Expert Commentary

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Thoma ME, Declercq ER. Changes in pregnancy-related mortality associated with the coronavirus disease 2019 (COVID-19) pandemic in the United States. Obstet Gynecol. 2023. doi:10.1097/AOG0000000000005182.

EXPERT COMMENTARY

Maternal mortality rates in the United States were embarrassingly high and rising compared with other high-income countries prior to the onset of the COVID-19 pandemic. Recently, Thoma and Declercq aimed to assess the impact of COVID-19 on pregnancy-related deaths within 42 days of childbirth as well as out to 12 months postpartum.¹

During the pandemic, many issues may have affected maternity care and birthing experiences, including changes in prenatal care, restrictions that prevented support people from attending labor, and staffing shortages related to hospital overcrowding with personnel assignments away from labor and delivery. The study by Thoma and Declercq looked at maternal mortality from prior to the onset of the pandemic through changes in the health care environment, availability of vaccines, and emergence of more highly contagious and potentially more lethal viral variants.¹ All data were stratified by race, ethnicity, and locale. Death rates were compared between urban, metropolitan regions; suburban, mid-size regions; and rural locations.

Details of the study

Data were collected from the Centers for Disease Control and Prevention’s (CDC) publicly available WONDER database from 2019 to 2021. Because the absolute number of deaths within the American Indian/Alaska Native community was relatively small during that timeframe, data from 2018 also were accessed in order to verify reliability. The authors used the CDC’s definition of pregnancy-related death as “a death while pregnant or within 1 year of the end of pregnancy from any cause related to or aggravated by the pregnancy.”² International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify maternal deaths. The multiple causes of death file was queried to match maternal deaths with COVID-19 as a contributory cause.

Patterns of maternal deaths were compared with overall COVID-19 cases and COVID-19 death rates for reproductive-age women (ages 15 to 44) by quarters beginning in quarter 1 of 2019. Quarters through the first quarter of 2020 were prepandemic, then quarterly statistics were analyzed from the second quarter of 2020 through the end of 2021 to assess the impact of COVID-19 on early and late maternal mortality.

Findings. Overall maternal mortality rose by 26% from the beginning of 2020 to the second quarter, remained stable through mid-2021, then increased dramatically in the second half of 2021. Maternal mortality unrelated to COVID-19 remained fairly consistent at prior levels, whereas the COVID-19 associateddeaths mirrored the pattern of mortality among reproductive-age nonpregnant women attributed to COVID-19. In addition, the disparities in health outcomes observed in the population at large related to COVID-19 were similar among pregnant people.

American Indian/Alaska Native populations had the largest increase in mortality—more than doubling between early 2020 and the end of 2021. Black people experienced the largest absolute increase in mortality (up to 97.7/100,000 births) while Hispanic birthing people had the highest relative increase (from 19.3 to 29.8/100,000 births). While there were increases in maternal mortality among White and Asian birthing people, these variances were much smaller than for Black, Hispanic, and American Indian/Alaska Native populations.

When comparing mortality stratified by residence areas, early pandemic deaths were higher among birthing people in large urban areas (a 33% increase in 2020); however, later in the pandemic the rates increased substantially in medium-small metropolitan areas (39%) and rural areas (21%).

Study strengths and limitations

The administrative data used to inform this study is a relatively reliable dataset, although errors in both coding for COVID-19 as a contributory cause of maternal death and appropriate ascertainment of race and ethnicity may have occurred. Administrative data can highlight the trends in maternal mortality but cannot identify the root causes of these deaths. We are left with many questions regarding the contribution of staffing, support in labor, changes in prenatal care, and instability in food, housing, and comorbid medical conditions to this devastating rise in maternal mortality. ●

Thoma ME, Declercq ER. Changes in pregnancy-related mortality associated with the coronavirus disease 2019 (COVID-19) pandemic in the United States. Obstet Gynecol. 2023. doi:10.1097/AOG0000000000005182.

EXPERT COMMENTARY

Maternal mortality rates in the United States were embarrassingly high and rising compared with other high-income countries prior to the onset of the COVID-19 pandemic. Recently, Thoma and Declercq aimed to assess the impact of COVID-19 on pregnancy-related deaths within 42 days of childbirth as well as out to 12 months postpartum.¹

During the pandemic, many issues may have affected maternity care and birthing experiences, including changes in prenatal care, restrictions that prevented support people from attending labor, and staffing shortages related to hospital overcrowding with personnel assignments away from labor and delivery. The study by Thoma and Declercq looked at maternal mortality from prior to the onset of the pandemic through changes in the health care environment, availability of vaccines, and emergence of more highly contagious and potentially more lethal viral variants.¹ All data were stratified by race, ethnicity, and locale. Death rates were compared between urban, metropolitan regions; suburban, mid-size regions; and rural locations.

Details of the study

Data were collected from the Centers for Disease Control and Prevention’s (CDC) publicly available WONDER database from 2019 to 2021. Because the absolute number of deaths within the American Indian/Alaska Native community was relatively small during that timeframe, data from 2018 also were accessed in order to verify reliability. The authors used the CDC’s definition of pregnancy-related death as “a death while pregnant or within 1 year of the end of pregnancy from any cause related to or aggravated by the pregnancy.”² International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify maternal deaths. The multiple causes of death file was queried to match maternal deaths with COVID-19 as a contributory cause.

Patterns of maternal deaths were compared with overall COVID-19 cases and COVID-19 death rates for reproductive-age women (ages 15 to 44) by quarters beginning in quarter 1 of 2019. Quarters through the first quarter of 2020 were prepandemic, then quarterly statistics were analyzed from the second quarter of 2020 through the end of 2021 to assess the impact of COVID-19 on early and late maternal mortality.

Findings. Overall maternal mortality rose by 26% from the beginning of 2020 to the second quarter, remained stable through mid-2021, then increased dramatically in the second half of 2021. Maternal mortality unrelated to COVID-19 remained fairly consistent at prior levels, whereas the COVID-19 associateddeaths mirrored the pattern of mortality among reproductive-age nonpregnant women attributed to COVID-19. In addition, the disparities in health outcomes observed in the population at large related to COVID-19 were similar among pregnant people.

American Indian/Alaska Native populations had the largest increase in mortality—more than doubling between early 2020 and the end of 2021. Black people experienced the largest absolute increase in mortality (up to 97.7/100,000 births) while Hispanic birthing people had the highest relative increase (from 19.3 to 29.8/100,000 births). While there were increases in maternal mortality among White and Asian birthing people, these variances were much smaller than for Black, Hispanic, and American Indian/Alaska Native populations.

When comparing mortality stratified by residence areas, early pandemic deaths were higher among birthing people in large urban areas (a 33% increase in 2020); however, later in the pandemic the rates increased substantially in medium-small metropolitan areas (39%) and rural areas (21%).

Study strengths and limitations

The administrative data used to inform this study is a relatively reliable dataset, although errors in both coding for COVID-19 as a contributory cause of maternal death and appropriate ascertainment of race and ethnicity may have occurred. Administrative data can highlight the trends in maternal mortality but cannot identify the root causes of these deaths. We are left with many questions regarding the contribution of staffing, support in labor, changes in prenatal care, and instability in food, housing, and comorbid medical conditions to this devastating rise in maternal mortality. ●

Thoma ME, Declercq ER. Changes in pregnancy-related mortality associated with the coronavirus disease 2019 (COVID-19) pandemic in the United States. Obstet Gynecol. 2023. doi:10.1097/AOG0000000000005182.

EXPERT COMMENTARY

Maternal mortality rates in the United States were embarrassingly high and rising compared with other high-income countries prior to the onset of the COVID-19 pandemic. Recently, Thoma and Declercq aimed to assess the impact of COVID-19 on pregnancy-related deaths within 42 days of childbirth as well as out to 12 months postpartum.¹

During the pandemic, many issues may have affected maternity care and birthing experiences, including changes in prenatal care, restrictions that prevented support people from attending labor, and staffing shortages related to hospital overcrowding with personnel assignments away from labor and delivery. The study by Thoma and Declercq looked at maternal mortality from prior to the onset of the pandemic through changes in the health care environment, availability of vaccines, and emergence of more highly contagious and potentially more lethal viral variants.¹ All data were stratified by race, ethnicity, and locale. Death rates were compared between urban, metropolitan regions; suburban, mid-size regions; and rural locations.

Details of the study

Data were collected from the Centers for Disease Control and Prevention’s (CDC) publicly available WONDER database from 2019 to 2021. Because the absolute number of deaths within the American Indian/Alaska Native community was relatively small during that timeframe, data from 2018 also were accessed in order to verify reliability. The authors used the CDC’s definition of pregnancy-related death as “a death while pregnant or within 1 year of the end of pregnancy from any cause related to or aggravated by the pregnancy.”² International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify maternal deaths. The multiple causes of death file was queried to match maternal deaths with COVID-19 as a contributory cause.

Patterns of maternal deaths were compared with overall COVID-19 cases and COVID-19 death rates for reproductive-age women (ages 15 to 44) by quarters beginning in quarter 1 of 2019. Quarters through the first quarter of 2020 were prepandemic, then quarterly statistics were analyzed from the second quarter of 2020 through the end of 2021 to assess the impact of COVID-19 on early and late maternal mortality.

Findings. Overall maternal mortality rose by 26% from the beginning of 2020 to the second quarter, remained stable through mid-2021, then increased dramatically in the second half of 2021. Maternal mortality unrelated to COVID-19 remained fairly consistent at prior levels, whereas the COVID-19 associateddeaths mirrored the pattern of mortality among reproductive-age nonpregnant women attributed to COVID-19. In addition, the disparities in health outcomes observed in the population at large related to COVID-19 were similar among pregnant people.

American Indian/Alaska Native populations had the largest increase in mortality—more than doubling between early 2020 and the end of 2021. Black people experienced the largest absolute increase in mortality (up to 97.7/100,000 births) while Hispanic birthing people had the highest relative increase (from 19.3 to 29.8/100,000 births). While there were increases in maternal mortality among White and Asian birthing people, these variances were much smaller than for Black, Hispanic, and American Indian/Alaska Native populations.

When comparing mortality stratified by residence areas, early pandemic deaths were higher among birthing people in large urban areas (a 33% increase in 2020); however, later in the pandemic the rates increased substantially in medium-small metropolitan areas (39%) and rural areas (21%).

Study strengths and limitations

The administrative data used to inform this study is a relatively reliable dataset, although errors in both coding for COVID-19 as a contributory cause of maternal death and appropriate ascertainment of race and ethnicity may have occurred. Administrative data can highlight the trends in maternal mortality but cannot identify the root causes of these deaths. We are left with many questions regarding the contribution of staffing, support in labor, changes in prenatal care, and instability in food, housing, and comorbid medical conditions to this devastating rise in maternal mortality. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Although the past 30 years have stirred up a whirlwind of neurological research that has dramatically expanded therapeutic options for patients with epilepsy, historical pioneers in the field might be disappointed at the fact that treatment response has remained stubbornly stagnant. “Plus ça change, plus c’est la même chose,” they might say: The more things change, the more they stay the same. In fact, since 1993, despite an explosion of third-generation drugs, an abundance of new surgical approaches, and a whole new category of treatment in the form of neurostimulation devices, response rates in epilepsy have not budged, with roughly two-thirds of patients achieving seizure freedom and a third still struggling with treatment resistance.

But if you widen the lens and look towards the horizon, things are “on the cusp and going like a rocket,” said Jacqueline A. French, MD, professor of neurology in the Comprehensive Epilepsy Center at NYU Langone Health, New York. While treatment response rates may be stuck, adverse effects of those treatments have plummeted, and even treatment-resistant patients dealing with residual seizures live a much freer life with far fewer and less serious episodes.
 

Simpler times

In the late 1980s, just as Dr. French was finishing her second epilepsy fellowship at Yale, it was “almost laughable that things were so simple,” she recalls. “There were a few major centers that were doing epilepsy surgery … and in the world of medication, there were just five major drugs: phenobarbital, primidone, carbamazepine, phenytoin, and valproate.” That all changed as she was settling in to her first academic position at the University of Pennsylvania, with the “explosive” introduction of felbamate, a new antiseizure drug whose precipitous rise and fall from favor cast a sobering shadow which set the course for future drug development in the field.

“The felbamate story has a lot to do with what came after, but it was a drug that was much more advantageous in regards to a lot of the things that we didn’t like about antiseizure medicines or antiepileptic drugs as we called them at that time,” she said. The older drugs affected the cerebellum, making people sleepy and unable to concentrate. They also came with the risk of serious adverse effects such as hepatic enzyme induction and teratogenicity. Not only was felbamate nonsedating, “it actually was a little bit alerting,” said Dr. French. “People felt so different and so great on it, and it was effective for some seizure types that we didn’t really have good drugs for.” Very quickly, felbamate became a first-line therapy. Within its first year on the market, 150,000 newly diagnosed patients were started on it, “which is unthinkable now,” she said.

Sure enough, it all came crashing down a year later, on Aug. 1, 1994, when the drug was urgently withdrawn by the U.S. Food and Drug Administration after being linked to the development of aplastic anemia. “There was a day that anybody who was there at the time will remember when we all got the news, that everybody had to be taken off the drug,” Dr. French recalled. “We spent the weekend in the chart room, looking chart by chart by chart, for who was on felbamate.”

Until then, Dr. French had been straddling the line between her interests in pharmacologic versus surgical treatments for epilepsy. In fact, during her second epilepsy fellowship, which was dedicated to surgery, she published “Characteristics of medial temporal lobe epilepsy” in Annals of Neurology, one of the most-cited papers of her career. “Epilepsy from the temporal lobe is the biggest and best shot on goal when you’re talking about sending somebody to epilepsy surgery and rendering them completely seizure free,” she said. “Early in my career at the University of Pennsylvania, it was all about identifying those patients. And you know, there is nothing more gratifying than taking somebody whose life has been devastated by frequent seizures, who is injuring themselves and not able to be independent, and doing a surgery, which is very safe, and then all the seizures are gone – which is probably why I was so excited by surgery at the time.”

For a while, in the early 1990s, temporal lobectomy eclipsed many of the other avenues in epilepsy treatment, but it too has given way to a much wider variety of more complex techniques, which may be less curative but more palliative.
 

More drug options

Meanwhile, the felbamate story had ignited debate in the field about safer drug development – pushing Dr. French into establishing what was then known as the Antiepileptic Drug Trials conference, later renamed the Epilepsy Therapies & Diagnostics Development Symposium – a forum that encouraged safer, but also swifter movement of drugs through the pipeline and onto the market. “After felbamate, came gabapentin, and then came to topiramate and lamotrigine, and very quickly there were many, many, many choices,” she explained. “But once stung, twice shy. Felbamate really gave us a new perspective on which patients we put on the new drugs. Now we have a process of starting them in people with treatment-resistant epilepsy first. The risk-benefit equation is more reasonable because they have lots of risks. And then we work our way back to people with newly diagnosed epilepsy.”

Disease-modifying therapies

Today, the medications used to treat epilepsy are referred to as antiseizure rather than antiepileptic drugs because they simply suppress seizure symptoms and do not address the cause. But the rocket that Dr. French is watching gain speed and momentum is the disease-modifying gene therapies – true antiepileptics that may significantly move the needle on the number and type of patients who can reach seizure freedom. “We spent the last 25 years not even thinking we would ever have antiepileptic therapies, and now in the last 5 years or so, we were pretty sure we will,” she said. “We have gene therapies that can intervene now – none yet that have actually reached approval, these are all currently in trials – but we certainly have high expectations that they will very soon be available.”

Improving patients’ lives

While gene therapy rockets ahead, new device developments are already improving life for patients, even despite ongoing seizures. A drug-delivering pump is still in trials, but could make a big difference to daily medication adherence, and wearable or implantable devices are being developed to track seizures. More accurate tracking has also revealed that many people’s seizures are actually quite predictable, with regular cycles allowing for the possibility of prophylactic medication when increased seizure activity is expected.

Despite 30 years of no change in the proportion of epilepsy patients experiencing treatment resistance, Dr. French said that drugs, devices, and surgeries have improved the lives of all patients – both treatment resistant and treatment sensitive. “The difference between almost seizure free and completely seizure free is a big one because it means you can’t drive, you may have difficulty with your employment, but being able to take a pill every day and feel otherwise completely normal? We’ve come a long way.”

Although the past 30 years have stirred up a whirlwind of neurological research that has dramatically expanded therapeutic options for patients with epilepsy, historical pioneers in the field might be disappointed at the fact that treatment response has remained stubbornly stagnant. “Plus ça change, plus c’est la même chose,” they might say: The more things change, the more they stay the same. In fact, since 1993, despite an explosion of third-generation drugs, an abundance of new surgical approaches, and a whole new category of treatment in the form of neurostimulation devices, response rates in epilepsy have not budged, with roughly two-thirds of patients achieving seizure freedom and a third still struggling with treatment resistance.

But if you widen the lens and look towards the horizon, things are “on the cusp and going like a rocket,” said Jacqueline A. French, MD, professor of neurology in the Comprehensive Epilepsy Center at NYU Langone Health, New York. While treatment response rates may be stuck, adverse effects of those treatments have plummeted, and even treatment-resistant patients dealing with residual seizures live a much freer life with far fewer and less serious episodes.
 

Simpler times

In the late 1980s, just as Dr. French was finishing her second epilepsy fellowship at Yale, it was “almost laughable that things were so simple,” she recalls. “There were a few major centers that were doing epilepsy surgery … and in the world of medication, there were just five major drugs: phenobarbital, primidone, carbamazepine, phenytoin, and valproate.” That all changed as she was settling in to her first academic position at the University of Pennsylvania, with the “explosive” introduction of felbamate, a new antiseizure drug whose precipitous rise and fall from favor cast a sobering shadow which set the course for future drug development in the field.

“The felbamate story has a lot to do with what came after, but it was a drug that was much more advantageous in regards to a lot of the things that we didn’t like about antiseizure medicines or antiepileptic drugs as we called them at that time,” she said. The older drugs affected the cerebellum, making people sleepy and unable to concentrate. They also came with the risk of serious adverse effects such as hepatic enzyme induction and teratogenicity. Not only was felbamate nonsedating, “it actually was a little bit alerting,” said Dr. French. “People felt so different and so great on it, and it was effective for some seizure types that we didn’t really have good drugs for.” Very quickly, felbamate became a first-line therapy. Within its first year on the market, 150,000 newly diagnosed patients were started on it, “which is unthinkable now,” she said.

Sure enough, it all came crashing down a year later, on Aug. 1, 1994, when the drug was urgently withdrawn by the U.S. Food and Drug Administration after being linked to the development of aplastic anemia. “There was a day that anybody who was there at the time will remember when we all got the news, that everybody had to be taken off the drug,” Dr. French recalled. “We spent the weekend in the chart room, looking chart by chart by chart, for who was on felbamate.”

Until then, Dr. French had been straddling the line between her interests in pharmacologic versus surgical treatments for epilepsy. In fact, during her second epilepsy fellowship, which was dedicated to surgery, she published “Characteristics of medial temporal lobe epilepsy” in Annals of Neurology, one of the most-cited papers of her career. “Epilepsy from the temporal lobe is the biggest and best shot on goal when you’re talking about sending somebody to epilepsy surgery and rendering them completely seizure free,” she said. “Early in my career at the University of Pennsylvania, it was all about identifying those patients. And you know, there is nothing more gratifying than taking somebody whose life has been devastated by frequent seizures, who is injuring themselves and not able to be independent, and doing a surgery, which is very safe, and then all the seizures are gone – which is probably why I was so excited by surgery at the time.”

For a while, in the early 1990s, temporal lobectomy eclipsed many of the other avenues in epilepsy treatment, but it too has given way to a much wider variety of more complex techniques, which may be less curative but more palliative.
 

More drug options

Meanwhile, the felbamate story had ignited debate in the field about safer drug development – pushing Dr. French into establishing what was then known as the Antiepileptic Drug Trials conference, later renamed the Epilepsy Therapies & Diagnostics Development Symposium – a forum that encouraged safer, but also swifter movement of drugs through the pipeline and onto the market. “After felbamate, came gabapentin, and then came to topiramate and lamotrigine, and very quickly there were many, many, many choices,” she explained. “But once stung, twice shy. Felbamate really gave us a new perspective on which patients we put on the new drugs. Now we have a process of starting them in people with treatment-resistant epilepsy first. The risk-benefit equation is more reasonable because they have lots of risks. And then we work our way back to people with newly diagnosed epilepsy.”

Disease-modifying therapies

Today, the medications used to treat epilepsy are referred to as antiseizure rather than antiepileptic drugs because they simply suppress seizure symptoms and do not address the cause. But the rocket that Dr. French is watching gain speed and momentum is the disease-modifying gene therapies – true antiepileptics that may significantly move the needle on the number and type of patients who can reach seizure freedom. “We spent the last 25 years not even thinking we would ever have antiepileptic therapies, and now in the last 5 years or so, we were pretty sure we will,” she said. “We have gene therapies that can intervene now – none yet that have actually reached approval, these are all currently in trials – but we certainly have high expectations that they will very soon be available.”

Improving patients’ lives

While gene therapy rockets ahead, new device developments are already improving life for patients, even despite ongoing seizures. A drug-delivering pump is still in trials, but could make a big difference to daily medication adherence, and wearable or implantable devices are being developed to track seizures. More accurate tracking has also revealed that many people’s seizures are actually quite predictable, with regular cycles allowing for the possibility of prophylactic medication when increased seizure activity is expected.

Despite 30 years of no change in the proportion of epilepsy patients experiencing treatment resistance, Dr. French said that drugs, devices, and surgeries have improved the lives of all patients – both treatment resistant and treatment sensitive. “The difference between almost seizure free and completely seizure free is a big one because it means you can’t drive, you may have difficulty with your employment, but being able to take a pill every day and feel otherwise completely normal? We’ve come a long way.”

Although the past 30 years have stirred up a whirlwind of neurological research that has dramatically expanded therapeutic options for patients with epilepsy, historical pioneers in the field might be disappointed at the fact that treatment response has remained stubbornly stagnant. “Plus ça change, plus c’est la même chose,” they might say: The more things change, the more they stay the same. In fact, since 1993, despite an explosion of third-generation drugs, an abundance of new surgical approaches, and a whole new category of treatment in the form of neurostimulation devices, response rates in epilepsy have not budged, with roughly two-thirds of patients achieving seizure freedom and a third still struggling with treatment resistance.

But if you widen the lens and look towards the horizon, things are “on the cusp and going like a rocket,” said Jacqueline A. French, MD, professor of neurology in the Comprehensive Epilepsy Center at NYU Langone Health, New York. While treatment response rates may be stuck, adverse effects of those treatments have plummeted, and even treatment-resistant patients dealing with residual seizures live a much freer life with far fewer and less serious episodes.
 

Simpler times

In the late 1980s, just as Dr. French was finishing her second epilepsy fellowship at Yale, it was “almost laughable that things were so simple,” she recalls. “There were a few major centers that were doing epilepsy surgery … and in the world of medication, there were just five major drugs: phenobarbital, primidone, carbamazepine, phenytoin, and valproate.” That all changed as she was settling in to her first academic position at the University of Pennsylvania, with the “explosive” introduction of felbamate, a new antiseizure drug whose precipitous rise and fall from favor cast a sobering shadow which set the course for future drug development in the field.

“The felbamate story has a lot to do with what came after, but it was a drug that was much more advantageous in regards to a lot of the things that we didn’t like about antiseizure medicines or antiepileptic drugs as we called them at that time,” she said. The older drugs affected the cerebellum, making people sleepy and unable to concentrate. They also came with the risk of serious adverse effects such as hepatic enzyme induction and teratogenicity. Not only was felbamate nonsedating, “it actually was a little bit alerting,” said Dr. French. “People felt so different and so great on it, and it was effective for some seizure types that we didn’t really have good drugs for.” Very quickly, felbamate became a first-line therapy. Within its first year on the market, 150,000 newly diagnosed patients were started on it, “which is unthinkable now,” she said.

Sure enough, it all came crashing down a year later, on Aug. 1, 1994, when the drug was urgently withdrawn by the U.S. Food and Drug Administration after being linked to the development of aplastic anemia. “There was a day that anybody who was there at the time will remember when we all got the news, that everybody had to be taken off the drug,” Dr. French recalled. “We spent the weekend in the chart room, looking chart by chart by chart, for who was on felbamate.”

Until then, Dr. French had been straddling the line between her interests in pharmacologic versus surgical treatments for epilepsy. In fact, during her second epilepsy fellowship, which was dedicated to surgery, she published “Characteristics of medial temporal lobe epilepsy” in Annals of Neurology, one of the most-cited papers of her career. “Epilepsy from the temporal lobe is the biggest and best shot on goal when you’re talking about sending somebody to epilepsy surgery and rendering them completely seizure free,” she said. “Early in my career at the University of Pennsylvania, it was all about identifying those patients. And you know, there is nothing more gratifying than taking somebody whose life has been devastated by frequent seizures, who is injuring themselves and not able to be independent, and doing a surgery, which is very safe, and then all the seizures are gone – which is probably why I was so excited by surgery at the time.”

For a while, in the early 1990s, temporal lobectomy eclipsed many of the other avenues in epilepsy treatment, but it too has given way to a much wider variety of more complex techniques, which may be less curative but more palliative.
 

More drug options

Meanwhile, the felbamate story had ignited debate in the field about safer drug development – pushing Dr. French into establishing what was then known as the Antiepileptic Drug Trials conference, later renamed the Epilepsy Therapies & Diagnostics Development Symposium – a forum that encouraged safer, but also swifter movement of drugs through the pipeline and onto the market. “After felbamate, came gabapentin, and then came to topiramate and lamotrigine, and very quickly there were many, many, many choices,” she explained. “But once stung, twice shy. Felbamate really gave us a new perspective on which patients we put on the new drugs. Now we have a process of starting them in people with treatment-resistant epilepsy first. The risk-benefit equation is more reasonable because they have lots of risks. And then we work our way back to people with newly diagnosed epilepsy.”

Disease-modifying therapies

Today, the medications used to treat epilepsy are referred to as antiseizure rather than antiepileptic drugs because they simply suppress seizure symptoms and do not address the cause. But the rocket that Dr. French is watching gain speed and momentum is the disease-modifying gene therapies – true antiepileptics that may significantly move the needle on the number and type of patients who can reach seizure freedom. “We spent the last 25 years not even thinking we would ever have antiepileptic therapies, and now in the last 5 years or so, we were pretty sure we will,” she said. “We have gene therapies that can intervene now – none yet that have actually reached approval, these are all currently in trials – but we certainly have high expectations that they will very soon be available.”

Improving patients’ lives

While gene therapy rockets ahead, new device developments are already improving life for patients, even despite ongoing seizures. A drug-delivering pump is still in trials, but could make a big difference to daily medication adherence, and wearable or implantable devices are being developed to track seizures. More accurate tracking has also revealed that many people’s seizures are actually quite predictable, with regular cycles allowing for the possibility of prophylactic medication when increased seizure activity is expected.

Despite 30 years of no change in the proportion of epilepsy patients experiencing treatment resistance, Dr. French said that drugs, devices, and surgeries have improved the lives of all patients – both treatment resistant and treatment sensitive. “The difference between almost seizure free and completely seizure free is a big one because it means you can’t drive, you may have difficulty with your employment, but being able to take a pill every day and feel otherwise completely normal? We’ve come a long way.”

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

Photo: Shutterstock

Tita ATN, Carlo WA, McClure EM, et al; for the A-PLUS Trial Group. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023;388:1161-1170. doi:10:1056/NEJMoa2212111.

EXPERT COMMENTARY

Maternal peripartum infection is 1 of the top 5 causes of maternal death, accounting for about 10% of cases of maternal mortality. Cesarean delivery (CD), of course, is the most important risk factor for puerperal infection. However, even vaginal delivery, particularly in low- to middle-resource countries, where deliveries often occur under less-than-optimal conditions, may be associated with a surprisingly high frequency of both maternal and neonatal infections. The beneficial effect of prophylactic antibiotics for CD is well established. An important remaining question is whether similar benefit can be achieved with prophylaxis for women planning to have a vaginal birth.

In 2017, Oluwalana and colleagues conducted a prospective, randomized, double-blind, placebo-controlled trial of a single 2-g oral dose of azithromycin in Gambian women undergoing labor.¹ During the 8 weeks after delivery, maternal infections were lower in the azithromycin group, 3.6% versus 9.2% (relative risk [RR], 0.40; 95% confidence interval [CI], 0.22–0.71; P=.002). Infections also were lower in the newborns, 18.1% versus 23.8% (RR, 0.76; 95% CI, 0.58–0.99; P=.052), delivered to mothers who received azithromycin. The greatest impact on neonatal infections was the reduced frequency of skin infections.

In 2021, Subramaniam and colleagues evaluated the effect of a single dose of oral azithromycin with, or without, amoxicillin on the prevalence of peripartum infection in laboring women in Cameroon.² Patients and their newborns were followed for 6 weeks after delivery. Unlike the previous investigation, the authors were unable to show a protective effect of prophylaxis on either maternal or neonatal infection.

Against this backdrop, Tita and colleagues conducted a remarkably large, well-designed, randomized, placebo-controlled study of azithromycin prophylaxis in women at 8 different sites in 7 low- or middle-income countries (the A-PLUS investigation).³

Details of the study

The investigators randomly assigned 29,278 patients at or beyond 28 weeks’ gestation to receive either a 2-g oral dose of azithromycin or placebo during labor. This particular drug was chosen because it is readily available, inexpensive, well tolerated, and has a broad range of activity against many important pelvic pathogens, including genital mycoplasmas. Some patients also received other antibiotics, for example, for group B streptococcal (GBS) prophylaxis or for CD prophylaxis if abdominal delivery was indicated.

The 2 primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis within 4 weeks of delivery. Secondary outcomes included individual components of the primary outcomes.

Results. The results of the investigation were compelling, and the data safety monitoring committee recommended stopping the trial early because of clear maternal benefit. The groups were well balanced with respect to important characteristics, such as incidence of CD, receipt of other prophylactic antibiotics, and median time between randomization and delivery.

The incidence of maternal sepsis or death was lower in the azithromycin group (1.6% vs 2.4%; RR, 0.67; 95% CI, 0.56–0.79; P<.001). The key effect was on the frequency of maternal sepsis because the incidence of maternal death was very low in both groups, 0.1%. With respect to secondary outcomes, prophylaxis was effective in reducing the frequency of endometritis (RR, 0.66; 95% CI, 0.55–0.79) and perineal and incisional infection (RR, 0.71; 95% CI, 0.56–0.85).

There was no difference in the frequency of neonatal sepsis or death. There also was no difference in the frequency of adverse drug effects in either group. Of note, more cases of neonatal pyloric stenosis were observed in the azithromycin group, but the overall incidence was lower than the expected background rate. This possible “signal” is important because this effect has been noted with increased frequency in neonates who received this antibiotic. ●

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.