providing an in-depth look at the numbers, the report compares current findings to the breastfeeding goals outlined in Healthy People 2020. This year, it looked at data on breastfeeding practices and support in all 50 states, the District of Columbia, Puerto Rico, the Virgin Islands, and – for the first time – Guam.
The report is published every 2 years, but the data comprising it are updated annually. The latest rates reflect breastfeeding practices among U.S. infants born in 2015 and are based on results of the 2016 and 2017 U.S. National Immunization Surveys.
Since the first report card in 2007, rates of exclusive breastfeeding at 3 and 6 months have increased. However, although rates for any breastfeeding at 6 and 12 months increased in 2015 from 2014 rates, there was no appreciable increase in exclusive breastfeeding at 3 and 6 months, the report noted. And about 17% of infants who were breastfed at birth still got some formula supplementation in the first 2 days of life.
Recognizing that breastfeeding support at the birth facility is a key driver of success, Healthy People 2020 tracks the proportion of live births in facilities that provided the recommended support. These “baby-friendly hospitals” receive a special designation from the WHO/UNICEF Baby-Friendly Hospital Initiative, and their numbers are increasing, the report noted. In 12 states, more than 40% of births occurred in such facilities, comprising more than 1 million infants in 2015 (26%), and far exceeding the HP2020 8% goal.
In a nation in which many new mothers must return to employment outside the home, breastfeeding support at work is crucial. Just 49% of employers provide breastfeeding facilities for these women, the report found. While this may seem less than optimal, it still exceeds the HP2020 goal of 38%.
“All sectors of society – family and friends, hospitals, health care offices/clinics, childcare facilities, community-based organizations, and workplaces – can play a role in improving the health of families by supporting breastfeeding,” the report said. “To reach their breastfeeding goals, mothers need continuity of care, which is achieved by consistent, collaborative, and high-quality breastfeeding services and support.”
SOURCE: CDC Breastfeeding Report Card
More than half the infants born in the United States in 2015 (57.6%) were still breastfeeding at 6 months old – an improvement over 2014 survey results, and another step toward the 61% goal set forth in Healthy People 2020.
The CDC Breastfeeding Report Card for 2018 found that about 83% of infants born in 2015 started to breastfeed at birth. Further, five of eight Healthy People 2020 breastfeeding goals were met in 2015.
Yet, the numbers also paint a picture familiar to many clinicians and families: By 1 year, only 36% of infants were still breastfeeding, and just 25% of infants were exclusively breastfed through 6 months, as the American Academy of Pediatrics recommends. This puts the U.S. on the lower end of the global breastfeeding scale, with most countries reporting rates of 30% and higher, according to World Health Organization data. Globally, 41% of mothers breastfeed exclusively through 6 months, according to the latest UNICEF data.
The report concludes that U.S. mothers may not be getting the support they need from health care providers, family members, and employers to meet their breastfeeding goals.
“High breastfeeding initiation rates show that most mothers in the United States want to breastfeed and start out doing so,” the report states. “However, despite the recommendation to breastfeed exclusively for about the first 6 months, less than 50% of infants were exclusively breastfed through 3 months and about 25% were exclusively breastfed through 6 months.”
The CDC Breastfeeding Report Card provides national- and state-level data to help clinicians, child care providers, and families promote breastfeeding and support the women who choose it. In addition to providing an in-depth look at the numbers, the report compares current findings to the breastfeeding goals outlined in Healthy People 2020. This year, it looked at data on breastfeeding practices and support in all 50 states, the District of Columbia, Puerto Rico, the Virgin Islands, and – for the first time – Guam.
The report is published every 2 years, but the data comprising it are updated annually. The latest rates reflect breastfeeding practices among U.S. infants born in 2015 and are based on results of the 2016 and 2017 U.S. National Immunization Surveys.
Since the first report card in 2007, rates of exclusive breastfeeding at 3 and 6 months have increased. However, although rates for any breastfeeding at 6 and 12 months increased in 2015 from 2014 rates, there was no appreciable increase in exclusive breastfeeding at 3 and 6 months, the report noted. And about 17% of infants who were breastfed at birth still got some formula supplementation in the first 2 days of life.
Recognizing that breastfeeding support at the birth facility is a key driver of success, Healthy People 2020 tracks the proportion of live births in facilities that provided the recommended support. These “baby-friendly hospitals” receive a special designation from the WHO/UNICEF Baby-Friendly Hospital Initiative, and their numbers are increasing, the report noted. In 12 states, more than 40% of births occurred in such facilities, comprising more than 1 million infants in 2015 (26%), and far exceeding the HP2020 8% goal.
In a nation in which many new mothers must return to employment outside the home, breastfeeding support at work is crucial. Just 49% of employers provide breastfeeding facilities for these women, the report found. While this may seem less than optimal, it still exceeds the HP2020 goal of 38%.
“All sectors of society – family and friends, hospitals, health care offices/clinics, childcare facilities, community-based organizations, and workplaces – can play a role in improving the health of families by supporting breastfeeding,” the report said. “To reach their breastfeeding goals, mothers need continuity of care, which is achieved by consistent, collaborative, and high-quality breastfeeding services and support.”
SOURCE: CDC Breastfeeding Report Card
More than half the infants born in the United States in 2015 (57.6%) were still breastfeeding at 6 months old – an improvement over 2014 survey results, and another step toward the 61% goal set forth in Healthy People 2020.
The CDC Breastfeeding Report Card for 2018 found that about 83% of infants born in 2015 started to breastfeed at birth. Further, five of eight Healthy People 2020 breastfeeding goals were met in 2015.
Yet, the numbers also paint a picture familiar to many clinicians and families: By 1 year, only 36% of infants were still breastfeeding, and just 25% of infants were exclusively breastfed through 6 months, as the American Academy of Pediatrics recommends. This puts the U.S. on the lower end of the global breastfeeding scale, with most countries reporting rates of 30% and higher, according to World Health Organization data. Globally, 41% of mothers breastfeed exclusively through 6 months, according to the latest UNICEF data.
The report concludes that U.S. mothers may not be getting the support they need from health care providers, family members, and employers to meet their breastfeeding goals.
“High breastfeeding initiation rates show that most mothers in the United States want to breastfeed and start out doing so,” the report states. “However, despite the recommendation to breastfeed exclusively for about the first 6 months, less than 50% of infants were exclusively breastfed through 3 months and about 25% were exclusively breastfed through 6 months.”
The CDC Breastfeeding Report Card provides national- and state-level data to help clinicians, child care providers, and families promote breastfeeding and support the women who choose it. In addition to providing an in-depth look at the numbers, the report compares current findings to the breastfeeding goals outlined in Healthy People 2020. This year, it looked at data on breastfeeding practices and support in all 50 states, the District of Columbia, Puerto Rico, the Virgin Islands, and – for the first time – Guam.
The report is published every 2 years, but the data comprising it are updated annually. The latest rates reflect breastfeeding practices among U.S. infants born in 2015 and are based on results of the 2016 and 2017 U.S. National Immunization Surveys.
Since the first report card in 2007, rates of exclusive breastfeeding at 3 and 6 months have increased. However, although rates for any breastfeeding at 6 and 12 months increased in 2015 from 2014 rates, there was no appreciable increase in exclusive breastfeeding at 3 and 6 months, the report noted. And about 17% of infants who were breastfed at birth still got some formula supplementation in the first 2 days of life.
Recognizing that breastfeeding support at the birth facility is a key driver of success, Healthy People 2020 tracks the proportion of live births in facilities that provided the recommended support. These “baby-friendly hospitals” receive a special designation from the WHO/UNICEF Baby-Friendly Hospital Initiative, and their numbers are increasing, the report noted. In 12 states, more than 40% of births occurred in such facilities, comprising more than 1 million infants in 2015 (26%), and far exceeding the HP2020 8% goal.
In a nation in which many new mothers must return to employment outside the home, breastfeeding support at work is crucial. Just 49% of employers provide breastfeeding facilities for these women, the report found. While this may seem less than optimal, it still exceeds the HP2020 goal of 38%.
“All sectors of society – family and friends, hospitals, health care offices/clinics, childcare facilities, community-based organizations, and workplaces – can play a role in improving the health of families by supporting breastfeeding,” the report said. “To reach their breastfeeding goals, mothers need continuity of care, which is achieved by consistent, collaborative, and high-quality breastfeeding services and support.”
SOURCE: CDC Breastfeeding Report Card
The value of low-dose aspirin for prevention of preeclampsia
Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.
Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.
There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally,
Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.
Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.
Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin
The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).
Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).
It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.
The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).
Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.
The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.
The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.
Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.
Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.
Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.
When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).
In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.
What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).
My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
Dr. Abbott: Messaging and education to reduce disparities
Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).
At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.
To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.
To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.
Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.
We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”
Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].
Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.
Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.
There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally,
Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.
Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.
Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin
The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).
Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).
It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.
The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).
Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.
The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.
The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.
Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.
Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.
Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.
When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).
In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.
What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).
My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
Dr. Abbott: Messaging and education to reduce disparities
Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).
At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.
To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.
To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.
Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.
We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”
Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].
Low-dose aspirin for the prevention of preeclampsia has been studied for more than 25 years, often with contradictory and confusing results. Studies have enrolled patients with varying levels of risk, assessed risk differently, and used different definitions of preeclampsia as well as a variety of aspirin dosages and treatment-initiation dates. Undoubtedly, this heterogeneity has made interpretation and comparisons difficult and frustrating.
Recently, systematic reviews and meta-analyses have improved our understanding of the role of low-dose aspirin, providing solid evidence that low-dose aspirin started after the first-trimester reduces the occurrence of preeclampsia in high-risk women. Data also suggest that low-dose aspirin reduces the incidence of fetal growth restriction and preterm birth in these women.
There is reasonable evidence, moreover, that low-dose aspirin provides similar benefit in women with modest levels of risk and that it’s best to begin aspirin use at 12-14 weeks’ gestation rather than later in the second trimester. Finally,
Despite this evidence and current recommendations for low-dose aspirin use by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, its use in practice is varied. Obstetricians and other obstetrics providers are not consistently making the recommendation, and pharmacists are not consistently supporting it.
Without more consistent initiation of low-dose aspirin prophylaxis and more consistent adherence, we are losing an opportunity to reduce serious maternal morbidity and mortality. We also are underutilizing an important tool for the reduction of racial and other health disparities relating to preterm birth, maternal death, and other complications of preeclampsia.
Dr. Lockwood: Epidemiology, etiology, and clinical value of aspirin
The use of low-dose aspirin can have a high impact, considering that preeclampsia complicates 3.4% of pregnancies nationally and accounts for at least 9% of maternal deaths (BMJ. 2013 Nov;347:f6564).
Preeclampsia also has been shown in multiple long-term epidemiologic studies to be a strong risk factor for future cardiovascular disease and metabolic disorders in women – especially when it occurs in multiple pregnancies or develops preterm. Moreover, it is associated with stillbirth, intrauterine growth restriction (IUGR), and oligohydramnios in the fetus (BMJ. 2013 Nov;347:f6564).
It is important to remember that criteria for a diagnosis of preeclampsia changed in 2013 such that the detection of proteinuria is no longer required. Preeclampsia is defined today as the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks in a previously normotensive woman, according to the ACOG Task Force on Hypertension in Pregnancy.
The leading risk factor appears to be previous preeclampsia. In a systematic review and meta-analysis of 92 cohort studies that looked at the pooled relative risk of developing preeclampsia in the presence or absence of 14 commonly reported and accepted risk factors, prior preeclampsia topped the list, putting patients at an eightfold increased risk (relative risk 8.4) (BMJ. 2016 Apr 19;353:i1753).
Nulliparity (relative risk, 2.1) and multiple gestation (RR, 2.9) presented lesser risks but still were significant, and preexisting medical conditions increased risk as well. Notably, both chronic hypertension and a body mass index (BMI) greater than 30 had a fivefold increased risk (RR, 5.1), and preexisting diabetes presented more than a threefold increased risk (RR, 3.7). The review covered more than 25 million pregnancies in 27 countries.
The etiology of preeclampsia still is not completely understood. There is evidence that underlying decidual inflammation, including increased activated macrophages and decreased uterine natural killer cells (uNK), promotes shallow placentation leading to incomplete uterine spiral artery remodeling, relative placental hypoxia, and progressive release of placental antiangiogenic substances such as soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (Am J Pathol. 2013 Sep;183[3]:841-56; Reprod Sci. 2015 Nov;22[11]:1461-7). The latter result in systemic endothelial cell damage, reduced endothelial prostacyclin (PGI2), and increased platelet thromboxane A2, triggering vasospasm and increased platelet turnover that ultimately lead to the typical signs and symptoms of preeclampsia.
The research focus traditionally has been on the placenta, but more recently the uterine decidual contribution has received more attention. A recent study published in the Proceedings of the National Academy of Sciences offers evidence that affected women have defective decidualization during and after severe preeclampsia, suggesting that the defect could be detected prior to conception.
Investigators isolated endometrial cells from women at the end of a pregnancy complicated by preeclampsia and found a transcriptional signature that persisted for years. They then linked the defect to impaired cytotrophoblast invasion (Proc Natl Acad Sci. 2017;114[40]:E8468-77). This elegant and provocative study suggests that it might be possible in the future to evaluate the endometrium and try to enhance stromal cell decidualization before pregnancy.
Currently, the rationale for using aspirin to prevent preeclampsia lies with its ability to inhibit platelet production of thromboxane and block NF-kB, a protein complex that plays a role in systemic and/or decidual inflammation. There likely are numerous mechanisms of action, however, including some that improve placentation.
Among the most recent studies on timing and dosage is a systematic review and meta-analysis of 45 randomized controlled trials with 20,909 women randomized to 50-150 mg aspirin daily or to placebo or no treatment. The investigators stratified the results by gestational age at the time of aspirin initiation and found that timing matters. Women who began aspirin at or before 16 weeks had the most significant reductions in preeclampsia (RR, 0.57) and severe preeclampsia (RR, 0.47), as well as fetal growth restriction (RR, 0.56), with a dose-response effect up to 150 mg.
When aspirin was initiated after 16 weeks, there was a much smaller reduction of preeclampsia (RR, 0.81) and no effects for severe preeclampsia or IUGR. Nor was there any dose-response effect (Am J Obstet Gynecol. 2017; 216[2]:110-20.e6).
In contrast, another recent meta-analysis of individual participant data on 32,217 women recruited in 31 randomized controlled trials found no significant difference among women who were randomized before 16 weeks versus those who were randomized at 16 weeks or later (Am J Obstet Gynecol. 2017 Feb;216[2]:121-8.e2). It’s important to note that this analysis covered other antiplatelet agents as well and that it stratified outcomes by gestational age with a slightly later cutoff point.
What do official guidelines say? The USPSTF’s recommendation, issued in 2014, calls for low-dose aspirin at 81 mg/day after 12 weeks’ gestation in women who have one or more high-risk factors, and consideration of such treatment in patients with “several” moderate-risk factors (Ann Intern Med. 2014 Dec 2;161[11]:819-26). In July 2018, ACOG reaffirmed its earlier support for low-dose aspirin in a committee opinion that recommends 81 mg/day beginning at 12-28 weeks’ gestation, optimally before 16 weeks’, for women who have one or more high-risk factors or more than one moderate-risk factor (Obstet Gynecol. 2018 Jul;132[1]:e44-e52).
My own take, based on published literature, including my own research, is that low-dose aspirin reduces the frequency of preeclampsia, particularly cases occurring preterm, as well as related IUGR, by approximately 10%-20% in moderate- and high-risk women. Regarding dose and gestational age for initiation, I have split the difference of what’s reflected in the literature and in guidelines. I advise 122 mg (a tablet-and-a-half) a day, starting at 12-14 weeks’, for patients at high and moderate levels of risk. For patients who are not seen until later, low-dose aspirin can be started up to 28 weeks’ gestation.
Dr. Abbott: Messaging and education to reduce disparities
Black women are not only more likely to develop preeclampsia, but they’re also more likely to have more severe complications and worse outcomes. In one analysis, black women with preeclampsia experienced an almost threefold higher risk of maternal mortality and intrauterine fetal death than did white women with the disorder (Hypertens Pregnancy. 2015 Nov;34[4]:506-15).
At Boston Medical Center, 30% of pregnant women have a diagnosis of preeclampsia or hypertension at term. In addition to 68% identifying as Hispanic/black or black, half of the families we care for have incomes less than $20,000, and 30% are non–English speaking. Low-dose prenatal aspirin is therefore an important tool for reducing racial health disparities as well as disparities created by health literacy, economic status, and language and cultural barriers. At BMC, New England’s largest safety-net hospital, we’ve found that the factors driving health disparities often overlap.
To increase the use of low-dose aspirin for women at moderate to high risk, we marry education about aspirin’s effectiveness and safety with education about the potential severity of hypertension and preeclampsia. We counsel patients who are hospitalized at delivery with gestational or chronic hypertension, or fetal growth restriction, about how preeclampsia can be very serious – contrary to what they’ve experienced or what friends or family may have shared. We also counsel them about signs and symptoms of severe preeclampsia that warrant consulting their provider. And overall, we deliberately use the term “prenatal aspirin” so that, over time and in the broader community, it will become associated with good prenatal care and risk reduction.
To counter perceived risks and dangers that we identified through focus groups and interviews, our patient education materials state that low-dose aspirin in pregnancy will not cause increased bleeding, does not reach the baby’s blood, does not increase the risk of miscarriage, and has not been shown to have negative effects on the baby’s initial development (www.prenatalaspirin.com/education-materials). We try to engage family members whenever possible, and we recognize that the black population has historical reasons to be concerned or suspicious that aspirin might not be safe for them.
Especially for underserved patients who receive prescriptions for low-dose aspirin, we must ensure that pharmacists will dispense the medication. A national survey of pharmacists (not yet published) found that over two-thirds were unaware of the USPSTF guidelines, and that only a minority would feel comfortable dispensing low-dose aspirin during pregnancy. In our community, some pharmacists have told patients to return to their physician and inquire more. Until recently, one of the major pharmacy chains placed a warning label on aspirin bottles being dispensed to women who also had an active prescription for prenatal vitamins.
We are working both with pharmacies and with pharmacy schools to impact the education of current and future pharmacists on guidelines and recommendations for low-dose aspirin prophylaxis. In addition, when I write a prescription for prenatal aspirin, starting at 12 weeks’ whenever possible, I include the message “for the purpose of trying to reduce pregnancy complications.”
Dr. Lockwood is senior vice president at University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa. He said he had no relevant financial disclosures or conflicts of interest. Dr. Abbot is a specialist in maternal-fetal medicine, the director of obstetrics and gynecology, and assistant dean for patient safety and quality improvement education at Boston Medical Center. She also is an associate professor of obstetrics and gynecology at Boston University. She disclosed a grant from the March of Dimes. Email them at [email protected].
Aspirin has myriad benefits
Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.
Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.
It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.
To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.
Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.
It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.
To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Some of our readers might remember the old saying, “Take two aspirin and call me in the morning,” as advice physicians gave to patients experiencing a minor malady. Aspirin often has been called a “wonder drug” as its uses continue to expand. From its first recorded use in the Ebers papyrus as an anti-inflammatory agent, to its first use in a clinical trial showing that it induces remission of fever and joint inflammation, to the discovery that it could prevent death from heart attack, to its anticancer properties, aspirin remains one of the most researched drugs in use today. According to ClinicalTrials.gov, there are over 465 active and nearly 1,000 completed aspirin-related clinical trials around the world.
Despite its myriad benefits, aspirin has been linked to bleeding, nausea, and gastrointestinal ulcers. Additionally, more research is needed to determine the risks/benefits of daily aspirin in younger adults (under age 50 years) or older adults (over age 70 years), although the ASPREE (Aspirin in Reducing Events in the Elderly) trial, expected to be completed in 2019, is working to determine the effects of daily low-dose aspirin (100 mg) on the health of people over age 65.
It is tempting to consider aspirin one of modern medicine’s so-called silver bullets, and, for women with a history of gestational hypertension and preeclampsia, it just might be. Aspirin use, especially daily aspirin, is typically not recommended during pregnancy, and most ob.gyns. will include aspirin on the “do not take” list they give to their patients during prenatal examinations. Women at risk for developing preeclampsia are the exceptions to this general rule, and a number of clinical studies have indicated that use of low-dose aspirin can help prevent disease as well as secondary outcomes for mother (i.e., placental abruption, antepartum hemorrhage) and baby (i.e., intrauterine growth restriction, stillbirth). In addition, aspirin is an easily obtainable, low-cost preventive measure for any patient at high risk.
To discuss the value of low-dose aspirin to prevent preeclampsia and how ob.gyns. can educate their patients and other health care professionals about its benefits, we have invited Charles J. Lockwood, MD, MHCM, senior vice president of University of South Florida Health and dean of Morsani College of Medicine at the University of South Florida, Tampa, and Jodi F. Abbott, MD, MSc, MHCM, director of obstetrics and gynecology at Boston Medical Center, and associate professor of obstetrics and gynecology at Boston University, to coauthor this month’s Master Class.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Prenatal marijuana use higher in women with severe nausea and vomiting
Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.
In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.
Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.
“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.
In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.
The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.
The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.
Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.
“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”
The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.
Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.
In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.
Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.
“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.
In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.
The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.
The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.
Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.
“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”
The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.
Pregnant women who experience severe nausea and vomiting have nearly fourfold greater odds of prenatal marijuana use compared with women not experiencing nausea and vomiting, according to data from 220,510 first-trimester screenings.
In a research letter published in JAMA Internal Medicine, researchers reported the results of a health care system data analysis, which found a 3.80-fold greater prevalence of prenatal marijuana use among women with severe nausea and vomiting in pregnancy, compared with those who did not experience nausea and vomiting.
Among women with mild nausea and vomiting in pregnancy, there was still a significant twofold higher prevalence of marijuana use.
“Use of marijuana, an antiemetic, is increasing among pregnant women, and data from two small surveys indicate that women self-report using marijuana to alleviate nausea and vomiting in pregnancy (NVP),” wrote Kelly C. Young-Wolff, PhD, of the division of research at Kaiser Permanente Northern California, Oakland, and her coauthors.
In this study, 2% of the women experienced severe and 15% experienced mild nausea and vomiting during pregnancy.
The overall prevalence of marijuana use – assessed either by self-report or toxicological test findings – was 5.3%, with 0.7% positive on self-report only, 3.1% positive on toxicologic testing only, and 1.5% positive on both.
The authors said the findings supported the hypothesis that pregnant women were using marijuana to self-medicate for NVP. However, they also noted that clinicians may diagnose NVP more frequently among women who report using marijuana to treat it.
Dr. Young-Wolff and her coauthors said that they would not have been able to distinguish prenatal marijuana use from use before the women knew they were pregnant, “and misclassification is possible given variability in the time that marijuana is detectable in urine.
“The health effects of prenatal marijuana use are unclear, and national guidelines recommend that pregnant women discontinue use,” the authors wrote. “Patients with NVP should be screened for marijuana use and educated about effective and safe NVP treatments.”
The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
SOURCE: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.
FROM JAMA INTERNAL MEDICINE
Key clinical point:
Major finding: Women with severe nausea and vomiting in pregnancy have nearly fourfold higher odds of prenatal marijuana use.
Study details: Analysis of health insurance data from 220,510 prenatal screenings.
Disclosures: The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health. No conflicts of interest were declared.
Source: Young-Wolff K et al. JAMA Intern Med. 2018 Aug 20. doi: 10.1001/jamainternmed.2018.3581.
What should you tell your patients about the risks of ART?
CORONADO, CALIF. –
In addition, multiples conceived using ART – including twins – continue to be the biggest preventable risk factor for adverse pregnancy and fetal outcomes.
Those are key points that Joseph C. Gambone, DO, MPH, made during a wide-ranging talk about the adverse pregnancy and fetal outcomes related to ART at a meeting on in vitro fertilization (IVF) and embryo transfer sponsored by the University of California, San Diego.
In 2016, Barbara Luke, ScD, MPH, and her colleagues published results from the ongoing Massachusetts Outcomes Study of Reproductive Technologies (J Reprod Med. 2016 Mar-Apr;61[3-4]:114-27). They found that pregnancy plurality is the predominant risk factor for infants and mothers. Of 8,948 birth outcomes resulting from ART, risks for pregnancy-induced hypertension, cesarean delivery, gestational diabetes, preterm birth, birth defects, and small for gestational age were significantly increased among twins.
“Lowering the plurality rate, including twins, should substantially reduce morbidity with ART,” said Dr. Gambone, professor emeritus at the David Geffen School of Medicine at the University of California, Los Angeles, who was not affiliated with the study. Thawed embryos were associated with a higher risk for pregnancy-induced hypertension and large for gestational age offspring, but a lower risk for low birth weight and small for gestational age.
According to data from the Society for Assisted Reproductive Technology, elective singleton embryo transfer increased from 35% of all cycles in 2015 to 42% in 2016, while singleton births increased from 80.5% to 84% during the same time period. In addition, the proportion of twins born in 2015 was 19% and declined to 16% in 2016, while the percentage of triplets or greater born was the same in both years (0.4%).
Meanwhile, in an analysis of more than 1.1 million cycles between 2000 and 2011 drawn from Centers for Disease Control and Prevention surveillance data, researchers found that the most commonly reported patient complication was ovarian hyperstimulation syndrome (a peak of 154 per 10,000 autologous cycles) and hospitalization (a peak of 35 per 10,000 autologous cycles; JAMA. 2015 Jan 6;313[1]:88-90). Other complications remained below 10 per 10,000 cycles and included infection, hemorrhage with transfusion, adverse event from medication, adverse event to anesthesia, and patient death. In all, 58 deaths were reported: 18 because of stimulation and 40 during pregnancy. “Some deaths were due to potentially preventable complications because of unrecognized comorbidities or conditions,” said Dr. Gambone, who was not affiliated with the study. “Women with Turner syndrome who receive donor embryos could be an example.”
Today, the most feared maternal and pregnancy outcome from ART is breast and ovarian cancer from treatment, he said, while the most feared outcome in offspring is birth defects from treatment. On the breast cancer front, an analysis of nearly 2 million women provided some reassurance (Fertil Steril. 2017 Jul;108:137-44). It found no increased risk of breast cancer in women who have birth after ART, compared with women who gave birth after spontaneous conception (adjusted hazard ratio, 0.84). It also found no increased risk in women who received ovarian stimulation or other hormonal treatment for infertility (HRs, 0.86 and 0.79, respectively). A smaller study with a median follow-up of 21 years found no difference in the rate of invasive and in situ breast cancer between women who received IVF treatment and those who did not (JAMA. 2016 Jul 19;316[3]:300-12). However, a recent analysis from Great Britain found a slight increase for in situ breast cancer that was associated with women who had a higher number of treatment cycles (BMJ. 2018;362:k2644).
On the ovarian cancer front, a case-control analysis of 1,900 women conducted by researchers at Mayo Clinic found that infertile women who used fertility drugs were not at increased risk of developing ovarian tumors, compared with infertile women who did not use fertility drugs (adjusted odds ratio, 0.64; Fertil Steril. 2013;99[7]:2031-6). There also was no increased risk because of underlying infertility or any increase in borderline tumors. More recently, an abstract presented at the annual meeting of the European Society of Human Reproduction and Embryology, based on a large cohort study from Denmark, found a slightly higher overall risk of ovarian cancer among the ART women (0.11%), compared with non-ART controls (0.06%). However, the analysis also showed comparably higher rates of ovarian cancer in women who were nulliparous (a risk factor for ovarian cancer) and in the ART women who had a female cause of infertility. In an analysis from Great Britain, increased ovarian tumor risk was limited to women with endometriosis, low parity, or both (BMJ. 2018;362:k2644). Dr. Gambone noted that an article published online Oct. 23, 2017 in Nature Communication implicates the fallopian tube, rather than the ovaries, as a probable source of papillary serous cancers.
Women who are subfertile should be counseled about the increased risk of birth defects, irrespective of whether they undergo IVF or not, said Dr. Gambone, who also runs a private infertility practice in Durango, Colo. Studies consistently show an increased risk associated with subfertility. A large, retrospective cohort analysis of live and stillbirths from 2004 to 2010 in Massachusetts found that congenital anomalies were reported in 2% of ART births, 1.7% of subfertile births, and 1.4% of fertile births (Birth Defects Res. 2017 Aug 15;109[14]:1144-53). The adjusted prevalence ratios for birth defects were 1.5 for ART births and 1.3 for subfertile births, compared with fertile mother births. The researchers observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects.
“The absolute risk of birth defects is small with ART,” Dr. Gambone said. “A significant portion [but not all] is related to multiple births and underlying subfertility.” A more recent analysis found that subfertile women were 21% more likely to have babies born with birth defects, compared with fertile women (Pediatrics. 2018 Jul; e20174069).
In a study of the overall risk and etiology of major birth defects, researchers from Utah determined that they affect 1 in 33 babies in the United States at an annual direct cost of $2.6 billion per year (BMJ. 2017;357:j2249). Although major birth defects are the leading cause of infant mortality (20%), a known cause of the defect was established in only 20.2% of cases. “Of that percentage, the majority are chromosome or genetic causes,” Dr. Gambone said. “Interestingly, ART and/or subfertility were not listed in this analysis as causes of birth defects. However, the authors speculated that as genetic technology improves, both genetic and epigenetic causes will be identified.”
Dr. Gambone reported no relevant financial disclosures.
[email protected]
CORONADO, CALIF. –
In addition, multiples conceived using ART – including twins – continue to be the biggest preventable risk factor for adverse pregnancy and fetal outcomes.
Those are key points that Joseph C. Gambone, DO, MPH, made during a wide-ranging talk about the adverse pregnancy and fetal outcomes related to ART at a meeting on in vitro fertilization (IVF) and embryo transfer sponsored by the University of California, San Diego.
In 2016, Barbara Luke, ScD, MPH, and her colleagues published results from the ongoing Massachusetts Outcomes Study of Reproductive Technologies (J Reprod Med. 2016 Mar-Apr;61[3-4]:114-27). They found that pregnancy plurality is the predominant risk factor for infants and mothers. Of 8,948 birth outcomes resulting from ART, risks for pregnancy-induced hypertension, cesarean delivery, gestational diabetes, preterm birth, birth defects, and small for gestational age were significantly increased among twins.
“Lowering the plurality rate, including twins, should substantially reduce morbidity with ART,” said Dr. Gambone, professor emeritus at the David Geffen School of Medicine at the University of California, Los Angeles, who was not affiliated with the study. Thawed embryos were associated with a higher risk for pregnancy-induced hypertension and large for gestational age offspring, but a lower risk for low birth weight and small for gestational age.
According to data from the Society for Assisted Reproductive Technology, elective singleton embryo transfer increased from 35% of all cycles in 2015 to 42% in 2016, while singleton births increased from 80.5% to 84% during the same time period. In addition, the proportion of twins born in 2015 was 19% and declined to 16% in 2016, while the percentage of triplets or greater born was the same in both years (0.4%).
Meanwhile, in an analysis of more than 1.1 million cycles between 2000 and 2011 drawn from Centers for Disease Control and Prevention surveillance data, researchers found that the most commonly reported patient complication was ovarian hyperstimulation syndrome (a peak of 154 per 10,000 autologous cycles) and hospitalization (a peak of 35 per 10,000 autologous cycles; JAMA. 2015 Jan 6;313[1]:88-90). Other complications remained below 10 per 10,000 cycles and included infection, hemorrhage with transfusion, adverse event from medication, adverse event to anesthesia, and patient death. In all, 58 deaths were reported: 18 because of stimulation and 40 during pregnancy. “Some deaths were due to potentially preventable complications because of unrecognized comorbidities or conditions,” said Dr. Gambone, who was not affiliated with the study. “Women with Turner syndrome who receive donor embryos could be an example.”
Today, the most feared maternal and pregnancy outcome from ART is breast and ovarian cancer from treatment, he said, while the most feared outcome in offspring is birth defects from treatment. On the breast cancer front, an analysis of nearly 2 million women provided some reassurance (Fertil Steril. 2017 Jul;108:137-44). It found no increased risk of breast cancer in women who have birth after ART, compared with women who gave birth after spontaneous conception (adjusted hazard ratio, 0.84). It also found no increased risk in women who received ovarian stimulation or other hormonal treatment for infertility (HRs, 0.86 and 0.79, respectively). A smaller study with a median follow-up of 21 years found no difference in the rate of invasive and in situ breast cancer between women who received IVF treatment and those who did not (JAMA. 2016 Jul 19;316[3]:300-12). However, a recent analysis from Great Britain found a slight increase for in situ breast cancer that was associated with women who had a higher number of treatment cycles (BMJ. 2018;362:k2644).
On the ovarian cancer front, a case-control analysis of 1,900 women conducted by researchers at Mayo Clinic found that infertile women who used fertility drugs were not at increased risk of developing ovarian tumors, compared with infertile women who did not use fertility drugs (adjusted odds ratio, 0.64; Fertil Steril. 2013;99[7]:2031-6). There also was no increased risk because of underlying infertility or any increase in borderline tumors. More recently, an abstract presented at the annual meeting of the European Society of Human Reproduction and Embryology, based on a large cohort study from Denmark, found a slightly higher overall risk of ovarian cancer among the ART women (0.11%), compared with non-ART controls (0.06%). However, the analysis also showed comparably higher rates of ovarian cancer in women who were nulliparous (a risk factor for ovarian cancer) and in the ART women who had a female cause of infertility. In an analysis from Great Britain, increased ovarian tumor risk was limited to women with endometriosis, low parity, or both (BMJ. 2018;362:k2644). Dr. Gambone noted that an article published online Oct. 23, 2017 in Nature Communication implicates the fallopian tube, rather than the ovaries, as a probable source of papillary serous cancers.
Women who are subfertile should be counseled about the increased risk of birth defects, irrespective of whether they undergo IVF or not, said Dr. Gambone, who also runs a private infertility practice in Durango, Colo. Studies consistently show an increased risk associated with subfertility. A large, retrospective cohort analysis of live and stillbirths from 2004 to 2010 in Massachusetts found that congenital anomalies were reported in 2% of ART births, 1.7% of subfertile births, and 1.4% of fertile births (Birth Defects Res. 2017 Aug 15;109[14]:1144-53). The adjusted prevalence ratios for birth defects were 1.5 for ART births and 1.3 for subfertile births, compared with fertile mother births. The researchers observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects.
“The absolute risk of birth defects is small with ART,” Dr. Gambone said. “A significant portion [but not all] is related to multiple births and underlying subfertility.” A more recent analysis found that subfertile women were 21% more likely to have babies born with birth defects, compared with fertile women (Pediatrics. 2018 Jul; e20174069).
In a study of the overall risk and etiology of major birth defects, researchers from Utah determined that they affect 1 in 33 babies in the United States at an annual direct cost of $2.6 billion per year (BMJ. 2017;357:j2249). Although major birth defects are the leading cause of infant mortality (20%), a known cause of the defect was established in only 20.2% of cases. “Of that percentage, the majority are chromosome or genetic causes,” Dr. Gambone said. “Interestingly, ART and/or subfertility were not listed in this analysis as causes of birth defects. However, the authors speculated that as genetic technology improves, both genetic and epigenetic causes will be identified.”
Dr. Gambone reported no relevant financial disclosures.
[email protected]
CORONADO, CALIF. –
In addition, multiples conceived using ART – including twins – continue to be the biggest preventable risk factor for adverse pregnancy and fetal outcomes.
Those are key points that Joseph C. Gambone, DO, MPH, made during a wide-ranging talk about the adverse pregnancy and fetal outcomes related to ART at a meeting on in vitro fertilization (IVF) and embryo transfer sponsored by the University of California, San Diego.
In 2016, Barbara Luke, ScD, MPH, and her colleagues published results from the ongoing Massachusetts Outcomes Study of Reproductive Technologies (J Reprod Med. 2016 Mar-Apr;61[3-4]:114-27). They found that pregnancy plurality is the predominant risk factor for infants and mothers. Of 8,948 birth outcomes resulting from ART, risks for pregnancy-induced hypertension, cesarean delivery, gestational diabetes, preterm birth, birth defects, and small for gestational age were significantly increased among twins.
“Lowering the plurality rate, including twins, should substantially reduce morbidity with ART,” said Dr. Gambone, professor emeritus at the David Geffen School of Medicine at the University of California, Los Angeles, who was not affiliated with the study. Thawed embryos were associated with a higher risk for pregnancy-induced hypertension and large for gestational age offspring, but a lower risk for low birth weight and small for gestational age.
According to data from the Society for Assisted Reproductive Technology, elective singleton embryo transfer increased from 35% of all cycles in 2015 to 42% in 2016, while singleton births increased from 80.5% to 84% during the same time period. In addition, the proportion of twins born in 2015 was 19% and declined to 16% in 2016, while the percentage of triplets or greater born was the same in both years (0.4%).
Meanwhile, in an analysis of more than 1.1 million cycles between 2000 and 2011 drawn from Centers for Disease Control and Prevention surveillance data, researchers found that the most commonly reported patient complication was ovarian hyperstimulation syndrome (a peak of 154 per 10,000 autologous cycles) and hospitalization (a peak of 35 per 10,000 autologous cycles; JAMA. 2015 Jan 6;313[1]:88-90). Other complications remained below 10 per 10,000 cycles and included infection, hemorrhage with transfusion, adverse event from medication, adverse event to anesthesia, and patient death. In all, 58 deaths were reported: 18 because of stimulation and 40 during pregnancy. “Some deaths were due to potentially preventable complications because of unrecognized comorbidities or conditions,” said Dr. Gambone, who was not affiliated with the study. “Women with Turner syndrome who receive donor embryos could be an example.”
Today, the most feared maternal and pregnancy outcome from ART is breast and ovarian cancer from treatment, he said, while the most feared outcome in offspring is birth defects from treatment. On the breast cancer front, an analysis of nearly 2 million women provided some reassurance (Fertil Steril. 2017 Jul;108:137-44). It found no increased risk of breast cancer in women who have birth after ART, compared with women who gave birth after spontaneous conception (adjusted hazard ratio, 0.84). It also found no increased risk in women who received ovarian stimulation or other hormonal treatment for infertility (HRs, 0.86 and 0.79, respectively). A smaller study with a median follow-up of 21 years found no difference in the rate of invasive and in situ breast cancer between women who received IVF treatment and those who did not (JAMA. 2016 Jul 19;316[3]:300-12). However, a recent analysis from Great Britain found a slight increase for in situ breast cancer that was associated with women who had a higher number of treatment cycles (BMJ. 2018;362:k2644).
On the ovarian cancer front, a case-control analysis of 1,900 women conducted by researchers at Mayo Clinic found that infertile women who used fertility drugs were not at increased risk of developing ovarian tumors, compared with infertile women who did not use fertility drugs (adjusted odds ratio, 0.64; Fertil Steril. 2013;99[7]:2031-6). There also was no increased risk because of underlying infertility or any increase in borderline tumors. More recently, an abstract presented at the annual meeting of the European Society of Human Reproduction and Embryology, based on a large cohort study from Denmark, found a slightly higher overall risk of ovarian cancer among the ART women (0.11%), compared with non-ART controls (0.06%). However, the analysis also showed comparably higher rates of ovarian cancer in women who were nulliparous (a risk factor for ovarian cancer) and in the ART women who had a female cause of infertility. In an analysis from Great Britain, increased ovarian tumor risk was limited to women with endometriosis, low parity, or both (BMJ. 2018;362:k2644). Dr. Gambone noted that an article published online Oct. 23, 2017 in Nature Communication implicates the fallopian tube, rather than the ovaries, as a probable source of papillary serous cancers.
Women who are subfertile should be counseled about the increased risk of birth defects, irrespective of whether they undergo IVF or not, said Dr. Gambone, who also runs a private infertility practice in Durango, Colo. Studies consistently show an increased risk associated with subfertility. A large, retrospective cohort analysis of live and stillbirths from 2004 to 2010 in Massachusetts found that congenital anomalies were reported in 2% of ART births, 1.7% of subfertile births, and 1.4% of fertile births (Birth Defects Res. 2017 Aug 15;109[14]:1144-53). The adjusted prevalence ratios for birth defects were 1.5 for ART births and 1.3 for subfertile births, compared with fertile mother births. The researchers observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects.
“The absolute risk of birth defects is small with ART,” Dr. Gambone said. “A significant portion [but not all] is related to multiple births and underlying subfertility.” A more recent analysis found that subfertile women were 21% more likely to have babies born with birth defects, compared with fertile women (Pediatrics. 2018 Jul; e20174069).
In a study of the overall risk and etiology of major birth defects, researchers from Utah determined that they affect 1 in 33 babies in the United States at an annual direct cost of $2.6 billion per year (BMJ. 2017;357:j2249). Although major birth defects are the leading cause of infant mortality (20%), a known cause of the defect was established in only 20.2% of cases. “Of that percentage, the majority are chromosome or genetic causes,” Dr. Gambone said. “Interestingly, ART and/or subfertility were not listed in this analysis as causes of birth defects. However, the authors speculated that as genetic technology improves, both genetic and epigenetic causes will be identified.”
Dr. Gambone reported no relevant financial disclosures.
[email protected]
EXPERT ANALYSIS FROM A CME MEETING SPONSORED BY UCSD
Two approaches lowered opioid use after cesarean deliveries
An individual prescribing plan based on inpatient use for women who delivered by cesarean section was associated with a lower number of unused oxycodone tablets, according to research published in Obstetrics & Gynecology.
In a second study, there was a significantly lower number of opioid tablets prescribed for women who delivered by cesarean section after a shared decision-making quality improvement plan was implemented on an inpatient basis.
Sarah S. Osmundson, MD, MS, of Vanderbilt University Medical Center in Nashville, Tenn., and her colleagues conducted a randomized, controlled trial of women who underwent cesarean delivery between June and August 2017. Of these women, 85 were randomized to receive standard care of 30 oxycodone tablets (5 mg) and 87 received an individualized care plan based on inpatient use of oxycodone. Patients were a minimum of 18 years old with similar baseline characteristics and inpatient pain scores.
The investigators found that women who were randomized to the individual care group received 14 oxycodone tablets (interquartile range, 12-16) and had 5 tablets (IQR, 1-8) left 2 weeks after discharge, compared with women who were prescribed 30 tablets in the standard care group (IQR, 30-30; P less than .001) and left 10 tablets unused (IQR, 0-22; P less than .001). There were no significant differences regarding patient-reported pain outcomes in either group, and women used about half as many prescribed tablets in the individualized group (8; IQR, 4-14), compared with women in the standard care group (15; IQR, 6-30; P less than .001).
Most women reported that they used opioids to treat pain and 30% said they believed they were supposed to finish all the tablets that were prescribed, the researchers noted. There were 11 patients (13%) in the standard care group and 12 (14%) in the individualized group who did not use any opioids; similarly, 23 patients (27%) in the standard care group and 21 (24%) in the individual care group used all tablets prescribed.
“If pain were the only determinant of opioid use, randomization should yield similar opioid use in both study groups,” Dr. Osmundson and her colleagues wrote. “These findings suggest that factors other than pain influence opioid use patterns.”
In a second study, Malavika Prabhu, MD, of Massachusetts General Hospital in Boston, and her colleagues employed a prospective quality improvement (QI) initiative for women prescribed opioids after cesarean delivery. They evaluated the opioid use of 624 women and counseled them at discharge on the need for prescription opioids, using shared decision-making to determine the number of opioid tablets, with a maximum number of 30 oxycodone tablets (5 mg). The investigators also changed their protocol for multimodal analgesia to scheduled acetaminophen and NSAIDs. Patients were a mean of 30 years old and more than 50% were white. Median gestational age was 39 weeks at delivery. In a second phase of the study, the investigators lowered the maximum number of opioid tablets prescribed to 25 tablets.
At discharge, the mean number of prescribed opioid tablets decreased to 27 tablets from 33 tablets in phase 1 (P less than .01). In phase 2, the number of tablets further decreased to 22 tablets from 25 tablets (P less than .01). The investigators noted no significant difference in the refill rate during phase 1 (8% vs. 9%; P less than .79) and phase 2 (6% vs. 6%; P = .72). There was a significant increase in prescribing of acetaminophen from 33% at baseline to 77% at the end of phase 1 and an increase at the beginning of phase 2 at 91% to 92% at the end of phase 2. There were no statistically significant differences among prescriptions of ibuprofen at any phase time point.
“As a result of our success in decreasing opioid prescribing after cesarean delivery, our current protocol has again been amended to recommend a maximum of 20 tablets of 5-mg oxycodone (or equivalent opioid) prescribed at the time of discharge,” Dr. Prabhu and her colleagues wrote. “This decrease, which represents a 50% decrease in the departmental standard before this study, has been successfully implemented in 18 months. In addition, efforts to optimize multimodal analgesic use continue both inpatient and on discharge.”
Dr. Osmundson was supported by a grant from the National Institutes of Health, and the research also was supported by an award from the National Center for Advancing Translational Sciences; the authors of the study reported no relevant conflicts of interest. The authors led by Dr. Prabhu had no relevant financial disclosures.
SOURCE: Prabhu M et al. Obstet Gyncol. 2018 Aug 4; doi: 10.1097/AOG.0000000000002789, and Osmundson SS et al. Obstet Gynecol. 2018 Aug 6; doi: 10.1097/AOG.0000000000002782.
While overprescribing opioids for women after cesarean delivery will probably have little effect on the opioid crisis, reducing prescription rates for these women post partum still has benefits for mother and child, Bankole Johnson, MD, DSc, said in an interview.
“The larger problem is with mothers who are dependent on opiates who get pregnant,” Dr. Johnson said. “These mothers give birth to children who need significant support and weaning off opiates, sometime in the NICU, and the mother also has to be treated by the addiction services. Sometimes, the mother simply abandons the baby who is difficult to nurse and comfort because he or she is weaning off opiates.”
Dr. Johnson said overprescribing has three main implications or risks: a risk of developing dependence in newborn babies that are breastfed, an increased risk of dependence for the mother, and a decrease in nurturing skills and bonding from the mother due to high opioid use.
He said these studies had “notable caveats” and noted there may not be much clinical significance because of the small numeric difference in opioid use.
“The best take-home message from these papers is that individualized care with supportive services decreases opioid use and optimizes the care of mothers and their babies after a cesarean section,” he said.
Dr. Johnson is the Dr. Irving J. Taylor Professor and Chair in the department of psychiatry; professor of both neurology and pharmacology, among others; and director of the Brain Science Research Consortium Unit at the University of Maryland, Baltimore. He had no relevant financial disclosures.
While overprescribing opioids for women after cesarean delivery will probably have little effect on the opioid crisis, reducing prescription rates for these women post partum still has benefits for mother and child, Bankole Johnson, MD, DSc, said in an interview.
“The larger problem is with mothers who are dependent on opiates who get pregnant,” Dr. Johnson said. “These mothers give birth to children who need significant support and weaning off opiates, sometime in the NICU, and the mother also has to be treated by the addiction services. Sometimes, the mother simply abandons the baby who is difficult to nurse and comfort because he or she is weaning off opiates.”
Dr. Johnson said overprescribing has three main implications or risks: a risk of developing dependence in newborn babies that are breastfed, an increased risk of dependence for the mother, and a decrease in nurturing skills and bonding from the mother due to high opioid use.
He said these studies had “notable caveats” and noted there may not be much clinical significance because of the small numeric difference in opioid use.
“The best take-home message from these papers is that individualized care with supportive services decreases opioid use and optimizes the care of mothers and their babies after a cesarean section,” he said.
Dr. Johnson is the Dr. Irving J. Taylor Professor and Chair in the department of psychiatry; professor of both neurology and pharmacology, among others; and director of the Brain Science Research Consortium Unit at the University of Maryland, Baltimore. He had no relevant financial disclosures.
While overprescribing opioids for women after cesarean delivery will probably have little effect on the opioid crisis, reducing prescription rates for these women post partum still has benefits for mother and child, Bankole Johnson, MD, DSc, said in an interview.
“The larger problem is with mothers who are dependent on opiates who get pregnant,” Dr. Johnson said. “These mothers give birth to children who need significant support and weaning off opiates, sometime in the NICU, and the mother also has to be treated by the addiction services. Sometimes, the mother simply abandons the baby who is difficult to nurse and comfort because he or she is weaning off opiates.”
Dr. Johnson said overprescribing has three main implications or risks: a risk of developing dependence in newborn babies that are breastfed, an increased risk of dependence for the mother, and a decrease in nurturing skills and bonding from the mother due to high opioid use.
He said these studies had “notable caveats” and noted there may not be much clinical significance because of the small numeric difference in opioid use.
“The best take-home message from these papers is that individualized care with supportive services decreases opioid use and optimizes the care of mothers and their babies after a cesarean section,” he said.
Dr. Johnson is the Dr. Irving J. Taylor Professor and Chair in the department of psychiatry; professor of both neurology and pharmacology, among others; and director of the Brain Science Research Consortium Unit at the University of Maryland, Baltimore. He had no relevant financial disclosures.
An individual prescribing plan based on inpatient use for women who delivered by cesarean section was associated with a lower number of unused oxycodone tablets, according to research published in Obstetrics & Gynecology.
In a second study, there was a significantly lower number of opioid tablets prescribed for women who delivered by cesarean section after a shared decision-making quality improvement plan was implemented on an inpatient basis.
Sarah S. Osmundson, MD, MS, of Vanderbilt University Medical Center in Nashville, Tenn., and her colleagues conducted a randomized, controlled trial of women who underwent cesarean delivery between June and August 2017. Of these women, 85 were randomized to receive standard care of 30 oxycodone tablets (5 mg) and 87 received an individualized care plan based on inpatient use of oxycodone. Patients were a minimum of 18 years old with similar baseline characteristics and inpatient pain scores.
The investigators found that women who were randomized to the individual care group received 14 oxycodone tablets (interquartile range, 12-16) and had 5 tablets (IQR, 1-8) left 2 weeks after discharge, compared with women who were prescribed 30 tablets in the standard care group (IQR, 30-30; P less than .001) and left 10 tablets unused (IQR, 0-22; P less than .001). There were no significant differences regarding patient-reported pain outcomes in either group, and women used about half as many prescribed tablets in the individualized group (8; IQR, 4-14), compared with women in the standard care group (15; IQR, 6-30; P less than .001).
Most women reported that they used opioids to treat pain and 30% said they believed they were supposed to finish all the tablets that were prescribed, the researchers noted. There were 11 patients (13%) in the standard care group and 12 (14%) in the individualized group who did not use any opioids; similarly, 23 patients (27%) in the standard care group and 21 (24%) in the individual care group used all tablets prescribed.
“If pain were the only determinant of opioid use, randomization should yield similar opioid use in both study groups,” Dr. Osmundson and her colleagues wrote. “These findings suggest that factors other than pain influence opioid use patterns.”
In a second study, Malavika Prabhu, MD, of Massachusetts General Hospital in Boston, and her colleagues employed a prospective quality improvement (QI) initiative for women prescribed opioids after cesarean delivery. They evaluated the opioid use of 624 women and counseled them at discharge on the need for prescription opioids, using shared decision-making to determine the number of opioid tablets, with a maximum number of 30 oxycodone tablets (5 mg). The investigators also changed their protocol for multimodal analgesia to scheduled acetaminophen and NSAIDs. Patients were a mean of 30 years old and more than 50% were white. Median gestational age was 39 weeks at delivery. In a second phase of the study, the investigators lowered the maximum number of opioid tablets prescribed to 25 tablets.
At discharge, the mean number of prescribed opioid tablets decreased to 27 tablets from 33 tablets in phase 1 (P less than .01). In phase 2, the number of tablets further decreased to 22 tablets from 25 tablets (P less than .01). The investigators noted no significant difference in the refill rate during phase 1 (8% vs. 9%; P less than .79) and phase 2 (6% vs. 6%; P = .72). There was a significant increase in prescribing of acetaminophen from 33% at baseline to 77% at the end of phase 1 and an increase at the beginning of phase 2 at 91% to 92% at the end of phase 2. There were no statistically significant differences among prescriptions of ibuprofen at any phase time point.
“As a result of our success in decreasing opioid prescribing after cesarean delivery, our current protocol has again been amended to recommend a maximum of 20 tablets of 5-mg oxycodone (or equivalent opioid) prescribed at the time of discharge,” Dr. Prabhu and her colleagues wrote. “This decrease, which represents a 50% decrease in the departmental standard before this study, has been successfully implemented in 18 months. In addition, efforts to optimize multimodal analgesic use continue both inpatient and on discharge.”
Dr. Osmundson was supported by a grant from the National Institutes of Health, and the research also was supported by an award from the National Center for Advancing Translational Sciences; the authors of the study reported no relevant conflicts of interest. The authors led by Dr. Prabhu had no relevant financial disclosures.
SOURCE: Prabhu M et al. Obstet Gyncol. 2018 Aug 4; doi: 10.1097/AOG.0000000000002789, and Osmundson SS et al. Obstet Gynecol. 2018 Aug 6; doi: 10.1097/AOG.0000000000002782.
An individual prescribing plan based on inpatient use for women who delivered by cesarean section was associated with a lower number of unused oxycodone tablets, according to research published in Obstetrics & Gynecology.
In a second study, there was a significantly lower number of opioid tablets prescribed for women who delivered by cesarean section after a shared decision-making quality improvement plan was implemented on an inpatient basis.
Sarah S. Osmundson, MD, MS, of Vanderbilt University Medical Center in Nashville, Tenn., and her colleagues conducted a randomized, controlled trial of women who underwent cesarean delivery between June and August 2017. Of these women, 85 were randomized to receive standard care of 30 oxycodone tablets (5 mg) and 87 received an individualized care plan based on inpatient use of oxycodone. Patients were a minimum of 18 years old with similar baseline characteristics and inpatient pain scores.
The investigators found that women who were randomized to the individual care group received 14 oxycodone tablets (interquartile range, 12-16) and had 5 tablets (IQR, 1-8) left 2 weeks after discharge, compared with women who were prescribed 30 tablets in the standard care group (IQR, 30-30; P less than .001) and left 10 tablets unused (IQR, 0-22; P less than .001). There were no significant differences regarding patient-reported pain outcomes in either group, and women used about half as many prescribed tablets in the individualized group (8; IQR, 4-14), compared with women in the standard care group (15; IQR, 6-30; P less than .001).
Most women reported that they used opioids to treat pain and 30% said they believed they were supposed to finish all the tablets that were prescribed, the researchers noted. There were 11 patients (13%) in the standard care group and 12 (14%) in the individualized group who did not use any opioids; similarly, 23 patients (27%) in the standard care group and 21 (24%) in the individual care group used all tablets prescribed.
“If pain were the only determinant of opioid use, randomization should yield similar opioid use in both study groups,” Dr. Osmundson and her colleagues wrote. “These findings suggest that factors other than pain influence opioid use patterns.”
In a second study, Malavika Prabhu, MD, of Massachusetts General Hospital in Boston, and her colleagues employed a prospective quality improvement (QI) initiative for women prescribed opioids after cesarean delivery. They evaluated the opioid use of 624 women and counseled them at discharge on the need for prescription opioids, using shared decision-making to determine the number of opioid tablets, with a maximum number of 30 oxycodone tablets (5 mg). The investigators also changed their protocol for multimodal analgesia to scheduled acetaminophen and NSAIDs. Patients were a mean of 30 years old and more than 50% were white. Median gestational age was 39 weeks at delivery. In a second phase of the study, the investigators lowered the maximum number of opioid tablets prescribed to 25 tablets.
At discharge, the mean number of prescribed opioid tablets decreased to 27 tablets from 33 tablets in phase 1 (P less than .01). In phase 2, the number of tablets further decreased to 22 tablets from 25 tablets (P less than .01). The investigators noted no significant difference in the refill rate during phase 1 (8% vs. 9%; P less than .79) and phase 2 (6% vs. 6%; P = .72). There was a significant increase in prescribing of acetaminophen from 33% at baseline to 77% at the end of phase 1 and an increase at the beginning of phase 2 at 91% to 92% at the end of phase 2. There were no statistically significant differences among prescriptions of ibuprofen at any phase time point.
“As a result of our success in decreasing opioid prescribing after cesarean delivery, our current protocol has again been amended to recommend a maximum of 20 tablets of 5-mg oxycodone (or equivalent opioid) prescribed at the time of discharge,” Dr. Prabhu and her colleagues wrote. “This decrease, which represents a 50% decrease in the departmental standard before this study, has been successfully implemented in 18 months. In addition, efforts to optimize multimodal analgesic use continue both inpatient and on discharge.”
Dr. Osmundson was supported by a grant from the National Institutes of Health, and the research also was supported by an award from the National Center for Advancing Translational Sciences; the authors of the study reported no relevant conflicts of interest. The authors led by Dr. Prabhu had no relevant financial disclosures.
SOURCE: Prabhu M et al. Obstet Gyncol. 2018 Aug 4; doi: 10.1097/AOG.0000000000002789, and Osmundson SS et al. Obstet Gynecol. 2018 Aug 6; doi: 10.1097/AOG.0000000000002782.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point: Individualized opioid prescription and a quality improvement plan for opioid prescribing among women who underwent cesarean delivery lowered the number of overall tablets used among these patients.
Major finding: Patients who were prescribed at discharge the number of inpatient opioid tablets used had fewer leftover tablets than did patients prescribed the standard of care; there was a mean lower number of opioid tablets prescribed after delivery in the study with a quality improvement plan, from 33 tablets to 27 tablets.
Data source: A randomized controlled trial of 323 women who underwent cesarean delivery and were prescribed opioid tablets, and a quality improvement trial of 624 women.
Disclosures: Dr. Osmundson was supported by a grant from the National Institutes of Health, and the research also was supported by an award from the National Center for Advancing Translational Sciences; the authors of the study reported no relevant conflicts of interest. The authors led by Dr. Prabhu had no relevant financial disclosures.
Source: Prabhu M et al. Obstet Gyncol. 2018 Aug 4. doi: 10.1097/AOG.0000000000002789 and Osmundson SS et al. Obstet Gynecol. 2018 Aug 6. doi: 10.1097/AOG.0000000000002782.