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FDA proposes withdrawing Makena’s approval
Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.
The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.
The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.
Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.
The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.
The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.
Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.
A version of this article originally appeared on Medscape.com.
Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.
The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.
The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.
Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.
The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.
The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.
Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.
A version of this article originally appeared on Medscape.com.
Makena should be withdrawn from the market because a postmarketing study did not show clinical benefit, according to a statement released today from the Center for Drug Evaluation and Research at the Food and Drug Administration.
The drug, hydroxyprogesterone caproate injection, was approved in 2011 to reduce the risk of preterm birth in women who with previous spontaneous preterm birth. The FDA approved the medication under an accelerated pathway that required another trial to confirm clinical benefit.
The required postmarketing study “not only failed to demonstrate Makena’s benefit to the neonate, but also failed to substantiate any effect of Makena on the surrogate endpoint of gestational age at delivery that was the basis of the initial approval,” Patrizia Cavazzoni, MD, acting director of the CDER, wrote in a letter to AMAG Pharma USA, which markets Makena. The letter also was sent to other companies developing products that use the drug.
Beyond the lack of efficacy, risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention. “The risk of exposing treated pregnant women to these harms, in addition to false hopes, costs, and additional healthcare utilization outweighs Makena’s unproven benefit,” Dr. Cavazzoni said.
The letter notifies companies about the opportunity for a hearing on the proposed withdrawal of marketing approval. Makena and its generic equivalents will remain on the market until the manufacturers remove the drugs or the FDA commissioner mandates their removal, the CDER said.
The FDA commissioner ultimately will decide whether to withdraw approval of the drug. An FDA panel previously voted to withdraw the drug from the market in October 2019, and the drug has remained in limbo since.
Health care professionals should discuss “Makena’s benefits, risks, and uncertainties with their patients to decide whether to use Makena while a final decision is being made about the drug’s marketing status,” the CDER announcement said.
A version of this article originally appeared on Medscape.com.
Pregnancy studies on psoriasis, PsA medications pick up
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Women with MS may have increased subclinical disease activity during pregnancy
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
The increase in sNfL is independent of relapses, which suggests that patients have increased subclinical disease activity during this period, according to the researchers.
When the investigators controlled their data for exposure to disease-modifying therapy (DMT), the effect of pregnancy on sNfL was no longer evident. These data were presented said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
The results suggest that “sNfL may qualify as a sensitive and minimally invasive measure of disease activity in pregnancy,” said Özgür Yaldizli, MD, consultant neurologist at University Hospital Basel (Switzerland). “Strategies allowing the continuation of DMT during pregnancy may be warranted.”
MS preferentially affects women in their reproductive years, said Dr. Yaldizli. Almost one-third of women with MS become pregnant after they receive their diagnosis. A decrease in disease activity is typical in the third trimester, as is an increase in relapse frequency post partum.
DMTs reduce the risk of relapse, but have potential side effects for the woman and the fetus. Some DMTs are immunosuppressants, and they increase the risk of infection during pregnancy. Other DMTs may harm the development of the fetus, particularly if administered early during pregnancy.
“There is an urgent need to identify patients with high disease activity during pregnancy,” said Dr. Yaldizli. Increased levels of NfL, a specific biomarker of neuroaxonal injury, are associated with relapses, MRI activity, and disability worsening among patients with MS. Response to DMT is associated with decreased NfL levels. But few data about sNfL during pregnancy or post partum are available.
Relapses were associated with increased sNfL
Dr. Yaldizli and colleagues examined data from the Swiss MS Cohort Study to describe DMT use before, during, and after pregnancy. They also sought to assess sNfL as a marker of disease activity during and after pregnancy and to evaluate whether interrupting DMT because of pregnancy leads to increased sNfL levels.
Eligible participants had prospectively documented pregnancies, and Dr. Yaldizli’s group excluded pregnancies with early termination from their analysis. Serum samples were collected every 6 or 12 months and analyzed using the Simoa NF-light assay. The investigators used univariable and multivariable mixed-effects models to investigate associations between clinical characteristics and longitudinal sNfL levels in women before pregnancy, during pregnancy, and post partum.
Dr. Yaldizli and colleagues included 72 pregnancies in 63 patients with relapsing MS in their analysis. Nine patients had two pregnancies during follow-up. The population’s median age was 31.4 years, and median disease duration was 7.1 years. Median Expanded Disability Status Scale (EDSS) score at last visit before birth was 1.5. Median follow-up time was 6 years.
Most patients were treated with DMT before or during pregnancy. For most patients (39), fingolimod or natalizumab was the last DMT given before birth. Four patients did not use DMT before, during, or after pregnancy. In 14 pregnancies, the patient continued DMT for more than 6 months.
The univariable analysis showed that sNfL levels were 22% higher during pregnancy, compared with outside the pregnancy and postpartum period. The investigators recorded 29 relapses during the pregnancy and postpartum period. Relapses were more likely to occur during the first trimester and the first 3 months post partum. In the multivariable analysis, relapses that occurred within 120 days before serum sampling were associated with 98% higher levels of sNfL. In addition, sNfL was 7% higher for each step increase in EDSS and 13% higher during the pregnancy and postpartum period, compared with outside of that period.
When the investigators included DMT exposure at sampling time in the model, however, the pregnancy and postpartum period no longer had an effect on sNfL. The sNfL levels were 12% lower among patients exposed to DMT, compared with patients without DMT exposure.
Some DMTs, such as interferon-beta, are relatively safe during pregnancy, but the greater the medication’s efficacy, the more problematic it can be, said Dr. Yaldizi. “There are medications that are given, for example, every 6 months, like ocrelizumab. There are other medications that have to be taken daily. Probably the safest medications are those that are not given so often during pregnancy.”
Future research should examine the escalation therapies (i.e., the newer and more effective DMTs) during pregnancy in patients with MS, he added. “Not only in pregnancy, but also in general, we have to look for ways to measure disease activity in patients who switch therapy, who deescalate therapy.”
Pregnancy may not forestall disease activity
“The results of this study demonstrate that DMT withdrawal in the context of pregnancy can lead to subclinical disease re-emergence, as evidenced by increased sNfL levels in the DMT-free period,” said Vilija G. Jokubaitis, PhD, senior research fellow in the department of neuroscience at Monash University, Melbourne. Dr. Jokubaitis was not involved in the study.
“Interestingly, the median EDSS score in this cohort was quite low, demonstrating that, even in women with mild disease, pregnancy may not be sufficient to protect against ongoing MS activity.” Nevertheless, 28 of the 63 women were exposed to monoclonal antibody therapy, so it is unclear whether these women have mild disease or well-managed disease on DMT, she added.
“This study provides further evidence that pregnancy planning requires advanced planning, and that therapy continuation into pregnancy should be considered, particularly in women with moderate disease activity, to protect against disease reactivation,” said Dr. Jokubaitis.
The strengths of the study include its prospective design, the investigators’ ability to describe the various DMT exposures before and during pregnancy, and the multivariable mixed-effects modeling, she added. On the other hand, the results are at the group level, individual trajectories in sNfL level are not described, and the small sample size prevented the investigators from differentiating between the effects of various DMTs on sNfL outcomes. In addition, Dr. Yaldizli and colleagues did not take time off DMT into account in the models; they considered DMT exposure as a dichotomous variable.
“More work is needed to determine the therapeutic strategies that will give women with MS the greatest protection against disease reactivation in pregnancy and post partum, whilst also protecting fetal and neonatal outcomes,” said Dr. Jokubaitis. Group studies will enable researchers to identify trends, but neurologists ultimately need to provide individualized advice to their patients. “There is a need to look at [the effect of] DMT identity, timing, and duration of DMT withdrawal on fluctuation of sNfL levels, and how these relate to baseline disease severity,” Dr. Jokubaitis added. Furthermore, researchers must compare sNfL changes in pregnancy between patients with MS and healthy women in large cohorts.
The analysis by Dr. Yaldizli and colleagues was conducted without outside funding. The Swiss MS Cohort receives funding from the Swiss MS society, Biogen, Celgene, Sanofi, Merck, Novartis, Roche, and research associations such as the International Progressive MS Alliance and the Swiss National Science Foundation. Dr. Yaldizli received grants from ECTRIMS/MAGNIMS, the University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, and the Swiss MS Society. He has received advisory board fees from Sanofi Genzyme, Biogen, Almirall, and Novartis. Dr. Jokubaitis has received conference travel support from Merck and Roche and speakers honoraria from Biogen and Roche. These relationships are not related to the current study. Dr. Jokubaitis receives research support from the Australian National Health and Medical Research Grant and MS Research Australia.
FROM MSVIRTUAL2020
Nearly half of brachial plexus injury cases occur without shoulder dystocia
according to research published in Obstetrics & Gynecology.
Grace J. Johnson, MD, and colleagues at Baylor College of Medicine in Houston performed a medical review of 41,525 deliveries at Texas Children’s Hospital between March 2012 and July 2019, identifying cases of brachial plexus injury, with and without shoulder dystocia, occurring and persisting. The researchers also evaluated whether clinical experience (5 years or fewer, 6-15 years, or more than 15 years since training) and education impacted the risk of children developing shoulder dystocia or brachial plexus injury.
There were 547 cases of shoulder dystocia in 26,163 vaginal births (2.1%) and 9 cases in 15,362 cesarean births (0.06%), while 33 cases of brachial plexus injury occurred overall. Nearly all brachial plexus injuries were in vaginal deliveries (30 cases; 0.1%), while 3 cases occurred in cesarean deliveries (0.02%). Of these, 14 cases (42%) of brachial plexus injury did not co-occur with shoulder dystocia. Brachial plexus injury that persisted to discharge was similar for children with shoulder dystocia (17 of 19 cases; 89%) and without shoulder dystocia (10 of 14 cases; 71%). In the 27 children with persistent brachial plexus injury, 2 of 23 children who received follow-up care continued to experience persistent brachial plexus injury at 9 months (1 case with shoulder dystocia) and 12 months (1 case without shoulder dystocia).
“The frequent co-occurrence of shoulder dystocia and brachial plexus injury coupled with the equally frequent occurrence of isolated brachial plexus injury suggests that both brachial plexus injury and shoulder dystocia often reflect two causally unrelated complications of uterine forces driving a fetus through the birth canal in the presence of disproportion between the passage and the shoulder girdle of the passenger,” Dr. Johnson and colleagues wrote.
Results unchanged by clinician experience
Factors that impacted the risk of brachial plexus injury in children without shoulder dystocia were lack of maternal diabetes (0 women vs. 6 women; P = .03) and second-stage labor length (mean 103 minutes vs. 53 minutes; P = .08). Dr. Johnson and colleagues found no significant between-group differences regarding operative delivery, maternal age, or gestational age.
The researchers also examined the experience of the clinician who delivered children with brachial plexus injuries, and discovered there were no significant differences in children who had transient as opposed to persistent brachial plexus injury based on the number of years a clinician had been in practice (P = .97). There also were no significant changes in the “ratios of brachial plexus injury per total deliveries, brachial plexus injury per vaginal deliveries, and brachial plexus injury per shoulder dystocia” despite the presence of education and training for shoulder dystocia.
Questions require further study
Torri Metz, MD, MS, a maternal-fetal medicine subspecialist and associate professor of obstetrics and gynecology at University of Utah Health in Salt Lake City, said in an interview that the review by Johnson and colleagues was able to address limitations in previous studies by looking at the medical records of shoulder dystocia cases at a single tertiary care center.
“Brachial plexus injury occurs both with and without a diagnosis of shoulder dystocia. The finding that the non–shoulder dystocia brachial plexus injuries were associated with a longer second stage of labor suggests that these injuries can occur even prior to delivery of the fetal head and are often not related to maneuvers employed by an obstetrician during delivery,” Dr. Metz said.
The findings that brachial plexus injury severity was unrelated to clinician experience suggests “the occurrence, severity, and persistence of brachial plexus injury may be unrelated to maneuvers by the practitioner at the time of delivery,” she said.
Although Johnson et al. found education and training initiatives did not significantly impact the ratio of brachial plexus injury cases, “importantly, there are likely many other benefits to shoulder dystocia simulation including team communication and comfort of the practitioner in an obstetrical emergency. Thus, the conclusion should not be that simulation training should be abandoned,” Dr. Metz explained.
The results of the study should be confirmed in future research, she noted. “Despite looking at all cases of shoulder dystocia at a tertiary center over a 7-year period, the incidence of brachial plexus injury is low enough that only 33 cases were evaluated. As such, many questions about obstetrical management and the risk of brachial plexus injury still require further study,” said Dr. Metz, who was asked to comment on the study.
The authors reported no relevant financial disclosures. Dr. Metz is an editorial board member for Obstetrics and Gynecology. She was not involved in the review of this manuscript or the decision to publish it.
SOURCE: Johnson GJ et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004013.
according to research published in Obstetrics & Gynecology.
Grace J. Johnson, MD, and colleagues at Baylor College of Medicine in Houston performed a medical review of 41,525 deliveries at Texas Children’s Hospital between March 2012 and July 2019, identifying cases of brachial plexus injury, with and without shoulder dystocia, occurring and persisting. The researchers also evaluated whether clinical experience (5 years or fewer, 6-15 years, or more than 15 years since training) and education impacted the risk of children developing shoulder dystocia or brachial plexus injury.
There were 547 cases of shoulder dystocia in 26,163 vaginal births (2.1%) and 9 cases in 15,362 cesarean births (0.06%), while 33 cases of brachial plexus injury occurred overall. Nearly all brachial plexus injuries were in vaginal deliveries (30 cases; 0.1%), while 3 cases occurred in cesarean deliveries (0.02%). Of these, 14 cases (42%) of brachial plexus injury did not co-occur with shoulder dystocia. Brachial plexus injury that persisted to discharge was similar for children with shoulder dystocia (17 of 19 cases; 89%) and without shoulder dystocia (10 of 14 cases; 71%). In the 27 children with persistent brachial plexus injury, 2 of 23 children who received follow-up care continued to experience persistent brachial plexus injury at 9 months (1 case with shoulder dystocia) and 12 months (1 case without shoulder dystocia).
“The frequent co-occurrence of shoulder dystocia and brachial plexus injury coupled with the equally frequent occurrence of isolated brachial plexus injury suggests that both brachial plexus injury and shoulder dystocia often reflect two causally unrelated complications of uterine forces driving a fetus through the birth canal in the presence of disproportion between the passage and the shoulder girdle of the passenger,” Dr. Johnson and colleagues wrote.
Results unchanged by clinician experience
Factors that impacted the risk of brachial plexus injury in children without shoulder dystocia were lack of maternal diabetes (0 women vs. 6 women; P = .03) and second-stage labor length (mean 103 minutes vs. 53 minutes; P = .08). Dr. Johnson and colleagues found no significant between-group differences regarding operative delivery, maternal age, or gestational age.
The researchers also examined the experience of the clinician who delivered children with brachial plexus injuries, and discovered there were no significant differences in children who had transient as opposed to persistent brachial plexus injury based on the number of years a clinician had been in practice (P = .97). There also were no significant changes in the “ratios of brachial plexus injury per total deliveries, brachial plexus injury per vaginal deliveries, and brachial plexus injury per shoulder dystocia” despite the presence of education and training for shoulder dystocia.
Questions require further study
Torri Metz, MD, MS, a maternal-fetal medicine subspecialist and associate professor of obstetrics and gynecology at University of Utah Health in Salt Lake City, said in an interview that the review by Johnson and colleagues was able to address limitations in previous studies by looking at the medical records of shoulder dystocia cases at a single tertiary care center.
“Brachial plexus injury occurs both with and without a diagnosis of shoulder dystocia. The finding that the non–shoulder dystocia brachial plexus injuries were associated with a longer second stage of labor suggests that these injuries can occur even prior to delivery of the fetal head and are often not related to maneuvers employed by an obstetrician during delivery,” Dr. Metz said.
The findings that brachial plexus injury severity was unrelated to clinician experience suggests “the occurrence, severity, and persistence of brachial plexus injury may be unrelated to maneuvers by the practitioner at the time of delivery,” she said.
Although Johnson et al. found education and training initiatives did not significantly impact the ratio of brachial plexus injury cases, “importantly, there are likely many other benefits to shoulder dystocia simulation including team communication and comfort of the practitioner in an obstetrical emergency. Thus, the conclusion should not be that simulation training should be abandoned,” Dr. Metz explained.
The results of the study should be confirmed in future research, she noted. “Despite looking at all cases of shoulder dystocia at a tertiary center over a 7-year period, the incidence of brachial plexus injury is low enough that only 33 cases were evaluated. As such, many questions about obstetrical management and the risk of brachial plexus injury still require further study,” said Dr. Metz, who was asked to comment on the study.
The authors reported no relevant financial disclosures. Dr. Metz is an editorial board member for Obstetrics and Gynecology. She was not involved in the review of this manuscript or the decision to publish it.
SOURCE: Johnson GJ et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004013.
according to research published in Obstetrics & Gynecology.
Grace J. Johnson, MD, and colleagues at Baylor College of Medicine in Houston performed a medical review of 41,525 deliveries at Texas Children’s Hospital between March 2012 and July 2019, identifying cases of brachial plexus injury, with and without shoulder dystocia, occurring and persisting. The researchers also evaluated whether clinical experience (5 years or fewer, 6-15 years, or more than 15 years since training) and education impacted the risk of children developing shoulder dystocia or brachial plexus injury.
There were 547 cases of shoulder dystocia in 26,163 vaginal births (2.1%) and 9 cases in 15,362 cesarean births (0.06%), while 33 cases of brachial plexus injury occurred overall. Nearly all brachial plexus injuries were in vaginal deliveries (30 cases; 0.1%), while 3 cases occurred in cesarean deliveries (0.02%). Of these, 14 cases (42%) of brachial plexus injury did not co-occur with shoulder dystocia. Brachial plexus injury that persisted to discharge was similar for children with shoulder dystocia (17 of 19 cases; 89%) and without shoulder dystocia (10 of 14 cases; 71%). In the 27 children with persistent brachial plexus injury, 2 of 23 children who received follow-up care continued to experience persistent brachial plexus injury at 9 months (1 case with shoulder dystocia) and 12 months (1 case without shoulder dystocia).
“The frequent co-occurrence of shoulder dystocia and brachial plexus injury coupled with the equally frequent occurrence of isolated brachial plexus injury suggests that both brachial plexus injury and shoulder dystocia often reflect two causally unrelated complications of uterine forces driving a fetus through the birth canal in the presence of disproportion between the passage and the shoulder girdle of the passenger,” Dr. Johnson and colleagues wrote.
Results unchanged by clinician experience
Factors that impacted the risk of brachial plexus injury in children without shoulder dystocia were lack of maternal diabetes (0 women vs. 6 women; P = .03) and second-stage labor length (mean 103 minutes vs. 53 minutes; P = .08). Dr. Johnson and colleagues found no significant between-group differences regarding operative delivery, maternal age, or gestational age.
The researchers also examined the experience of the clinician who delivered children with brachial plexus injuries, and discovered there were no significant differences in children who had transient as opposed to persistent brachial plexus injury based on the number of years a clinician had been in practice (P = .97). There also were no significant changes in the “ratios of brachial plexus injury per total deliveries, brachial plexus injury per vaginal deliveries, and brachial plexus injury per shoulder dystocia” despite the presence of education and training for shoulder dystocia.
Questions require further study
Torri Metz, MD, MS, a maternal-fetal medicine subspecialist and associate professor of obstetrics and gynecology at University of Utah Health in Salt Lake City, said in an interview that the review by Johnson and colleagues was able to address limitations in previous studies by looking at the medical records of shoulder dystocia cases at a single tertiary care center.
“Brachial plexus injury occurs both with and without a diagnosis of shoulder dystocia. The finding that the non–shoulder dystocia brachial plexus injuries were associated with a longer second stage of labor suggests that these injuries can occur even prior to delivery of the fetal head and are often not related to maneuvers employed by an obstetrician during delivery,” Dr. Metz said.
The findings that brachial plexus injury severity was unrelated to clinician experience suggests “the occurrence, severity, and persistence of brachial plexus injury may be unrelated to maneuvers by the practitioner at the time of delivery,” she said.
Although Johnson et al. found education and training initiatives did not significantly impact the ratio of brachial plexus injury cases, “importantly, there are likely many other benefits to shoulder dystocia simulation including team communication and comfort of the practitioner in an obstetrical emergency. Thus, the conclusion should not be that simulation training should be abandoned,” Dr. Metz explained.
The results of the study should be confirmed in future research, she noted. “Despite looking at all cases of shoulder dystocia at a tertiary center over a 7-year period, the incidence of brachial plexus injury is low enough that only 33 cases were evaluated. As such, many questions about obstetrical management and the risk of brachial plexus injury still require further study,” said Dr. Metz, who was asked to comment on the study.
The authors reported no relevant financial disclosures. Dr. Metz is an editorial board member for Obstetrics and Gynecology. She was not involved in the review of this manuscript or the decision to publish it.
SOURCE: Johnson GJ et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004013.
FROM OBSTETRICS & GYNECOLOGY
Pandemic drives demand for self-managed abortions
Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.
Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.
“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.
In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.
The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.
Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.
Patients want alternatives to in-person care
“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.
The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.
In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.
Lift barriers to protect patients
Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.
“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.
“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.
“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.
“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.
Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.
SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.
Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.
Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.
“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.
In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.
The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.
Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.
Patients want alternatives to in-person care
“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.
The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.
In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.
Lift barriers to protect patients
Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.
“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.
“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.
“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.
“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.
Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.
SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.
Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.
Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.
“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.
In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.
The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.
Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.
Patients want alternatives to in-person care
“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.
The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.
In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.
Lift barriers to protect patients
Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.
“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.
“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.
“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.
“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.
Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.
SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.
FROM OBSTETRICS & GYNECOLOGY
Combination beats misoprostol monotherapy on cost effectiveness
A combination of mifepristone followed by misoprostol was significantly more cost effective for the medical management of miscarriage than misoprostol alone, based on a decision-tree model and simulations using a range of patient income levels, cost variables, and practice patterns.
Although the American College of Obstetricians and Gynecologists recommends a combination of mifepristone and misoprostol for the medical management of miscarriage, some physicians may hesitate because of the high cost of mifepristone, wrote Holly H. Berkley, MD, of the Naval Medical Center, San Diego, and colleagues.
Previous research has supported the cost effectiveness of combination therapy, but the data came from a secondary analysis that limited the generalizability of the findings, they wrote. In a study published in Obstetrics & Gynecology, the researchers created a decision-tree model using two standard practice patterns.
In the first, patients received mifepristone and one dose of misoprostol (combination therapy) or one dose of misoprostol alone (monotherapy) at their initial visit with follow-up within 3 days. Combination therapy was defined as 200 mg of oral mifepristone followed by one or two doses of 800 micrograms of vaginal misoprostol; monotherapy was defined as one or two doses of 800 micrograms of vaginal misoprostol.
“If miscarriage is not completed, a second dose of misoprostol is given, and the patient will have a second follow-up visit 8 days after initiation of treatment. If miscarriage is not complete at the second follow-up visit, surgical management is prescribed,” Dr. Berkley and associates reported.
In the second pattern, patients receive two doses of misoprostol at the first visit and an initial follow-up visit 8 days later.
Patient hourly income was based on the wages of three employment levels of the military patient population, estimated at $7.25/hour, $15.90/hour, and $35.10 per hour. “For clinicians outside of the military health system, these wage categories may also serve as an estimate of earnings for low-income, low-middle income, and middle-income patients across the United States,” Dr. Berkley and colleagues noted.
The researchers also considered costs for time of work, transportation, and the costs of the medical visits. Costs also were computed for surgical management with in–operating room dilation and curettage or in-office manual vacuum aspiration, if needed.
The greatest difference in favor of combination therapy resulted in a savings of $190.20 per patient, compared with monotherapy, in the first practice pattern and the lowest wage group (19.5%).
“In every scenario, and for every wage level, the average cost of combination therapy is less than that of monotherapy,” Dr. Berkley and associates noted. In addition, the differences in cost between combination therapy and monotherapy increased with patients’ wages, “reflecting wage differences as well as the net savings owing to increased completion rates.”
Completion rates are key to cost effectiveness
“The higher completion rate of combination therapy leads to decreased time spent on treatment and therefore decreased time off work, decreased office visits, and a decreased need for surgical management for persistent pregnancy, which significantly reduces cost,” they noted.
The model shows that the cost of mifepristone, which some clinicians may see as a barrier, contributes little to the overall treatment costs, Dr. Berkley and colleagues emphasized.
The study findings were limited by several factors including the large ranges in costs for office visits and procedures and the inability to replicate all clinical settings and variables, the researchers noted. However, the results were strengthened by the use of current practice patterns and costs, and they support the mifepristone/misoprostol combination as being the most cost effective for medical management of miscarriage, they said.
The findings of the current study, combined with higher effectiveness reported in recent randomized controlled trials and the endorsement of the American College of Obstetricians and Gynecologists “make a strong case for mifepristone followed by misoprostol to become the standard, first-line treatment regimen for the medical management of miscarriage,” Dr. Berkley and associates concluded.
Research is clear, policy needs to catch up
“There is clear research showing that using mifepristone with misoprostol to medically manage early pregnancy loss is significantly more effective than misoprostol alone,” Sarah Prager, MD, of the University of Washington, Seattle, said in an interview. “The combination protocol does include an expensive medication, so it’s important to evaluate if the cost of this more effective method is ‘worth it,’ ” she said. “ including fewer projected days off work and fewer patients needing procedures to complete their miscarriage.”
Dr. Prager said she was not surprised by the study findings because similar results have been found in other studies evaluating treatment of abortion with misoprostol alone versus mifepristone and misoprostol. “When something is significantly more effective, it usually will also come with a cost benefit.”
Potential barriers to the use of combination therapy are related to policy rather than drug safety or effectiveness, according to Dr. Prager.
“The primary barrier is that mifepristone use is regulated by a REMS [Risk Evaluation and Mitigation Strategy] restriction which requires that providers dispense the medication directly to patients, rather than being able to prescribe it and have patients then pick it up at a pharmacy,” she said. “This restriction is typically used for medications that are dangerous and need to be closely controlled. In the case of mifepristone, the restriction does not serve a safety purpose; it simply limits access to the medication which is still primarily used to medically treat abortion.
“The secondary barrier is stigma against using a medication that is seen as an abortion medication. I fear many providers or practices may avoid putting it on formulary due to this stigma,” Dr. Prager noted.
“There is already sufficient evidence that the combination therapy is superior to monotherapy, and there is also evidence that mifepristone can be safely prescribed [not dispensed] and does not need the REMS requirement,” Dr. Prager said. “I don’t believe more research is needed; just policy change.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Prager had no financial conflicts to disclose.
SOURCE: Berkley HH et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004063.
A combination of mifepristone followed by misoprostol was significantly more cost effective for the medical management of miscarriage than misoprostol alone, based on a decision-tree model and simulations using a range of patient income levels, cost variables, and practice patterns.
Although the American College of Obstetricians and Gynecologists recommends a combination of mifepristone and misoprostol for the medical management of miscarriage, some physicians may hesitate because of the high cost of mifepristone, wrote Holly H. Berkley, MD, of the Naval Medical Center, San Diego, and colleagues.
Previous research has supported the cost effectiveness of combination therapy, but the data came from a secondary analysis that limited the generalizability of the findings, they wrote. In a study published in Obstetrics & Gynecology, the researchers created a decision-tree model using two standard practice patterns.
In the first, patients received mifepristone and one dose of misoprostol (combination therapy) or one dose of misoprostol alone (monotherapy) at their initial visit with follow-up within 3 days. Combination therapy was defined as 200 mg of oral mifepristone followed by one or two doses of 800 micrograms of vaginal misoprostol; monotherapy was defined as one or two doses of 800 micrograms of vaginal misoprostol.
“If miscarriage is not completed, a second dose of misoprostol is given, and the patient will have a second follow-up visit 8 days after initiation of treatment. If miscarriage is not complete at the second follow-up visit, surgical management is prescribed,” Dr. Berkley and associates reported.
In the second pattern, patients receive two doses of misoprostol at the first visit and an initial follow-up visit 8 days later.
Patient hourly income was based on the wages of three employment levels of the military patient population, estimated at $7.25/hour, $15.90/hour, and $35.10 per hour. “For clinicians outside of the military health system, these wage categories may also serve as an estimate of earnings for low-income, low-middle income, and middle-income patients across the United States,” Dr. Berkley and colleagues noted.
The researchers also considered costs for time of work, transportation, and the costs of the medical visits. Costs also were computed for surgical management with in–operating room dilation and curettage or in-office manual vacuum aspiration, if needed.
The greatest difference in favor of combination therapy resulted in a savings of $190.20 per patient, compared with monotherapy, in the first practice pattern and the lowest wage group (19.5%).
“In every scenario, and for every wage level, the average cost of combination therapy is less than that of monotherapy,” Dr. Berkley and associates noted. In addition, the differences in cost between combination therapy and monotherapy increased with patients’ wages, “reflecting wage differences as well as the net savings owing to increased completion rates.”
Completion rates are key to cost effectiveness
“The higher completion rate of combination therapy leads to decreased time spent on treatment and therefore decreased time off work, decreased office visits, and a decreased need for surgical management for persistent pregnancy, which significantly reduces cost,” they noted.
The model shows that the cost of mifepristone, which some clinicians may see as a barrier, contributes little to the overall treatment costs, Dr. Berkley and colleagues emphasized.
The study findings were limited by several factors including the large ranges in costs for office visits and procedures and the inability to replicate all clinical settings and variables, the researchers noted. However, the results were strengthened by the use of current practice patterns and costs, and they support the mifepristone/misoprostol combination as being the most cost effective for medical management of miscarriage, they said.
The findings of the current study, combined with higher effectiveness reported in recent randomized controlled trials and the endorsement of the American College of Obstetricians and Gynecologists “make a strong case for mifepristone followed by misoprostol to become the standard, first-line treatment regimen for the medical management of miscarriage,” Dr. Berkley and associates concluded.
Research is clear, policy needs to catch up
“There is clear research showing that using mifepristone with misoprostol to medically manage early pregnancy loss is significantly more effective than misoprostol alone,” Sarah Prager, MD, of the University of Washington, Seattle, said in an interview. “The combination protocol does include an expensive medication, so it’s important to evaluate if the cost of this more effective method is ‘worth it,’ ” she said. “ including fewer projected days off work and fewer patients needing procedures to complete their miscarriage.”
Dr. Prager said she was not surprised by the study findings because similar results have been found in other studies evaluating treatment of abortion with misoprostol alone versus mifepristone and misoprostol. “When something is significantly more effective, it usually will also come with a cost benefit.”
Potential barriers to the use of combination therapy are related to policy rather than drug safety or effectiveness, according to Dr. Prager.
“The primary barrier is that mifepristone use is regulated by a REMS [Risk Evaluation and Mitigation Strategy] restriction which requires that providers dispense the medication directly to patients, rather than being able to prescribe it and have patients then pick it up at a pharmacy,” she said. “This restriction is typically used for medications that are dangerous and need to be closely controlled. In the case of mifepristone, the restriction does not serve a safety purpose; it simply limits access to the medication which is still primarily used to medically treat abortion.
“The secondary barrier is stigma against using a medication that is seen as an abortion medication. I fear many providers or practices may avoid putting it on formulary due to this stigma,” Dr. Prager noted.
“There is already sufficient evidence that the combination therapy is superior to monotherapy, and there is also evidence that mifepristone can be safely prescribed [not dispensed] and does not need the REMS requirement,” Dr. Prager said. “I don’t believe more research is needed; just policy change.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Prager had no financial conflicts to disclose.
SOURCE: Berkley HH et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004063.
A combination of mifepristone followed by misoprostol was significantly more cost effective for the medical management of miscarriage than misoprostol alone, based on a decision-tree model and simulations using a range of patient income levels, cost variables, and practice patterns.
Although the American College of Obstetricians and Gynecologists recommends a combination of mifepristone and misoprostol for the medical management of miscarriage, some physicians may hesitate because of the high cost of mifepristone, wrote Holly H. Berkley, MD, of the Naval Medical Center, San Diego, and colleagues.
Previous research has supported the cost effectiveness of combination therapy, but the data came from a secondary analysis that limited the generalizability of the findings, they wrote. In a study published in Obstetrics & Gynecology, the researchers created a decision-tree model using two standard practice patterns.
In the first, patients received mifepristone and one dose of misoprostol (combination therapy) or one dose of misoprostol alone (monotherapy) at their initial visit with follow-up within 3 days. Combination therapy was defined as 200 mg of oral mifepristone followed by one or two doses of 800 micrograms of vaginal misoprostol; monotherapy was defined as one or two doses of 800 micrograms of vaginal misoprostol.
“If miscarriage is not completed, a second dose of misoprostol is given, and the patient will have a second follow-up visit 8 days after initiation of treatment. If miscarriage is not complete at the second follow-up visit, surgical management is prescribed,” Dr. Berkley and associates reported.
In the second pattern, patients receive two doses of misoprostol at the first visit and an initial follow-up visit 8 days later.
Patient hourly income was based on the wages of three employment levels of the military patient population, estimated at $7.25/hour, $15.90/hour, and $35.10 per hour. “For clinicians outside of the military health system, these wage categories may also serve as an estimate of earnings for low-income, low-middle income, and middle-income patients across the United States,” Dr. Berkley and colleagues noted.
The researchers also considered costs for time of work, transportation, and the costs of the medical visits. Costs also were computed for surgical management with in–operating room dilation and curettage or in-office manual vacuum aspiration, if needed.
The greatest difference in favor of combination therapy resulted in a savings of $190.20 per patient, compared with monotherapy, in the first practice pattern and the lowest wage group (19.5%).
“In every scenario, and for every wage level, the average cost of combination therapy is less than that of monotherapy,” Dr. Berkley and associates noted. In addition, the differences in cost between combination therapy and monotherapy increased with patients’ wages, “reflecting wage differences as well as the net savings owing to increased completion rates.”
Completion rates are key to cost effectiveness
“The higher completion rate of combination therapy leads to decreased time spent on treatment and therefore decreased time off work, decreased office visits, and a decreased need for surgical management for persistent pregnancy, which significantly reduces cost,” they noted.
The model shows that the cost of mifepristone, which some clinicians may see as a barrier, contributes little to the overall treatment costs, Dr. Berkley and colleagues emphasized.
The study findings were limited by several factors including the large ranges in costs for office visits and procedures and the inability to replicate all clinical settings and variables, the researchers noted. However, the results were strengthened by the use of current practice patterns and costs, and they support the mifepristone/misoprostol combination as being the most cost effective for medical management of miscarriage, they said.
The findings of the current study, combined with higher effectiveness reported in recent randomized controlled trials and the endorsement of the American College of Obstetricians and Gynecologists “make a strong case for mifepristone followed by misoprostol to become the standard, first-line treatment regimen for the medical management of miscarriage,” Dr. Berkley and associates concluded.
Research is clear, policy needs to catch up
“There is clear research showing that using mifepristone with misoprostol to medically manage early pregnancy loss is significantly more effective than misoprostol alone,” Sarah Prager, MD, of the University of Washington, Seattle, said in an interview. “The combination protocol does include an expensive medication, so it’s important to evaluate if the cost of this more effective method is ‘worth it,’ ” she said. “ including fewer projected days off work and fewer patients needing procedures to complete their miscarriage.”
Dr. Prager said she was not surprised by the study findings because similar results have been found in other studies evaluating treatment of abortion with misoprostol alone versus mifepristone and misoprostol. “When something is significantly more effective, it usually will also come with a cost benefit.”
Potential barriers to the use of combination therapy are related to policy rather than drug safety or effectiveness, according to Dr. Prager.
“The primary barrier is that mifepristone use is regulated by a REMS [Risk Evaluation and Mitigation Strategy] restriction which requires that providers dispense the medication directly to patients, rather than being able to prescribe it and have patients then pick it up at a pharmacy,” she said. “This restriction is typically used for medications that are dangerous and need to be closely controlled. In the case of mifepristone, the restriction does not serve a safety purpose; it simply limits access to the medication which is still primarily used to medically treat abortion.
“The secondary barrier is stigma against using a medication that is seen as an abortion medication. I fear many providers or practices may avoid putting it on formulary due to this stigma,” Dr. Prager noted.
“There is already sufficient evidence that the combination therapy is superior to monotherapy, and there is also evidence that mifepristone can be safely prescribed [not dispensed] and does not need the REMS requirement,” Dr. Prager said. “I don’t believe more research is needed; just policy change.”
The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Prager had no financial conflicts to disclose.
SOURCE: Berkley HH et al. Obstet Gynecol. 2020 Oct. doi: 10.1097/AOG.0000000000004063.
FROM OBSTETRICS & GYNECOLOGY
PRGLAC recommendations
1. Include and integrate pregnant women and lactating women in the clinical research agenda.
2. Increase the quantity, quality, and timeliness of research on safety and efficacy of therapeutic products used by pregnant women and lactating women.
3. Expand the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology and therapeutics.
4. Remove regulatory barriers to research in pregnant women.
5. Create a public awareness campaign to engage the public and health care providers in research on pregnant women and lactating women.
6. Develop and implement evidence-based communication strategies with health care providers on information relevant to research on pregnant women and lactating women.
7. Develop separate programs to study therapeutic products used off patent in pregnant women and lactating women using the National Institute of Health Best Pharmaceuticals for Children Act (BPCA) as a model.
8. Reduce liability to facilitate an evidence base for new therapeutic products that may be used by women who are or may become pregnant and by lactating women.
9. Implement a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research.
10. Develop programs to drive discovery and development of therapeutics and new therapeutic products for conditions specific to pregnant women and lactating women.
11. Utilize and improve existing resources for data to inform the evidence and provide a foundation for research on pregnant women and lactating women.
12. Leverage established and support new infrastructures/collaborations to perform research in pregnant women and lactating women.
13. Optimize registries for pregnancy and lactation.
14. The Department of Health & Human Services Secretary should consider exercising the authority provided in law to extend the PRGLAC Task Force when its charter expires in March 2019.
15. Establish an Advisory Committee to monitor and report on implementation of recommendations, updating regulations, and guidance, as applicable, regarding the inclusion of pregnant women and lactating women in clinical research.
Source: Task Force on Research Specific to Pregnant Women and Lactating Women; Report to Secretary, Health and Human Services, Congress, September 2018
1. Include and integrate pregnant women and lactating women in the clinical research agenda.
2. Increase the quantity, quality, and timeliness of research on safety and efficacy of therapeutic products used by pregnant women and lactating women.
3. Expand the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology and therapeutics.
4. Remove regulatory barriers to research in pregnant women.
5. Create a public awareness campaign to engage the public and health care providers in research on pregnant women and lactating women.
6. Develop and implement evidence-based communication strategies with health care providers on information relevant to research on pregnant women and lactating women.
7. Develop separate programs to study therapeutic products used off patent in pregnant women and lactating women using the National Institute of Health Best Pharmaceuticals for Children Act (BPCA) as a model.
8. Reduce liability to facilitate an evidence base for new therapeutic products that may be used by women who are or may become pregnant and by lactating women.
9. Implement a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research.
10. Develop programs to drive discovery and development of therapeutics and new therapeutic products for conditions specific to pregnant women and lactating women.
11. Utilize and improve existing resources for data to inform the evidence and provide a foundation for research on pregnant women and lactating women.
12. Leverage established and support new infrastructures/collaborations to perform research in pregnant women and lactating women.
13. Optimize registries for pregnancy and lactation.
14. The Department of Health & Human Services Secretary should consider exercising the authority provided in law to extend the PRGLAC Task Force when its charter expires in March 2019.
15. Establish an Advisory Committee to monitor and report on implementation of recommendations, updating regulations, and guidance, as applicable, regarding the inclusion of pregnant women and lactating women in clinical research.
Source: Task Force on Research Specific to Pregnant Women and Lactating Women; Report to Secretary, Health and Human Services, Congress, September 2018
1. Include and integrate pregnant women and lactating women in the clinical research agenda.
2. Increase the quantity, quality, and timeliness of research on safety and efficacy of therapeutic products used by pregnant women and lactating women.
3. Expand the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology and therapeutics.
4. Remove regulatory barriers to research in pregnant women.
5. Create a public awareness campaign to engage the public and health care providers in research on pregnant women and lactating women.
6. Develop and implement evidence-based communication strategies with health care providers on information relevant to research on pregnant women and lactating women.
7. Develop separate programs to study therapeutic products used off patent in pregnant women and lactating women using the National Institute of Health Best Pharmaceuticals for Children Act (BPCA) as a model.
8. Reduce liability to facilitate an evidence base for new therapeutic products that may be used by women who are or may become pregnant and by lactating women.
9. Implement a proactive approach to protocol development and study design to include pregnant women and lactating women in clinical research.
10. Develop programs to drive discovery and development of therapeutics and new therapeutic products for conditions specific to pregnant women and lactating women.
11. Utilize and improve existing resources for data to inform the evidence and provide a foundation for research on pregnant women and lactating women.
12. Leverage established and support new infrastructures/collaborations to perform research in pregnant women and lactating women.
13. Optimize registries for pregnancy and lactation.
14. The Department of Health & Human Services Secretary should consider exercising the authority provided in law to extend the PRGLAC Task Force when its charter expires in March 2019.
15. Establish an Advisory Committee to monitor and report on implementation of recommendations, updating regulations, and guidance, as applicable, regarding the inclusion of pregnant women and lactating women in clinical research.
Source: Task Force on Research Specific to Pregnant Women and Lactating Women; Report to Secretary, Health and Human Services, Congress, September 2018
Safe, effective therapies: Establishing a path forward
I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.
Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.
Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.
The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.
In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.
In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.
The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at [email protected].
I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.
Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.
Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.
The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.
In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.
In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.
The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at [email protected].
I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.
Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.
Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.
The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.
In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.
In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.
The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at [email protected].
Vacuum device quickly stops postpartum hemorrhage
A novel intrauterine device that uses suction to compress the uterus to control postpartum hemorrhage has received high marks for effectiveness and ease of use, researchers say.
Calling this approach “a stroke of brilliance,” and is less risky as well.
“This device can be placed in the uterus within a minute or so and does not need any initial anesthesia and would not be associated with the delay needed for a surgical approach,” Dr. Byrne explained. Dr. Byrne, who was not involved in the study, is chair of the department of obstetrics and gynecology at Santa Clara Valley Medical Center in San Jose, Calif.
To test the efficacy and safety of the device (Jada System, Alydia Health), Mary E. D’Alton, MD, and colleagues conducted a prospective, observational treatment study in 12 U.S. medical centers. They reported their findings in an article published online Sept. 9 in Obstetrics and Gynecology.
“The Jada System (novel intrauterine vacuum-induced hemorrhage-control device) was specifically designed to offer rapid treatment by applying low-level intrauterine vacuum to facilitate the physiologic forces of uterine contractions to constrict myometrial blood vessels and achieve hemostasis,” Dr. D’Alton, from New York–Presbyterian/Columbia University Irving Medical Center in New York, and colleagues wrote.
“The device had a low rate of adverse events during this study, all of which were expected risks and resolved with treatment without serious clinical sequelae. Investigators, all first-time users of the device, found the system easy to use, which suggests that, after device education and with availability of a quick reference guide outlining steps, there is a minimal learning curve for use,” they added.
Alydia Health, the company that developed the device, funded this study and supported the research staff, who recruited participants and gathered follow-up data on them. On Sept. 9, the U.S. Food and Drug Administration granted 510(k) clearance for the device, according to a company news release.
Effective, safe
The multicenter study included 107 patients (mean age, 29.7 years) with postpartum hemorrhage or abnormal postpartum uterine bleeding, 106 of whom received any study treatment with the device attached to vacuum. More than half (57%) of the participants were White, and just fewer than one-quarter (24%) were Black.
Treatment was successful in 94% (100/106) of participants, with “definitive control of abnormal bleeding” occurring in a median of 3 minutes after attachment to vacuum.
Eight adverse events were judged to have been possibly related to the device or procedure: four cases of endometritis, and one case each of presumed endometritis, bacterial vaginosis, vaginal candidiasis, and disruption of a vaginal laceration repair. The eight adverse events were identified as potential risks, and all resolved without serious clinical consequences.
Thirty-five patients required transfusions of 1-3 U of red blood cells, and five patients required at least 4 U of red blood cells.
Uterine atony most frequent culprit
As many as 80% of postpartum hemorrhages are caused by uterine atony, according to the authors.
Dr. Byrne explained that the uterus is a muscular organ that contains many “spiral arteries” that are “squeezed” by the uterus as it tightens down after childbirth, which prevents them from bleeding excessively.
“With uterine atony, the uterus muscle doesn’t squeeze effectively, and therefore it’s not one or two arteries, it’s hundreds and hundreds of small arteries and capillaries [and] arterioles all bleeding; it’s a wide area of uterus,” he continued.
When medications alone are ineffective at controlling bleeding, tamponade is often added to put outward pressure on the inner wall of the uterus for 12-24 hours. Although tamponade is effective in approximately 87% of atony-related cases of postpartum hemorrhage, the use of outward pressure on the uterine walls “is counterintuitive if the ultimate goal is uterine contraction,” the authors wrote.
Dr. Byrne said he and his colleagues saw this device several years ago, and they felt at the time that it appeared to be “more intuitive to use vacuum to compress the uterus inward compared to the nonetheless valuable and effective Bakri balloon and other techniques that expand the uterus outward.”
The fact that there is no need for prophylactic antibiotics also sets the vacuum device apart from the Bakri balloon, use of which routinely involves administration of prophylactic antibiotics, Dr. Byrne said.
In the current study, 64% of participants were obese, which makes management of postpartum hemorrhage “really challenging” because it’s difficult to effectively massage the uterus through adipose tissue, Dr. Byrne explained. Patients with obesity “also have different hemodynamics for how effectively [injected medications will] be delivered to the uterus,” he added.
“A device like this that could be placed and works so efficiently – even with an obese patient – that’s actually very powerful,” Dr. Byrne said.
Quick placement, almost immediate improvement
The discomfort experienced during placement of the device is similar to that experienced during sweeping of the uterus, Dr. Byrne explained. “You’d want a patient comfortable, ideally with an epidural already active, but if it’s an emergency, you wouldn’t have to wait for that; you could sweep the uterus quickly, place this, initiate suction, and it would all be so quick you could usually talk a patient through it and get it done,” Dr. Byrne continued.
Almost all of the investigators (98%) said the device was easy to use, and 97% said they would recommend it.
The vacuum device is made of medical-grade silicone and consists of an oval-shaped intrauterine loop at one end and a vacuum connector at the other end that can be attached to a standard suction cannister. On the inner side of the intrauterine loop are 20 vacuum pores covered by a shield that protects uterine tissue and prevents the vacuum pores from clogging with tissue or clotted blood.
Before insertion of the vacuum device, the clinician manually sweeps the uterus to identify retained placental fragments and to assess the uterine cavity. The distal end of the device is inserted into the uterus, and a cervical seal, positioned just outside the cervical os, is filled with 60 to 120 cc of sterile fluid. The proximal end is attached to low-level vacuum at a pressure of 80 ± 10 mm Hg. The device is left in place with continued suction for at least 1 hour after bleeding is controlled, at which time the suction is disconnected and the cervical seal is emptied. The device remains in place for at least 30 minutes, during which the patient is observed closely.
“It looks like 75%-80% of cases stop bleeding within 5 minutes. ... Then you stop the pressure after an hour [and] wait at least 30 minutes. You could actually have this out of the patient’s body within 2 hours,” Dr. Byrne said.
Dr. Byrne has disclosed no such financial relationships.
A version of this article originally appeared on Medscape.com.
A novel intrauterine device that uses suction to compress the uterus to control postpartum hemorrhage has received high marks for effectiveness and ease of use, researchers say.
Calling this approach “a stroke of brilliance,” and is less risky as well.
“This device can be placed in the uterus within a minute or so and does not need any initial anesthesia and would not be associated with the delay needed for a surgical approach,” Dr. Byrne explained. Dr. Byrne, who was not involved in the study, is chair of the department of obstetrics and gynecology at Santa Clara Valley Medical Center in San Jose, Calif.
To test the efficacy and safety of the device (Jada System, Alydia Health), Mary E. D’Alton, MD, and colleagues conducted a prospective, observational treatment study in 12 U.S. medical centers. They reported their findings in an article published online Sept. 9 in Obstetrics and Gynecology.
“The Jada System (novel intrauterine vacuum-induced hemorrhage-control device) was specifically designed to offer rapid treatment by applying low-level intrauterine vacuum to facilitate the physiologic forces of uterine contractions to constrict myometrial blood vessels and achieve hemostasis,” Dr. D’Alton, from New York–Presbyterian/Columbia University Irving Medical Center in New York, and colleagues wrote.
“The device had a low rate of adverse events during this study, all of which were expected risks and resolved with treatment without serious clinical sequelae. Investigators, all first-time users of the device, found the system easy to use, which suggests that, after device education and with availability of a quick reference guide outlining steps, there is a minimal learning curve for use,” they added.
Alydia Health, the company that developed the device, funded this study and supported the research staff, who recruited participants and gathered follow-up data on them. On Sept. 9, the U.S. Food and Drug Administration granted 510(k) clearance for the device, according to a company news release.
Effective, safe
The multicenter study included 107 patients (mean age, 29.7 years) with postpartum hemorrhage or abnormal postpartum uterine bleeding, 106 of whom received any study treatment with the device attached to vacuum. More than half (57%) of the participants were White, and just fewer than one-quarter (24%) were Black.
Treatment was successful in 94% (100/106) of participants, with “definitive control of abnormal bleeding” occurring in a median of 3 minutes after attachment to vacuum.
Eight adverse events were judged to have been possibly related to the device or procedure: four cases of endometritis, and one case each of presumed endometritis, bacterial vaginosis, vaginal candidiasis, and disruption of a vaginal laceration repair. The eight adverse events were identified as potential risks, and all resolved without serious clinical consequences.
Thirty-five patients required transfusions of 1-3 U of red blood cells, and five patients required at least 4 U of red blood cells.
Uterine atony most frequent culprit
As many as 80% of postpartum hemorrhages are caused by uterine atony, according to the authors.
Dr. Byrne explained that the uterus is a muscular organ that contains many “spiral arteries” that are “squeezed” by the uterus as it tightens down after childbirth, which prevents them from bleeding excessively.
“With uterine atony, the uterus muscle doesn’t squeeze effectively, and therefore it’s not one or two arteries, it’s hundreds and hundreds of small arteries and capillaries [and] arterioles all bleeding; it’s a wide area of uterus,” he continued.
When medications alone are ineffective at controlling bleeding, tamponade is often added to put outward pressure on the inner wall of the uterus for 12-24 hours. Although tamponade is effective in approximately 87% of atony-related cases of postpartum hemorrhage, the use of outward pressure on the uterine walls “is counterintuitive if the ultimate goal is uterine contraction,” the authors wrote.
Dr. Byrne said he and his colleagues saw this device several years ago, and they felt at the time that it appeared to be “more intuitive to use vacuum to compress the uterus inward compared to the nonetheless valuable and effective Bakri balloon and other techniques that expand the uterus outward.”
The fact that there is no need for prophylactic antibiotics also sets the vacuum device apart from the Bakri balloon, use of which routinely involves administration of prophylactic antibiotics, Dr. Byrne said.
In the current study, 64% of participants were obese, which makes management of postpartum hemorrhage “really challenging” because it’s difficult to effectively massage the uterus through adipose tissue, Dr. Byrne explained. Patients with obesity “also have different hemodynamics for how effectively [injected medications will] be delivered to the uterus,” he added.
“A device like this that could be placed and works so efficiently – even with an obese patient – that’s actually very powerful,” Dr. Byrne said.
Quick placement, almost immediate improvement
The discomfort experienced during placement of the device is similar to that experienced during sweeping of the uterus, Dr. Byrne explained. “You’d want a patient comfortable, ideally with an epidural already active, but if it’s an emergency, you wouldn’t have to wait for that; you could sweep the uterus quickly, place this, initiate suction, and it would all be so quick you could usually talk a patient through it and get it done,” Dr. Byrne continued.
Almost all of the investigators (98%) said the device was easy to use, and 97% said they would recommend it.
The vacuum device is made of medical-grade silicone and consists of an oval-shaped intrauterine loop at one end and a vacuum connector at the other end that can be attached to a standard suction cannister. On the inner side of the intrauterine loop are 20 vacuum pores covered by a shield that protects uterine tissue and prevents the vacuum pores from clogging with tissue or clotted blood.
Before insertion of the vacuum device, the clinician manually sweeps the uterus to identify retained placental fragments and to assess the uterine cavity. The distal end of the device is inserted into the uterus, and a cervical seal, positioned just outside the cervical os, is filled with 60 to 120 cc of sterile fluid. The proximal end is attached to low-level vacuum at a pressure of 80 ± 10 mm Hg. The device is left in place with continued suction for at least 1 hour after bleeding is controlled, at which time the suction is disconnected and the cervical seal is emptied. The device remains in place for at least 30 minutes, during which the patient is observed closely.
“It looks like 75%-80% of cases stop bleeding within 5 minutes. ... Then you stop the pressure after an hour [and] wait at least 30 minutes. You could actually have this out of the patient’s body within 2 hours,” Dr. Byrne said.
Dr. Byrne has disclosed no such financial relationships.
A version of this article originally appeared on Medscape.com.
A novel intrauterine device that uses suction to compress the uterus to control postpartum hemorrhage has received high marks for effectiveness and ease of use, researchers say.
Calling this approach “a stroke of brilliance,” and is less risky as well.
“This device can be placed in the uterus within a minute or so and does not need any initial anesthesia and would not be associated with the delay needed for a surgical approach,” Dr. Byrne explained. Dr. Byrne, who was not involved in the study, is chair of the department of obstetrics and gynecology at Santa Clara Valley Medical Center in San Jose, Calif.
To test the efficacy and safety of the device (Jada System, Alydia Health), Mary E. D’Alton, MD, and colleagues conducted a prospective, observational treatment study in 12 U.S. medical centers. They reported their findings in an article published online Sept. 9 in Obstetrics and Gynecology.
“The Jada System (novel intrauterine vacuum-induced hemorrhage-control device) was specifically designed to offer rapid treatment by applying low-level intrauterine vacuum to facilitate the physiologic forces of uterine contractions to constrict myometrial blood vessels and achieve hemostasis,” Dr. D’Alton, from New York–Presbyterian/Columbia University Irving Medical Center in New York, and colleagues wrote.
“The device had a low rate of adverse events during this study, all of which were expected risks and resolved with treatment without serious clinical sequelae. Investigators, all first-time users of the device, found the system easy to use, which suggests that, after device education and with availability of a quick reference guide outlining steps, there is a minimal learning curve for use,” they added.
Alydia Health, the company that developed the device, funded this study and supported the research staff, who recruited participants and gathered follow-up data on them. On Sept. 9, the U.S. Food and Drug Administration granted 510(k) clearance for the device, according to a company news release.
Effective, safe
The multicenter study included 107 patients (mean age, 29.7 years) with postpartum hemorrhage or abnormal postpartum uterine bleeding, 106 of whom received any study treatment with the device attached to vacuum. More than half (57%) of the participants were White, and just fewer than one-quarter (24%) were Black.
Treatment was successful in 94% (100/106) of participants, with “definitive control of abnormal bleeding” occurring in a median of 3 minutes after attachment to vacuum.
Eight adverse events were judged to have been possibly related to the device or procedure: four cases of endometritis, and one case each of presumed endometritis, bacterial vaginosis, vaginal candidiasis, and disruption of a vaginal laceration repair. The eight adverse events were identified as potential risks, and all resolved without serious clinical consequences.
Thirty-five patients required transfusions of 1-3 U of red blood cells, and five patients required at least 4 U of red blood cells.
Uterine atony most frequent culprit
As many as 80% of postpartum hemorrhages are caused by uterine atony, according to the authors.
Dr. Byrne explained that the uterus is a muscular organ that contains many “spiral arteries” that are “squeezed” by the uterus as it tightens down after childbirth, which prevents them from bleeding excessively.
“With uterine atony, the uterus muscle doesn’t squeeze effectively, and therefore it’s not one or two arteries, it’s hundreds and hundreds of small arteries and capillaries [and] arterioles all bleeding; it’s a wide area of uterus,” he continued.
When medications alone are ineffective at controlling bleeding, tamponade is often added to put outward pressure on the inner wall of the uterus for 12-24 hours. Although tamponade is effective in approximately 87% of atony-related cases of postpartum hemorrhage, the use of outward pressure on the uterine walls “is counterintuitive if the ultimate goal is uterine contraction,” the authors wrote.
Dr. Byrne said he and his colleagues saw this device several years ago, and they felt at the time that it appeared to be “more intuitive to use vacuum to compress the uterus inward compared to the nonetheless valuable and effective Bakri balloon and other techniques that expand the uterus outward.”
The fact that there is no need for prophylactic antibiotics also sets the vacuum device apart from the Bakri balloon, use of which routinely involves administration of prophylactic antibiotics, Dr. Byrne said.
In the current study, 64% of participants were obese, which makes management of postpartum hemorrhage “really challenging” because it’s difficult to effectively massage the uterus through adipose tissue, Dr. Byrne explained. Patients with obesity “also have different hemodynamics for how effectively [injected medications will] be delivered to the uterus,” he added.
“A device like this that could be placed and works so efficiently – even with an obese patient – that’s actually very powerful,” Dr. Byrne said.
Quick placement, almost immediate improvement
The discomfort experienced during placement of the device is similar to that experienced during sweeping of the uterus, Dr. Byrne explained. “You’d want a patient comfortable, ideally with an epidural already active, but if it’s an emergency, you wouldn’t have to wait for that; you could sweep the uterus quickly, place this, initiate suction, and it would all be so quick you could usually talk a patient through it and get it done,” Dr. Byrne continued.
Almost all of the investigators (98%) said the device was easy to use, and 97% said they would recommend it.
The vacuum device is made of medical-grade silicone and consists of an oval-shaped intrauterine loop at one end and a vacuum connector at the other end that can be attached to a standard suction cannister. On the inner side of the intrauterine loop are 20 vacuum pores covered by a shield that protects uterine tissue and prevents the vacuum pores from clogging with tissue or clotted blood.
Before insertion of the vacuum device, the clinician manually sweeps the uterus to identify retained placental fragments and to assess the uterine cavity. The distal end of the device is inserted into the uterus, and a cervical seal, positioned just outside the cervical os, is filled with 60 to 120 cc of sterile fluid. The proximal end is attached to low-level vacuum at a pressure of 80 ± 10 mm Hg. The device is left in place with continued suction for at least 1 hour after bleeding is controlled, at which time the suction is disconnected and the cervical seal is emptied. The device remains in place for at least 30 minutes, during which the patient is observed closely.
“It looks like 75%-80% of cases stop bleeding within 5 minutes. ... Then you stop the pressure after an hour [and] wait at least 30 minutes. You could actually have this out of the patient’s body within 2 hours,” Dr. Byrne said.
Dr. Byrne has disclosed no such financial relationships.
A version of this article originally appeared on Medscape.com.
Is vertical transmission of SARS-CoV-2 possible? Is that the right question?
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.
EXPERT COMMENTARY
Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.1,2
Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.3 Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,4 as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.
Details of the study
In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.5 Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.
As a caveat to their research, the authors noted that:
- transcription levels do not always correlate with protein expression
- it is possible that a noncanonical cell-entry mediator facilitates entry
- individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.
Study strengths and limitations
Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m2, and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.
The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.10
The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.
While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.
JANE VAN DIS, MD
- Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
- Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
- Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
- Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
- Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
- Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
- Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
- Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
- Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
- Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.
EXPERT COMMENTARY
Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.1,2
Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.3 Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,4 as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.
Details of the study
In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.5 Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.
As a caveat to their research, the authors noted that:
- transcription levels do not always correlate with protein expression
- it is possible that a noncanonical cell-entry mediator facilitates entry
- individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.
Study strengths and limitations
Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m2, and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.
The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.10
The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.
While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.
JANE VAN DIS, MD
Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS CoV-2? eLife. 2020;9:e58716.
EXPERT COMMENTARY
Maternal infection with the novel SARS-CoV-2 virus has been associated with severe maternal morbidity and mortality causing adverse pregnancy outcomes, such as preterm birth and, potentially, stillbirth, with vertical transmission of the virus to the fetus possible.1,2
Uniquely, maternal physiology supports both pro- and anti-inflammatory states within pregnancy—a system that not only must protect the mother but also must tolerate a semi-allogenic fetus. Studies demonstrate that the first and third trimesters are pro-inflammatory, while the second trimester is thought to be anti-inflammatory.3 Since the discovery of the SARS-CoV-2 virus, the question surrounding vertical transmission (infectivity from mother to fetus via the placenta) has occupied the imagination of physicians, scientists, and pregnant women. Importantly, the virus is transmitted to human cells via the ACE2 (angiotensin-converting enzyme 2) receptor, which aids in viral cell attachment. ACE2 receptors are expressed in placental stromal cells, perivascular cells of decidua, cytotrophoblast and syncytiotrophoblast,4 as well as blood vessel endothelium and vascular smooth muscle from both primary and secondary villi.
Details of the study
In their recent study, Pique-Regi and colleagues used single-cell RNA sequencing data to investigate whether the receptors responsible for SARS-CoV-2 infection are expressed in the human placenta.5 Their findings suggest that TMPRSS2 is present in insufficient quantity in the placenta to make vertical transmission possible and/or clinically relevant. Thus, despite the presence of ACE2 receptors in placental tissue, without the enzymatic assistance of a helper protein like TMPRSS2 (transmembrane protease, serine 2), vertical transmission is highly unlikely. The researchers found that there was negligible co-transcription for ACE2 and TMPRSS2 in the placenta and that placental tissue lacks the mRNA necessary to produce the enzyme; they concluded that the likelihood of vertical transmission to the fetus was therefore unlikely.
As a caveat to their research, the authors noted that:
- transcription levels do not always correlate with protein expression
- it is possible that a noncanonical cell-entry mediator facilitates entry
- individuals with complications related to the renin-angiotensin-aldosterone system (such as hypertensive disease) may have alterations to the expression of ACE2.
Study strengths and limitations
Methods for this study reveal that the researchers examined 32 placentas, all taken in the third trimester (32.9-39.1 weeks), with a median gestational age of 36.9 weeks. Notably, 81.3% of placentas were from Black women, 6.2% from White women, and 12.5% from Other women. The median maternal age was 25 years, median body mass index was 27.8 kg/m2, and 84.4% of women were multiparous. While this sample was not representative of race, gestational age, or parity, it is difficult to know whether those selection biases would have changed the researchers' findings.
The question regarding vertical transmission is one not answered solely on the basis of RNA sequencing data. Clinically, we know that neonates of mothers infected with SARS-CoV-2 have been born with immunoglobulin M antibodies, indicating antenatal exposure to the virus.6,7 In addition, infants have tested positive immediately after birth for coronavirus disease 2019 (COVID-19) via nasopharyngeal swab and amniotic fluid, and there are ample cases of histologic and polymerase chain reaction evidence of placental infection.8,9 We also know that inflammatory damage to the placenta could possibly break down the placental barrier.10
The destruction that SARS-CoV-2 often leaves in its wake is devastating for the maternal-fetal dyad. The effects of maternal infection on the placenta—where additional research is needed—can be profound, causing profuse endothelial damage, vascular malperfusion, thrombi, and infarcts, all of which can be lethal to some developing fetuses.
While the study by Pique-Regi and colleagues is an important contribution to the literature, it does not satisfactorily answer the question regarding vertical transmission. More research is needed, especially regarding maternal infection in the first and second trimesters, on the effects on placental vasculature (and timing of infection in each trimester), the potential breakdown of the maternal-fetal barrier, and, most important, the clinical courses and outcomes in both mother and infant.
JANE VAN DIS, MD
- Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
- Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
- Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
- Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
- Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
- Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
- Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
- Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
- Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
- Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.
- Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClinical Medicine. 2020;25:100446.
- Khalil A, von Dadelszen P, Draycott T, et al. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020;324:705-706.
- Liu H, Wang LL, Zhao SJ, et al. Why are pregnant women susceptible to COVID-19? An immunological viewpoint. J Reprod Immunol. 2020;139;103122.
- Li M, Chen L, Zhang J, et al. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One. 2020;15:e0230295.
- Pique-Regi R, Romero R, Tarca AL, et al. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? eLife. 2020;9:e58716.
- Zeng H, Xu C, Fan J, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020;323:1848-1849.
- Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323:1846-1848.
- Kotlyar A, Grechukhina O, Chen A, et al. Vertical transmission of COVID-19: a systematic review and meta-analysis. Am J Obstet Gynecol. 2020;S0002-9378(20)30823-1.
- Richtmann R, Torloni MR, Oyamada Otani AR, et al. Fetal deaths in pregnancies with SARS-CoV-2 infection in Brazil: a case series. Case Rep Womens Health. 2020;e00243.
- Wang C, Zhou YH, Yang HX, et al. Intrauterine vertical transmission of SARS-CoV-2: what we know so far. Ultrasound Obstet Gynecol. 2020;55:724-725.