Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

Retail Health Clinics (RHCs) are health care facilities located in high-traffic retail outlets with adjacent pharmacies that are intended to provide convenient and affordable care without sacrificing quality. The clinics add an option that complements services to individuals and families who otherwise would need to wait for an appointment with a traditional primary care physician or provider.¹ Appointments are not necessary for episodic health needs. Usually open 7 days a week, RHCs offer extended hours on weekdays.²

The clinics are staffed by licensed, qualified advance practice providers, such as nurse practitioners and physician assistants, who are supervised by family physicians where required by state law. These clinicians have advanced education to diagnose, treat, and prescribe for nonemergent ailments such as colds and flu, rashes and skin irritation, and muscle strains or sprains.³ They are supported by an electronic health record that contains established evidence-based protocols.^2,4

Evolution of retail health clinics

The first RHC, operated by QuickMedx, opened its doors in 2000 in Minneapolis– St. Paul.^1,5 Only patients with a very limited number of illnesses were seen, and payment was cash. In 2005, this clinic was acquired by a major pharmacy retailer, which led to several acquisitions by other retailers and health care systems. In addition to accepting cash for a visit, the clinics formed contracts with health insurance companies. The average cost of a visit to an RHC in 2016 was estimated to be $70, considerably less than the cost at urgent care clinics ($124) and emergency rooms ($356).⁶

Today, more than 20 companies provide health care services at RHCs (TABLE 1). CVS (MinuteClinic) has the most retail clinics, followed by Walgreens, Kroger, Rite Aid, and Zoom+Care.^1,2 There are now about 3,300 clinics in the United States, Canada, and Mexico (nearly all are located in the United States).² Currently, RHCs are present in 44 states and the District of Columbia. Alabama, Alaska, Idaho, North Dakota, Vermont, and Wyoming are the only states without an RHC, while large-population states (California, Florida, Ohio, Pennsylvania, and Texas) have experienced an explosion in clinic openings.²

RHCs are found in high foot traffic locations, such as large retailers and grocery stores, and in prioritizing services such as drug stores. By analyzing 2019 clinic openings and population centers, the Convenient Care Association determined that more than half of the US population now lives within a 10-minute drive of an RHC.² New locations are established on a regular basis, resulting in some flux in the total number of clinics.

Continue to: Services that RHCs provide...

As RHC locations expand, so do their services. Most RHCs pursue 1 of 2 models: health hubs or virtual care. Health hubs offer an expansion of services, which has resulted in retail health looking and operating more like the primary care providers in their communities.^1,2 While most chains intend for patient visits to be brief, the growing health hub model intends to expand the period for patient visits. The major companies, CVS, Kroger, and Walmart, are offering an increase in their services and granting their providers a greater capacity to screen and treat patients for a wider range of conditions. By contrast, other clinic operators, such as Rite Aid RediClinics, are pursuing a more episodic and convenient care model with a greater adoption and expansion of telehealth and telemedicine.

Services at RHCs involve primarily acute care as well as some basic chronic disease management. About 90% of visits are for the following conditions: influenza, immunizations, upper respiratory infections, sinusitis, bronchitis, sore throat, inner ear infection, conjunctivitis, urinary tract infections, and blood tests.^1-3 Other services available at most RHC locations involve screening and monitoring, wellness and physicals, travel health, treatment of minor injuries, and vaccinations and injections.

Women constitute half of all customers, and all RHCs offer women’s health services.⁷ Along with addressing acute care needs, women’s health services include contraception care and options, human papillomavirus (HPV) screening, pregnancy testing and initial prenatal evaluation, and evaluation for and treatment of urinary tract, bladder, and yeast infections.^2,6

All RHCs provide counseling on sexual health concerns. Nearly all retail clinics in the United States provide screening and treatment for patients and their partners with sexually transmitted infections. RHC providers are required to follow up with patients regarding any blood work or culture results. When positive test results are confirmed for serious infections, such as hepatitis B and C, syphilis, and HIV, patients customarily are referred for treatment.²

The RHC patient base

RHCs serve an expanding base of patients who cite convenience as their primary motivation for utilizing these clinics. This consumer-driven market now encompasses, by some measures, nearly 50 million visits annually.² These numbers have risen every year alongside a consistent increase in the number and spread of clinics across the country. During the COVID-19 pandemic, visits declined, consistent with other health care touchpoints, due to concerns about spreading the coronavirus.

The RHC industry has continued to adapt to a changing health care climate by embracing new telehealth solutions, enabling remote care, and expanding services by consumer demand.^1,7 While convenience is a primary motivation for visiting an RHC, about two-thirds of RHC patients do not have a primary care provider.¹ To support a broader continuum of care, RHCs regularly refer patients who do not have a primary care provider to other health care touchpoints when necessary.

Young and middle-aged adults (18–44 years) comprise the largest group of RHC patients. When patients were asked why they chose an RHC over “traditional doctors’ clinics,” many cited difficulties in accessing care, the appeal of lower costs, and proximity. The proportion of female RHC users was 50.9% and 56.8% for RHC nonusers.^1-3

How RHCs compare with other episodic care clinics

The consumer has more choices to seek episodic care other than at physicians’ clinics or emergency rooms. An RHC, urgent care clinic, or freestanding emergency clinic increase access points for consumers. Along with the expanding number of RHCs, there are nearly 9,000 US urgent care centers, according to the Urgent Care Association, and more than 550 freestanding emergency rooms.⁸

The main differences between these episodic care clinics are shown in TABLE 2. Hours of operation, types of conditions, available providers, location of the facility, and estimated costs are compared. All provide expanded business hours. Retail clinics address some chronic disease management along with acute care, engage only advanced practitioners, use retail stores, and are less costly to consumers.^3,4,9

An RHC, urgent care clinic, or emergency department increases access points for consumers. Many emergency department visits can be handled in ambulatory settings such as RHCs and urgent care clinics.^9,10 This can be helpful, especially in rural areas with a shortage of physicians. Most people want a relationship with a physician who will manage their care rather than seeing a different provider at every visit. While ObGyns deliver comprehensive care to women, however, in some underserved areas non-ObGyn clinics can fill the void. For example, RHCs can sometimes provide needed immunizations and health care information required in underserved areas.¹¹

Many physicians are frustrated when they see patients who do not have a complete copy of their medical record and must piecemeal how to treat a patient. RHCs have adopted electronic medical records, and they regularly encourage patients to contact their physician (or find one, which can be difficult). Another limitation can be a referral from an RHC to a subspecialist rather than a primary care physician who could equally handle the condition.

Continue to: What ObGyns can do...

What ObGyns can do

Consumers have become accustomed to obtaining services where and when they want them, and they expect the same from their health care providers. While ObGyn practices are less affected by RHCs than family physicians or general internists, health care delivery in traditional clinics must be user friendly—that is, better, cheaper, and faster—for the patient-consumer to be more satisfied. Looking ahead, a nearby women’s health care group needs to have someone on call 24 hours a day, 7 days a week. That way, you can tell your patients that they can call you first if they need help. In the case of an ObGyn recommending that a patient go to an RHC or urgent care center, you will be aware of the visit and can follow up with your patient afterward.

Traditional clinics need to create ways for patients with acute illnesses to be seen that same day. Offering extended hours or technology options, such as online support, can help. Text message reminders, same-day access for appointments, and price transparency are necessary. It is important to encourage your women’s health patients to become more responsible for their own health and care, while taking into consideration their social determinants of health. While ObGyns should discuss with their patients when to visit an RHC (especially when their clinic is closed), emphasize that your own clinic is the patient’s medical home and encourage the importance of communicating what occurred during the RHC visit.

Working as a team by communicating well can create a community of health. It would be appropriate for you to represent your group by meeting practitioners at the nearby RHC. Being accessible and helpful would create a friendly and open professional relationship. Conversely, providers at retail clinics need to continually appreciate that women’s health clinics offer more comprehensive care. Select referrals from RHCs would help the most important person, the patient herself. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Pregnant woman with herpes simplex virus

A 26-year-old primigravid woman at 12 weeks of gestation indicates that she had an initial episode of herpes simplex virus (HSV) 6 years prior to presentation. Subsequently, she has had 1 to 2 recurrent episodes each year. She asks about the implications of HSV infection in pregnancy, particularly if anything can be done to prevent a recurrent outbreak near her due date and reduce the need for a cesarean delivery.

How would you counsel this patient?

Meet our perpetrator

Herpes simplex virus (HSV), the most prevalent sexually transmitted infection, is a DNA virus that has 2 major strains: HSV-1 and HSV-2. HSV-1 frequently is acquired in early childhood through nonsexual contact and typically causes orolabial and, less commonly, genital outbreaks. HSV-2 is almost always acquired through sexual contact and causes mainly genital outbreaks.¹

There are 3 classifications of HSV infection: primary, initial-nonprimary, and recurrent (TABLE).

Primary infection refers to infection in a person without antibodies to either type of HSV.

Initial-nonprimary infection refers to acquisition of HSV-2 in a patient with preexisting antibodies to HSV-1 or vice versa. Patients tend to have more severe symptoms with primary as opposed to initial-nonprimary infection because, with the latter condition, preexisting antibodies provide partial protection against the opposing HSV type.¹ According to the Centers for Disease Control and Prevention, the seroprevalence of HSV-1 has decreased by approximately 23% in adolescents aged 14 to 19 years, with a resultant increase in the number of primary HSV-1 genital infections through oral-sexual contact in adulthood.²

Recurrent infection refers to reactivation of the same HSV type corresponding to the serum antibodies.

Clinical presentation

After an incubation period of 4 to 7 days, symptomatic patients with primary and initial-nonprimary genital HSV infections typically present with multiple, bilateral genital lesions at various stages of development. These lesions begin as small erythematous macules and then progress to papules, vesicles, pustules, ulcers, and crusted scabs over a period of 3 to 6 weeks¹ (FIGURE). Patients also may present with fever, headache, fatigue, dysuria, and painful inguinal lymphadenopathy. Patients with recurrent infections usually experience prodromal itching or tingling for 2 to 5 days prior to the appearance of unilateral lesions, which persist for only 5 to 10 days. Systemic symptoms rarely are present. HSV-1 genital infection has a symptomatic recurrence rate of 20% to 50% within the first year, while HSV-2 has a recurrence rate of 70% to 90%.¹

The majority of primary and initial-nonprimary infections are subclinical. One study showed that 74% of HSV-1 and 63% of HSV-2 initial genital herpes infections were asymptomatic.³ The relevance of this observation is that patients may not pre­sent for evaluation unless they experience a symptomatic recurrent infection. Meanwhile, they are asymptomatically shedding the virus and unknowingly transmitting HSV to their sexual partners. Asymptomatic viral shedding is more common with HSV-2 and is the most common source of transmission.⁴ The rate of asymptomatic shedding is unpredictable and has been shown to occur on 10% to 20% of days.¹

Diagnosis and treatment

The gold standard for diagnosing HSV infection is viral culture; however, polymerase chain reaction (PCR) assays are faster to result and more sensitive.^4,5 Both culture and PCR studies can distinguish the HSV type, allowing physicians to counsel patients regarding the expected clinical course, rate of recurrence, and implications for future pregnancies. After an initial infection, it may take up to 12 weeks for patients to develop detectable antibodies. Therefore, serology can be quite useful in determining the timing and classification of the infection. For example, a patient with HSV-2 isolated on viral culture or PCR and HSV-1 antibodies identified on serology is classified as having an initial-nonprimary infection.⁴

HSV treatment is dependent on the classification of infection. Treatment of primary and initial-nonprimary infection includes:

• acyclovir 400 mg orally 3 times daily
• valacyclovir 1,000 mg orally twice daily, or
• famciclovir 250 mg orally 3 times daily for 7 to 10 days.

Ideally, treatment should be initiated within 72 hours of symptom onset.

Recurrent infections may be treated with:

• acyclovir 400 mg orally three times daily for 5 days
• valacyclovir 1,000 mg orally once daily for 5 days, or
• famciclovir 1,000 mg orally every 12 hours for 2 doses.

Ideally, treatment should begin within 24 hours of symptom onset.^4,6

Patients with immunocompromising conditions, severe/frequent outbreaks (>6 per year), or who desire to reduce the risk of transmission to HSV-uninfected partners are candidates for chronic suppressive therapy. Suppressive options include acyclovir 400 mg orally twice daily, valacyclovir 500 mg orally once daily, and famciclovir 250 mg orally twice daily. Of note, there are many regimens available for acyclovir, valacyclovir, and famciclovir; all have similar efficacy in decreasing symptom severity, time to lesion healing, and duration of viral shedding.⁶ Acyclovir generally is the least expensive option.⁴

Continue to: Pregnancy and prevention...

During pregnancy, 2% of women will acquire HSV, and 70% of these women will be asymptomatic.^4,7 Approximately one-third to one-half of neonatal infections are caused by HSV-1.⁸ The most devastating complication of HSV infection in pregnancy is transmission to the newborn. Neonatal herpes is defined as the diagnosis of an HSV infection in a neonate within the first 28 days of life. The disease spectrum varies widely, and early recognition and treatment can substantially reduce the degree of morbidity and mortality associated with systemic infections.

HSV infection limited to the skin, eyes, and mucosal surfaces accounts for 45% of neonatal infections. When this condition is promptly recognized, neonates typically respond well to intravenous acyclovir, with prevention of systemic progression and overall good clinical outcomes. Infections of the central nervous system account for 30% of infections and are more difficult to diagnose due to the nonspecific symptomatology, including lethargy, poor feeding, seizures, and possible absence of lesions. The risk for death decreases from 50% to 6% with treatment; however, most neonates will still require close long-term surveillance for achievement of neurodevelopmental milestones and frequent ophthalmologic and hearing assessments.^8,9 Disseminated HSV accounts for 25% of infections and can cause multiorgan failure, with a 31% risk for death despite treatment.⁵ Therefore, the cornerstone of managing HSV infection in pregnancy is focusing clinical efforts on prevention of transmission to the neonate.

More than 90% of neonatal herpes infections are acquired intrapartum,⁴ with 60% to 80% of cases occurring in women who developed HSV in the third trimester near the time of delivery.⁵ Neonates delivered vaginally to these women have a 30% to 50% risk of infection, compared to a <1% risk in neonates born to women with recurrent HSV.^1,5,10 The discrepancy in infection risk is thought to be secondary to higher HSV viral loads after an initial infection as opposed to a recurrent infection. Furthermore, acquisition of HSV near term does not allow for the 6 to 12 weeks necessary to develop antibodies that can cross the placenta and provide neonatal protection. The risk of vertical transmission is approximately 25% with an initial-nonprimary episode, reflecting the partial protection afforded by antibody against the other viral serotype.¹¹

Prophylactic therapy has been shown to reduce the rate of asymptomatic viral shedding and recurrent infections near term.⁷ To reduce the risk of intrapartum transmission, women with a history of HSV prior to or during pregnancy should be treated with acyclovir 400 mg orally 3 times daily starting at 36 weeks of gestation. When patients present with rupture of membranes or labor, they should be asked about prodromal symptoms and thoroughly examined. If prodromal symptoms are present or genital lesions identified, patients should undergo cesarean delivery.¹² Some experts also recommend cesarean delivery for women who acquire primary or initial-nonprimary HSV infection in the third trimester due to higher viral loads and potential lack of antibodies at the time of delivery.^8,12 However, this recommendation has not been validated by a rigorous prospective randomized clinical trial. When clinically feasible, avoidance of invasive fetal monitoring during labor also has been shown to decrease the risk of HSV transmission by approximately 84% in women with asymptomatic viral shedding.¹² This concept may be extrapolated to include assisted delivery with vacuum or forceps.

Universal screening for HSV infection in pregnancy is controversial and widely debated. Most HSV seropositive patients are asymptomatic and will not report a history of HSV infection at the initial prenatal visit. Universal screening, therefore, may increase the rate of unnecessary cesarean deliveries and medical interventions. HSV serology may be beneficial, however, in identifying seronegative pregnant women who have seropositive partners. Two recent studies have shown that 15% to 25% of couples have discordant HSV serologies and consequently are at risk of acquiring primary or initial-nonprimary HSV near term.^4,5 These couples should be counseled concerning the use of condoms in the first and second trimester (50% reduction in HSV transmission) and abstinence in the third trimester.⁵ The seropositive partner also can be offered suppressive therapy, which provides a 48% reduction in the risk of HSV transmission.⁴ Ultimately, the difficulty lies in balancing the clinical benefits and cost of asymptomatic screening.¹¹

CASE Resolved

The patient should be counseled that HSV infection rarely affects the fetus in utero, and transmission almost always occurs during the delivery process. This patient should receive prophylactic treatment with acyclovir beginning at 36 weeks of gestation to reduce the risk of an outbreak near the time of delivery. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

Al-Hendy A, Lukes AS, Poindexter AN 3rd, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384:630-642. doi: 10.1056/NEJMoa2008283

Expert Commentary

By age 50, approximately 70% of White women and 80% of Black women will have uterine fibroids.¹ Of these, about 25% will have symptoms—most often including heavy menstrual bleeding,² and associated pain the second most common symptom.³ First-line treatment has traditionally been hormonal contraceptives. Injectable gonadotropin-releasing hormone (GnRH) antagonist like leuprolide acetate have been commonly employed, although their actual approved indication is “for concomitant use with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (fibroids).”⁴ Recently, an oral GnRH antagonist, elagolix, combined with estrogen and progestogen, was approved for treatment of uterine fibroids for up to 24 months. However, it is dosed twice per day because of its short half-life and results in a loss of bone mineral density at 1 year.^5,6

Details of the studies

Al-Hendy and colleagues report on two double-blind 24-week phase 3 trials involving women with heavy menstrual bleeding associated with fibroids. There were just under 400 women in each trial. There was a 1:1:1 randomization to: placebo, once-daily oral relugolix 40 mg with 1 mg estradiol and 0.5 mg norethindrone acetate, or oral relugolix by itself for 12 weeks followed by the combination for 12 weeks (referred to as the “delayed relugolix combination therapy” arm).

Results. The primary end point was the percentage of patients who had a volume of menstrual blood loss less than 80 mL and a ≥50% reduction in blood loss volume as measured by the alkaline hematin method. The baseline blood loss in these studies ranged from approximately 210–250 mL. Secondary end points included amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, uterine volume, and the largest fibroid volume.

In trials one and two, 73% and 71% of patients in the relugolix combination groups, respectively, achieved the primary endpoint, compared with 19% and 15% in the placebo groups (P <.001). In addition, all secondary endpoints except largest fibroid volume were significantly improved versus placebo. Adverse events, including any change in bone mineral density, were no different between the combination and placebo groups. The delayed combination groups did have more hot flashes and diminished bone density compared with both the placebo and combination groups.

Strengths and weaknesses

The studies appropriately enrolled women with a mean age of 41–42 years and a mean BMI >30 kg/m², and more than 50% were African American. Thus, the samples are adequately representative of the type of population most likely to have fibroids and associated symptoms. The results showed the advantages of built-in “add back therapy” with estrogen plus progestogen, as the vasomotor symptoms and bone loss that treatment with a GnRH antagonist alone produces were reduced.

Although the trials were only conducted for 24 weeks, efficacy was seen as early as 4 weeks, and was clearly maintained throughout the full trials—and there is no scientific reason to assume it would not be maintained indefinitely. However, one cannot make a similar assumption about long-term safety. As another GnRH antagonist, with a shorter half-life requiring twice-daily-dosing with add back therapy, has been approved for use for 2 years, it is likely that the once-daily formulation of combination relugolix will be approved for this timeframe as well. Still, with patients’ mean age of 41–42 years, what will clinicians do after 2-year treatment? Clearly, study of long-term safety would be valuable. ●

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.

A shorter period between eating and going to sleep increased the risk of GERD during pregnancy by approximately 12%, according to data from 400 women.

Antonio_Diaz/iStock/via Getty Images

Gastroesophageal reflux disease (GERD) is a common condition in pregnancy because of changes in gastrointestinal motility caused by hormonal changes, and a short meal-to-bed time (MTBT) also has been associated with increased GERD symptoms, but data on the impact of MTBT on GERD in pregnant women in particular are lacking, wrote Duc T. Quach, MD, of the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, and colleagues.

In a cross-sectional study published in the Journal of Clinical Gastroenterology, the researchers identified 400 pregnant women aged 18 years and older in various stages of pregnancy who were seen at a single hospital in Vietnam. A short MTBT was defined as going to bed 2 hours or less after eating. Primary outcomes were GERD, defined as troublesome heartburn and/or regurgitation at least once a week, and reflux-related insomnia, defined as trouble initiating or maintaining nighttime sleep. Participants also reported the number of days of troublesome reflux symptoms and frequency of reflux-related insomnia over the last 7 days.

A total of 154 participants had a diagnosis of GERD, for an overall prevalence of 38.5%, similar to that seen in GERD studies of GERD and pregnancy, the researchers noted, and of those with GERD, 20 participants (13.0%) reported reflux-related insomnia.

The overall prevalence of heartburn, regurgitation, nausea with or without vomiting, and epigastric pain were 11.8%, 35.8%, 30.0%, and 5.5%, respectively. A total of 139 women reported reflux symptoms on at least 2 of the past 7 days, and 40 women reported both daytime and nighttime reflux symptoms.
 

Short meal-to-bed time shows strongest association

A short MTBT was the strongest predictor of GERD in multivariate analysis (odds ratio, 12.73; 95% confidence interval, 2.92-55.45; P = .001); previous history of reflux symptoms (OR, 9.05; 95% CI, 5.29-15.50; P < 001) and being in the third trimester versus first or second of pregnancy (OR, 1.66, 95% CI, 1.03-2.69; P = .039) also remained significant predictors in a multivariate analysis. In addition, nighttime short MTBT (but not daytime short MTBT) was the strongest risk factor for reflux-related insomnia (OR, 4.60), although alcohol consumption and a history of reflux-related symptoms also remained significant in multivariate analysis.

“Interestingly, the number of days during which reflux symptoms were experienced during the last 7 days sequentially increased across subgroups of participants with no short MTBT, either daytime or nighttime short MTBT, and with both daytime and nighttime MTBT,” the researchers wrote. At 4-7 days, none of the patients with no short MTBT reported reflux symptoms, compared with 7.5% of those with either daytime or nighttime MTBT and 20.9% of those with both daytime and nighttime MTBT.

The study findings were limited by several factors, including the inability to accurately record participants’ diets and the potential for overestimating the odds ratio of risk factors in patients with reflux-related insomnia because of the small numbers. However, the results support findings from previous studies and suggest that dietary modifications could provide a nonpharmacological treatment target for managing GERD in pregnant women, they concluded.
 

Behavioral intervention may benefit pregnant women

The study is important because heartburn and regurgitation are common challenges during pregnancy, Ziad F. Gellad, MD, of Duke University, Durham, N.C., said in an interview. “Understanding risk factors for these conditions can be helpful in designing behavioral and pharmaceutical therapeutic interventions.”

The link between short MTBT and increased risk for GERD is well-known, said Dr. Gellad. “Lengthening the time to laying supine after a meal is a common recommendation given to patients with GERD and is included in published GERD guidelines.” Although pregnant woman may have been excluded from trials on which the guidelines and recommendations are based, “it is reasonable to expect that findings would translate to this population that is generally higher risk for reflux,” he noted.

Dr. Gellad was interested to see the dose response between MTBT and reflux, with those patients having both daytime and nighttime short MTBT experiencing reflux more often than those with short MTBT in only one of those time periods (4-7 days vs. 1-3 days).

The key message for clinicians is that, for all individuals, pregnant or not, “avoiding late night meals and short meal-to-bed time is an appropriate behavioral intervention to recommend for patients with troublesome heartburn or regurgitation,” Dr. Gellad emphasized. However, more research is needed in some areas, “implementation studies would be helpful to understand how best to educate patients on behavioral modifications known to decrease reflux symptoms.”

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Gellad had no relevant financial disclosures, but serves as a member of the GI & Hepatology News board of editors.

Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.

Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.

“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).

“Greater understanding of the influence of separation anxiety in patients with affective disorders may encourage personalized interventions for reducing suicide risk,” they add.

The study was published in the March/April issue of the Journal of Clinical Psychiatry.
 

Frequently underdiagnosed

The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”

Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.

“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.

ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.

An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.

“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”

The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.

The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.

Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.

Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
 

Waxing and waning

Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.

Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).

“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.

Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.

A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.

In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.

The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
 

Treatment target?

Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”

Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”

However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”

The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.

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

Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.

Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.

“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).

“Greater understanding of the influence of separation anxiety in patients with affective disorders may encourage personalized interventions for reducing suicide risk,” they add.

The study was published in the March/April issue of the Journal of Clinical Psychiatry.
 

Frequently underdiagnosed

The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”

Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.

“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.

ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.

An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.

“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”

The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.

The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.

Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.

Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
 

Waxing and waning

Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.

Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).

“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.

Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.

A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.

In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.

The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
 

Treatment target?

Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”

Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”

However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”

The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.

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

Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.

Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.

“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).

“Greater understanding of the influence of separation anxiety in patients with affective disorders may encourage personalized interventions for reducing suicide risk,” they add.

The study was published in the March/April issue of the Journal of Clinical Psychiatry.
 

Frequently underdiagnosed

The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”

Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.

“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.

ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.

An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.

“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”

The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.

The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.

Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.

Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
 

Waxing and waning

Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.

Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).

“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.

Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.

A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.

In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.

The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
 

Treatment target?

Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”

Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”

However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”

The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.

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

A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.

A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.

Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.

The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.

“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.

Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.

“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.

“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.

In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.

“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.

The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.

In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.

“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.

In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.

The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.

For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.

The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.

Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.

The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.

Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.

Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.

“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.

The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.

In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.

He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”

The researchers are now planning a larger phase 3 study in that group.

“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.

The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.

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

A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.

A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.

Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.

The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.

“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.

Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.

“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.

“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.

In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.

“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.

The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.

In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.

“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.

In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.

The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.

For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.

The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.

Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.

The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.

Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.

Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.

“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.

The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.

In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.

He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”

The researchers are now planning a larger phase 3 study in that group.

“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.

The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.

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

A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.

A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.

Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.

The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.

“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.

Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.

“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.

“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.

In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.

“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.

The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.

In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.

“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.

In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.

The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.

For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.

The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.

Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.

The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.

Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.

Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.

“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.

The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.

In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.

He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”

The researchers are now planning a larger phase 3 study in that group.

“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.

The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.

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

The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?

Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.

5. Average group size has increased

Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.

Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.

In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.

4. Shift-type is shifting

In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.

Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.

3. COVID-19 impacts hospitalist workflows

It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.

2. Schedules have been disrupted by COVID-19

More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.

While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.

1. COVID-19 has changed scheduling methodologies – perhaps for the long-term

Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.

Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.

As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.

Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
 

Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.

The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?

Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.

5. Average group size has increased

Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.

Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.

In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.

4. Shift-type is shifting

In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.

Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.

3. COVID-19 impacts hospitalist workflows

It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.

2. Schedules have been disrupted by COVID-19

More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.

While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.

1. COVID-19 has changed scheduling methodologies – perhaps for the long-term

Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.

Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.

As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.

Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
 

Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.

The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?

Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.

5. Average group size has increased

Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.

Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.

In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.

4. Shift-type is shifting

In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.

Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.

3. COVID-19 impacts hospitalist workflows

It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.

2. Schedules have been disrupted by COVID-19

More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.

While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.

1. COVID-19 has changed scheduling methodologies – perhaps for the long-term

Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.

Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.

As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.

Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
 

Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.

Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.

“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.

The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.

In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.

To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.

The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).

“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.

The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.

The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.

No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.

Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.

“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.

The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.

In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.

To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.

The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).

“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.

The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.

The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.

No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.

Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.

“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.

The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.

In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.

To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.

The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).

“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.

The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.

The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.

No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.