MDedge ObGyn

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

COVID-19 vaccines should not be withheld from people who are pregnant or lactating and want to be vaccinated, despite a lack of safety data in these populations, according to guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine.

Thye Aun Ngo/Fotolia.com

Pregnant women who opt not to receive the vaccine should be supported in that decision as well, a practice advisory from ACOG recommends.

“Pregnant women who experience fever following vaccination should be counseled to take acetaminophen,” the advisory notes.

In addition, women do not need to avoid pregnancy after receiving the Pfizer-BioNTech COVID-19 vaccine, according to the CDC’s interim clinical considerations for its use. The U.S. Food and Drug Administration issued an emergency use authorization for the vaccine on Dec. 11.

Although investigators excluded pregnant women from clinical trials, experts believe that mRNA vaccines, which are not live vaccines, “are unlikely to pose a risk for people who are pregnant” and “are not thought to be a risk to the breastfeeding infant,” the CDC notes.

Meanwhile, women who are pregnant may be at greater risk of severe COVID-19, even though the absolute risk of severe illness is low. COVID-19 also may increase the risk of adverse pregnancy outcomes, such as preterm birth, although the data have been mixed with some studies finding an association and others not.

“If pregnant people are part of a group that is recommended to receive a COVID-19 vaccine (e.g., health care personnel), they may choose to be vaccinated,” the CDC advises. “A conversation between the patient and their clinical team may assist with decisions regarding the use of vaccines approved under EUA for the prevention of COVID-19. While a conversation with a health care provider may be helpful, it is not required prior to vaccination.”
 

Acknowledging side effects and uncertainty

ACOG’s advisory reiterates that approach. The group notes that, based on the mRNA vaccine’s mechanism of action and its safety and efficacy in clinical trials, “it is expected that the safety and efficacy profile of the vaccine for pregnant individuals would be similar to that observed in nonpregnant individuals ... That said, there are no safety data specific to mRNA vaccine use in pregnant or lactating individuals and the potential risks to a pregnant individual and the fetus are unknown.” 

In clinical trials, most participants experienced mild influenza-like symptoms following vaccination, including injection site reactions, fatigue, chills, muscle and joint pain, and headache. Among participants aged 18-55 years, fever greater than 38°C occurred in 3.7% of participants after the first dose and in 15.8% after the second dose. Most symptoms resolved within a few days. 

Women who are pregnant should treat fever with acetaminophen because “fever has been associated with adverse pregnancy outcomes,” according to the ACOG guidance. “Acetaminophen has been proven to be safe for use in pregnancy and does not appear to impact antibody response to COVID-19 vaccines.” Patients may treat other vaccine side effects, such as injection-site soreness with acetaminophen as well.

When counseling patients, clinicians should explain that side effects are a normal part of developing antibodies to protect against COVID-19. “Regardless of their decision,” the group says, “these conversations provide an opportunity to remind patients about the importance of other prevention measures such as hand washing, physical distancing, and wearing a mask.”
 

More data expected

Data from developmental and reproductive toxicity studies in animals are expected soon, the CDC said. In addition, the manufacturer is following clinical trial participants who became pregnant during the study. 

Women who are pregnant and their physicians should weigh factors such as the extent of COVID-19 transmission in the community, the patient’s risk of contracting COVID-19, risks of COVID-19 to the patient and fetus, vaccine efficacy and side effects, and the lack of data about COVID-19 vaccination during pregnancy.

The Society for Maternal-Fetal Medicine recommends that pregnant and lactating women have access to COVID-19 vaccines in general and has advocated for the inclusion of women who are pregnant or lactating in vaccine trials. The society has suggested that health care professionals “counsel their patients that the theoretical risk of fetal harm from mRNA vaccines is very low.” It published resources this week for physicians and patients focused on COVID-19 vaccination and pregnancy.

In a review published online Dec. 10 in the American Journal of Obstetrics & Gynecology MFM, Amanda M. Craig, MD, of Duke University Health System in Durham, N.C., and coauthors note that there “is a theoretical risk for fetal harm from any untested medical intervention and this is no different for COVID-19 vaccines.”

“Pregnant individuals should be given the opportunity, along with their obstetric provider, to weigh the potential risk of severe maternal disease against the unknown risk of fetal exposure, and make an autonomous decision about whether or not to accept vaccine until pregnancy safety data are available,” they write.

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

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

What is more stressful in the mind of a patient – a diagnosis of cancer or infertility? An infertile woman’s anxiety and depression scores are equivalent to one with cancer (J Psychosom Obstet Gynecol. 1993;14 Suppl:45-52). These two diseases intersect in the burgeoning field of oncofertility, the collaboration of oncology with reproductive endocrinology to offer patients the option of fertility preservation. The term oncofertility was first coined by Teresa Woodruff, PhD, in 2005 during her invited lecture at the University of Calgary symposium called “Pushing the Boundaries – Advances that Will Change the World in 20 Years.” Her prediction has reached its fruition. This article will review fertility preservation options for female oncology patients.

The ability for oncofertility to exist is the result of improved cancer survival rates and advances in reproductive medicine. Improvements in the treatment of cancer enable many young women to survive and focus on the potential of having a family. Malignancies striking young people, particularly breast, lymphoma, and melanoma, have encouraging 5-year survival rates. If invasive cancer is located only in the breast (affecting 62% of women diagnosed), the 5-year survival rate is 99%. For all with Hodgkin lymphoma, the 5-year survival is 87%, increasing to 92% if the cancer is found in its earliest stages. Among all people with melanoma of the skin, from the time of initial diagnosis, the 5-year survival is 92%.

Long-term survival is expected for 80% of children and adolescents diagnosed with cancer (Obstet Gynecol. 2010;116: 1171-83).
 

Iatrogenic effects

The reproductive risk of cancer treatment is gonadotoxicity and the subsequent iatrogenic primary ovarian insufficiency (POI, prior termed premature ovarian failure) or infertility.

Chemotherapy with alkylating agents, such as cyclophosphamide, is associated with the greatest chance of amenorrhea (Breast Cancer Res Treat. 2014;145:113-28). Chemotherapy with cyclophosphamide, methotrexate, and 5 fluorouracil (CMF – commonly used for the treatment of breast cancer) will usually result in loss of ovarian function in 33% of women under age 30, 50% of women aged 30-35, 75% of women aged 35-40, and 95% of women over age 40 (J Clin Oncol. 2006;24:5769-79).

The dose at which 50% of oocytes are lost due to radiation is under 2 Gy (Hum Reprod. 2003;18:117-21). Unfortunately, the minimum dose decreases with advancing age of the woman, contributed by natural diminishing reserve and an increase in radiosensitivity of oocytes. Age, proximity of the radiation field to the ovaries, and total dose are important factors determining risk of POI. For brain tumors, cranial irradiation may result in hypothalamic amenorrhea.
 

Protection

The use of GnRH agonist for 6 months during chemotherapy has been controversial with mixed results in avoiding ovarian failure. A recent study suggests a GnRH agonist does reduce the prevalence of POI (J Clin Oncol. 2018;36:1981-90) in women treated for breast cancer but the subsequent ovarian reserve is low (Ann Oncol. 2017;28:1811-6). There are not enough data now to consider this the sole viable option for all patients to preserve fertility.

Patients requiring local pelvic radiation treatment may benefit from transposition of the ovaries to sites away from maximal radiation exposure.
 

Oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)

Since 2012, the American Society for Reproductive Medicine lifted the experimental designation on OC and, last year, the society removed the same label for OTC, providing an additional fertility preservation option.

Ovarian stimulation and egg retrieval for OC can now occur literally within 2 weeks because of a random start protocol whereby women are stimulated any day in their cycle, pre- and post ovulation. Studies have shown equivalent yield of oocytes.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a routine matter with egg donation cycles. While there remains debate over whether live birth rates using frozen eggs are inferior to fresh eggs, a learning curve with the new technology may be the important factor (Obstet Gynecol. 2020;135:709-16).

When urgent cancer treatment precludes ovarian stimulation for OC, then OTC is a viable option. Another population that could benefit from OTC are prepubertal girls facing gonadotoxic therapy. More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients. While leukemic patients are eligible for OTC, there is concern about reseeding malignant cells with future autologous transplantation of tissue.

OTC involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. To date, live birth rates are modest (Fertil Steril. 2015;104:1097-8).

Recent research has combined the freezing of both mature and immature eggs, the latter undergoing IVM (in-vitro maturation) to maximize the potential for fertilizable eggs. Women with polycystic ovary syndrome and certain cancers or medical conditions that warrant avoiding supraphysiologic levels of estradiol from ovarian stimulation, may benefit from the retrieval of immature eggs from unstimulated ovaries.

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans are not known but animal studies suggest there may be higher rates of miscarriage and birth defects.
 

Breast cancer – a special scenario

With every breast cancer patient, I review the theoretical concern over increasing estradiol levels during an IVF stimulation cycle with the potential impact on her cancer prognosis. Fortunately, the literature has not demonstrated an increased risk of breast cancer or recurrence after undergoing an IVF cycle. Currently, the use of aromatase inhibitors with gonadotropins along with a GnRH-antagonist is the protocol to maintain a lower estradiol level during stimulation, which may be of benefit for breast cancer prognosis. The use of aromatase inhibitors is an off-label indication for fertility with no definitive evidence of teratogenicity. Preimplantation genetic testing of embryos is available and approved by the American Society for Reproductive Medicine for BRCA gene mutation patients.

Oncofertility is an exciting field to allow cancer survivors the option for a biological child. We recommend all our cancer patients meet with our reproductive psychologist to assist in coping with the overwhelming information presented in a short time frame.
 

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and associate professor of obstetrics and gynecology at the University of Central Florida, Orlando.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) evaluated Moderna’s COVID-19 vaccine as highly effective with a favorable safety profile, based on interim data from an ongoing phase 3 trial.

The panel acknowledged that further studies will be required post issuance of an Emergency Use Authorization (EUA) to collect additional data on the safety and effectiveness of the vaccine. A briefing document released by the FDA on Dec. 17, 2020, summarized interim results and included recommendations from VRBPAC on use of Moderna’s mRNA-1273 COVID-19 vaccine.

“On November 30, 2020, ModernaTX (the Sponsor) submitted an EUA request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19,” the committee wrote.
 

The mRNA-1273 vaccine trial

Among 30,351 individuals aged 18 years and older, the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine candidate was evaluated in a randomized, stratified, observer-blind, placebo-controlled phase 3 study. Participants were randomly assigned (1:1) to receive two injections of either 100 mcg of mRNA-1273 (n = 15,181) or saline placebo (n = 15,170) administered intramuscularly on day 1 and day 29.

The primary efficacy endpoint was efficacy of mRNA-1273 against PCR-confirmed COVID-19 with onset at least 14 days following the second dose. The primary safety endpoint was to characterize the safety of the vaccine following one or two doses.
 

Efficacy

Among 27,817 subjects included in the first interim analysis (data cutoff: Nov. 7, 2020), 5 cases of COVID-19 with onset at least 14 days after the second dose occurred among vaccine recipients and 90 case occurred among placebo recipients, corresponding to 94.5% vaccine efficacy (95% confidence interval, 86.5%-97.8%).

“Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19,” they reported.

Data from the final scheduled analysis of the primary efficacy endpoint (data cutoff: Nov. 21, 2020; median follow-up of >2 months after dose 2), demonstrated 94.1% vaccine efficacy (95% confidence interval, 89.3%-96.8%), corresponding to 11 cases of COVID-19 in the vaccine group and 185 cases in the placebo group.

When stratified by age, the vaccine efficacy was 95.6% (95% CI, 90.6%-97.9%) for individuals 18-64 years of age and 86.4% (95% CI, 61.4%-95.5%) for those 65 years of age or older.

In addition, results from secondary analyses indicated benefit for mRNA-1273 in preventing severe COVID-19 cases, COVID-19 in those with prior SARS-CoV-2 infection, and infection after the first dose, but these data were not conclusive.
 

Safety

Among 30,350 subjects included in the first interim analysis (data cutoff: Nov. 11, 2020; median follow-up of 7 weeks post second dose), no specific safety concerns were observed that would prevent issuance of an EUA.

Additional safety data (data cutoff: Nov. 25, 2020; median follow-up of 9 weeks post second dose) were provided on Dec. 7, 2020, but did not change the conclusions from the first interim analysis.

The most common vaccine-related adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%).

“The frequency of serious adverse events (SAEs) was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms,” they reported.

Myocardial infarction (0.03%), nephrolithiasis (0.02%), and cholecystitis (0.02%) were the most common SAEs that were numerically greater in the vaccine arm than the placebo arm; however, the small number of cases does not infer a casual relationship.

“The 2-dose vaccination regimen was highly effective in preventing PCR-confirmed COVID-19 occurring at least 14 days after receipt of the second dose,” the committee wrote. “[However], it is critical to continue to gather data about the vaccine even after it is made available under EUA.”

The associated phase 3 study was sponsored by ModernaTX.

SOURCE: FDA Briefing Document: Moderna COVID-19 Vaccine. FDA Vaccines and Related Biological Products Advisory Committee. Published Dec. 17, 2020.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

With increasing whooping cough numbers, developing an effective new vaccine against Bordetella pertussis is a priority. Results from the multifactorial PERISCOPE Project will help scientists and clinicians move forward.

MarianVejcik/Getty Images

Dominic Kelly, PhD, talked about vaccine-induced immunity and provided an overview of ongoing clinical trials in the PERISCOPE (Pertussis Correlates of Protection Europe) project in a key research session at the start of the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. Dr. Kelly, a pediatrician at the Children’s Hospital in Oxford and a member of the Oxford Vaccines Group, leads one of the studies in the project looking at infant vaccination.

Dr. Kelly began his presentation by showing a figure depicting where vaccine-induced immunity fits into the larger suite of clinical studies. These studies involve mouse models, human challenge models, and infection patients. A key theme is the use of a core group of immunoassays across all studies, with the hope that they will allow effective cross comparisons.

Dr. Kelly stated, “If we find a correlate of protection in the challenge model, we can then interpret the vaccine studies in the light of that because we are using standardized constant immunoassays.”

The assays being used depend in part on the specific study and the volume of blood available. They will generally include Bordetella-specific antibody and functional antibody assays, as well as interesting studies collecting mucosal samples from infants and adults to look at serological responses. Also under examination are a range of enzyme-linked immune absorbent spot, flow cytometry, and culture techniques looking at Memory B cells, T cells, and gene expression.

Complementing these assay studies, PERISCOPE includes a series of clinical investigations designed to throw light on three areas of interest, described below:

First, researchers hope to gain a better understanding regarding the effects of the original whole cell vaccine versus the current acellular variety. The former uses an inactivated version of the whole organism. Epidemiological studies, animal data, and experience in the field demonstrate that whole-cell vaccination results in a broad, long-lasting, and effective immune response.

By comparison, the acellular pertussis vaccine consists of between three and five protein components, which are purified from cultured Bordetella pertussis. While it is an effective vaccine, its effects are less durable; routine use in some countries is associated with cyclical outbreaks of increasing severity.

A second issue for researchers involved in the PERISCOPE project concerns the effects of maternal immunization. In the United Kingdom in 2012, for example, an increasing number of cases were noted 6-7 years after adoption of an acellular vaccine for routine vaccination in the 2nd-3rd trimester of pregnancy. Vaccination appears to effectively control neonatal disease, but whether this influences infant immune responses and long-term control of pertussis for a population is unknown.

Finally, the group is interested in the effects of an acellular booster across all age groups. While the effects may be short-lived, the booster is a potential strategy for controlling a population by repeated boosting of immunity. This is another area where using novel immunoassays may aid better understanding.

To find answers, the consortium has established four studies: the Gambia Pertussis study (GaPs) in Gambia and AWARE, the sister study to GaPs in the United Kingdom, addressing the acellular pertussis versus cellular pertussis question; the Pertussis Maternal Immunization Study in Finland (MIFI) addressing maternal immunization; and the Booster against Pertussis (BERT) study across three countries (U.K., the Netherlands, and Finland) looking at acellular booster across age groups.
 

Gambia pertussis study

GaPs is the largest single study in the project and is being run at the Medical Research Council–funded London School of Tropical Medicine center in Gambia. Beate Kampmann, MD, PhD, of Imperial College London, England, is the project lead. It is due to complete in 2022. GaPs seeks to enroll 600 mother/infant pairs and randomize the mothers to either an acellular pertussis booster in pregnancy or a tetanus toxoid control vaccine. Infants are subsequently randomized to an acellular or whole-cell pertussis schedule of primary immunization. The vaccine doses are being given at 2, 3, and 4 months. The primary endpoint is a serological finding being measured at 9 months of age, when the infant would usually receive yellow fever, measles, and rubella vaccination.

GaPs has a number of pathways. Within each of the four arms generated by the two randomizations, the maternal randomization and the infant randomization, there are five subgroups. They are designed to study time points in subgroups A and B after the first dose in more detail, looking at the innate immune responses using gene expression. It will enable researchers to study adaptive immune responses to T cells and B cells after the second dose of vaccine. By employing a range of subgroups, the team can explore the immune profile using the assays referred to above. Such information should provide new insights into the differences between acellular and whole-cell vaccines.
 

The AWARE study

AWARE is the sister study to GaPs and looks at the acellular/whole pertussis issue. Because many developed countries, such as the United Kingdom, have established maternal immunization programs, it is not possible to randomize mothers. Consequently, researchers have opted to recruit infants of mothers who have received an acellular vaccine in pregnancy and randomize them to either an acellular schedule of primary immunization or a whole-cell schedule.

The selected vaccine is ComVac5 from Bharat Biotech. This whole-cell vaccine differs from that used in Gambia. An early obstacle for AWARE has been seeking permission to import a non-conventional vaccine into Europe. It has delayed the anticipated end date to 2023. Participating infants will receive a two-dose schedule at 2 and 4 months of age per their randomization; then, both groups will go on to receive an acellular pertussis booster at 12 months. At all time points, the team will sample blood for cells and serum, as well as mucosal fluid from the nose. Because the mucosal surface is where the action is, this approach will likely generate new data around antibody responses.
 

The MIFI

The Pertussis Maternal Immunization Study in Finland is being run by Jussi Mertsola, of the University of Turku, Finland, and Qiushui He, of the National Public Health Institute, Turku. It is due to complete in late 2021. Where, in the United Kingdom, researchers are unable to randomize mothers because of the current guidelines, researchers in Finland do not have a maternal immunization program to consider. MIFI will randomize 80 mothers, 40 to immunization with acellular pertussis and 40 to a control group. Dr. Kelly stated that whole cell vaccines are not available for use in Finland. Participants will receive a two-dose schedule at 3 and 5 months. Blood samples will then be taken to compare the serological and cellular responses, which will help researchers understand the effects of maternal immunization. In addition, there will be sampling of mucosal fluid using a device that collects a standardized aliquot of fluid.
 

The BERT study

The final clinical element of PERISCOPE presented by Dr. Kelly was the Booster against Pertussis study. This study is near completion. It seeks to examine the use of an acellular booster across different age groups and three countries: the United Kingdom, the Netherlands, and Finland. The study is being coordinated by Guy Berbers, PhD, at the National Institute for Public Health and the Environment in the Netherlands.

BERT comprises four cohorts (A, B, C, D) of different ages: 7-10 years (36 participants), 11-15 years (36 participants), mid-adult (25 participants), and older age (25 participants). After receiving an acellular booster, participants will undergo intense sampling. Sampling will take place immediately after immunization at day 7 and look at adaptive effects, then again at day 28 and day 365.

Because some participants will have already received whole cell or acellular vaccination, this approach will allow researchers to look at the effects of priming (i.e., how long the B cell/T cell antibody responses last).

Involving different countries across Europe ensures wide applicability of results, but also allows researchers to compare the effects of very different immunization histories.

At the end of this ESPID session, Dimitri Diavatopoulos, PhD, assistant professor at the Radboud University Medical Centre Nijmegen, the Netherlands, commented that a future problem in studying pertussis vaccines and their potential clinical application is that most vaccination schedules now involve combination products. Obtaining a stand-alone vaccination may prove difficult, and there may be resistance if it complicates current vaccination programs.

Dr. Kelly acknowledged funding for the PERISCOPE project from GlaxoSmithKline and Pasteur Sanofi.

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

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

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

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

As the first American health care workers rolled up their sleeves for a COVID-19 vaccine, the images were instantly frozen in history, marking the triumph of scientific know-how and ingenuity. Cameras captured the first trucks pulling out of a warehouse in Portage, Mich., to the applause of workers and area residents. A day later, Boston Medical Center employees – some dressed in scrubs and wearing masks, face shields, and protective gowns – literally danced on the sidewalk when doses arrived. Some have photographed themselves getting the vaccine and posted it on social media, tagging it #MyCOVIDVax.

But the real story of the debut of COVID-19 vaccination is more methodical than monumental, a celebration of teamwork rather than of conquest. As hospitals waited for their first allotment, they reviewed their carefully drafted plans. They relied on each other, reaching across the usual divisions of competition and working collaboratively to share the limited supply. Their priority lists for the first vaccinations included environmental services workers who clean patient rooms and the critical care physicians who work to save lives.

“Health care workers have pulled together throughout this pandemic,” said Melanie Swift, MD, cochair of the COVID-19 Vaccine Allocation and Distribution Work Group at Mayo Clinic in Rochester, Minn. “We’ve gone through the darkest of years relying so heavily on each other,” she said. “Now we’re pulling together to get out of it.”

Still, a rollout of this magnitude has hitches. Stanford issued an apology Dec. 18 after its medical residents protested a vaccine distribution plan that left out nearly all of its residents and fellows, many of whom regularly treat patients with COVID-19.

There have already been more than 287,000 COVID-19 cases and 953 deaths among health care workers, according to the Centers for Disease Control and Prevention. In its guidance, the agency pointed out that the “continued protection of them at work, at home, and in the community remains a national priority.” That means vaccinating a workforce of about 21 million people, often the largest group of employees in a community.

“It collectively takes all of us to vaccinate our teams to maintain that stability in our health care infrastructure across the metro Atlanta area,” Christy Norman, PharmD, vice president of pharmacy services at Emory Healthcare, told reporters in a briefing as the health system awaited its first delivery.
 

Don’t waste a dose

One overriding imperative prevails: Hospitals don’t want to waste any doses. The storage requirements of the Pfizer vaccine make that tricky.

Once vials are removed from the pizza-box-shaped containers in ultracold storage and placed in a refrigerator, they must be used within 5 days. Thawed five-dose vials must be brought to room temperature before they are diluted, and they can remain at room temperature for no more than 2 hours. Once they are diluted with 1.8 mL of a 0.9% sodium chloride injection, the vials must be used within 6 hours.

COVID-19 precautions require employees to stay physically distant while they wait their turn for vaccination, which means the process can’t mirror typical large-scale flu immunization programs.

To prioritize groups, the vaccination planners at Mayo conducted a thorough risk stratification, considering each employee’s duties. Do they work in a dedicated COVID-19 unit? Do they handle lab tests or collect swabs? Do they work in the ICU or emergency department?

“We have applied some principles to make sure that as we roll it out, we prioritize people who are at greatest risk of ongoing exposure and who are really critical to maintaining the COVID response and other essential health services,” said Dr. Swift, associate medical director of Mayo’s occupational health service.

Mayo employees who are eligible for the first doses can sign up for appointments through the medical record system. If it seems likely that some doses will be left over at the end of the vaccination period – perhaps because of missed appointments – supervisors in high-risk areas can refer other health care workers. Mayo gave its first vaccines on Dec. 18, but the vaccination program began in earnest the following week. With the pleasant surprise that each five-dose vial actually provides six doses, 474 vials will allow for the vaccination of 2,844 employees in the top-priority group. “It’s going to expand each week or few days as we get more and more vaccine,” Dr. Swift said.
 

Sharing vials with small rural hospitals

Minnesota is using a hub-and-spoke system to give small rural hospitals access to the Pfizer vaccine, even though they lack ultracold storage and can’t use a minimum order of 975 doses. Large hospitals, acting as hubs, are sharing their orders. (The minimum order for Moderna is 100 doses.)

In south-central Minnesota, for example, two hub hospitals each have six spoke hospitals. Five of the 14 hospitals are independent, and the rest are part of large hospital systems, but affiliation doesn’t matter, said Eric Weller, regional health care preparedness coordinator for the South Central Healthcare Coalition. “We are all working together. It doesn’t matter what system you’re from,” he said. “We’re working for the good of the community.”

Each hospital designed a process to provide vaccine education, prioritize groups, allocate appointments, register people for vaccination, obtain signed consent forms, administer vaccines in a COVID-safe way, and provide follow-up appointments for the second dose. “We’re using some of the lessons we learned during H1N1,” said Mr. Weller, referring to immunization during the 2009 influenza pandemic. “The difference is that during H1N1, you could have lines of people.”

Coordinating the appointments will be more important than ever. “One of the vaccination strategies is to get people in groups of five, so you use one vial on those five people and don’t waste it,” he said.

Logistics are somewhat different for the Moderna vaccine, which will come in 10-dose vials that can be refrigerated for up to 30 days.

Both vaccines may produce mild flulike symptoms, such as fatigue, headache, or muscle pain, particularly after the second dose. That’s a sign that the immune system is reacting to the vaccine, but it’s also another consideration in the vaccination plans, because health care workers might take a day or two off work. “We’re not going to vaccinate a whole department at one time. It will be staggered,” said Kevin Smith, MD, medical director of the occupational medicine program at ProMedica, a health care system based in Toledo, Ohio.

Dr. Smith said he plans to encourage employees to use V-Safe, an app created by the CDC to track adverse effects in people who receive the vaccine. He pointed out that a day or two of achiness will be better than coping with the symptoms of COVID-19. Some employees who recovered from the infection still feel fatigued or haven’t regained their sense of taste and smell. “We are still monitoring quite a few employees to make sure they get back to 100%,” he said.
 

Hope for ending the pandemic

Public health officials have worried about vaccine hesitancy, even among health care workers, but so far, that concern seems overshadowed by enthusiasm. Dr. Smith said his department has been fielding calls from employees who want to know when they will be able to get the vaccine. “I think everyone feels relief,” he said. “We’re at the beginning of the end.”

At Mayo, Dr. Swift is surveying staff to gauge the willingness to get the vaccine, but she already senses excitement among employees. “No doubt there are still people who are hesitant, but I’m feeling a shift,” she said. “I’m feeling this momentum building of health care workers coming on board and wanting to take this vaccine, which is good, because they will set an example for their patients.”

For Colleen Kelley, MD, an infectious disease physician at Emory University in Atlanta who was principal investigator for an Emory-affiliated Moderna clinical trial site, it has been an emotional time. “Things were looking very bleak and dark for a time, and then we started to get these efficacy results that were greater than anyone imagined,” she said.

Dr. Kelley spends time talking to journalists and educating physician colleagues and hospital employees about how the vaccine was developed so quickly and how it works. “Everyone asks me, ‘Should I get it? Are you going to get it?’ My answer is ‘yes’ and ‘yes,’ “ she said. “I am 1,000% confident that the benefits of widespread vaccination outweigh the risks of continued COVID and a continued pandemic.”

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

Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been “paused” because of futility and safety concerns, a statement from the U.S. National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the REMAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs. lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

“Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question,” the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke. 

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.  

The trials are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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

Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been “paused” because of futility and safety concerns, a statement from the U.S. National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the REMAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs. lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

“Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question,” the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke. 

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.  

The trials are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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

Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been “paused” because of futility and safety concerns, a statement from the U.S. National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the REMAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs. lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

“Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question,” the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke. 

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.  

The trials are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

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

Among women with type 2 endometrial cancer, diagnostic hysteroscopy may not be associated with increased odds of positive peritoneal cytology at the time of surgical staging or with decreased survival, according to a retrospective study of 127 patients.

Compared with another diagnostic method, dilation and curettage, hysteroscopy “might present equal safety” in this patient population, a researcher said at the meeting sponsored by AAGL, held virtually this year.
 

Possible associations between cytology and procedures

Prior research has found that positive peritoneal cytology may correlate with greater likelihood of death among patients with endometrial cancer, and researchers have wondered whether pressure on the uterine cavity during hysteroscopy increases the presence of positive peritoneal cytology. “According to some systematic reviews ... it seems that it does,” said study author Luiz Brito, MD, PhD, associate professor of obstetrics and gynecology at the University of Campinas in Brazil.

Nevertheless, research suggests that “most of the time hysteroscopy does not have a powerful impact on the prognosis of these patients,” he said.

Studies have tended to focus on patients with type 1 endometrial cancer, however. Type 2 endometrial cancer, which is more aggressive, “is scarcely studied,” Dr. Brito said. One retrospective study that focused on type 2 endometrial cancer included 140 patients. Among patients who underwent hysteroscopy, 30% had positive cytology. In comparison, 12% of patients in the curettage group had positive cytology. But the difference in disease-specific survival between groups was not statistically significant, and about 33% of the patients in each group developed a recurrence.

To examine associations between diagnostic methods and outcomes in another group of patients with type 2 endometrial cancer, Dr. Brito and colleagues analyzed data from a hospital registry in Brazil.

The database included 1,183 patients with endometrial cancer between 2002 and 2017, including 235 patients with type 2 endometrial cancer. After excluding patients with synchronous tumor and those who did not undergo surgery or did not have peritoneal cytology performed, 127 patients remained for the analysis. The study included follow-up to December 2019.

The researchers compared the prevalence of positive peritoneal cytology among 43 patients who underwent hysteroscopy with that among 84 patients who underwent curettage. The groups had similar baseline characteristics.

Positive peritoneal cytology was more common in the curettage group than in the hysteroscopy group (10.7% vs. 4.6%), although the difference was not statistically significant. Lymphovascular invasion and advanced surgical staging were more common in the curettage group.

In a multivariate analysis, older age and advanced cancer staging were the only factors associated with decreased disease-free survival. Age, advanced cancer staging, and vascular invasion were associated with decreased disease-specific survival.

The researchers also had considered factors such as peritoneal cytology, diagnostic method, age of menarche, menopause time, parity, comorbidities, smoking status, body mass index, abnormal uterine bleeding, histological type, and adjuvant treatment.

A limitation of the study is that it relied on data from a public health system that often has long wait times for diagnosis and treatment, Dr. Brito noted.
 

Some doctors may forgo cytology

The available research raises questions about the role and relevance of peritoneal cytology in caring for patients with endometrial cancer, René Pareja, MD, a gynecologic oncologist at Instituto Nacional de Cancerología, Bogotá, Colombia, said in a discussion following the presentation.

Peritoneal cytology has not been part of endometrial cancer staging since 2009, Dr. Pareja said. Still, guidelines recommend that surgeons collect cytology during surgical staging, with the idea that the results could inform adjuvant treatment decisions.

“Peritoneal cytology is recommended in the guidelines, but there are no recommendations on how to proceed if it is positive,” Dr. Pareja said. “While some gynecologic oncologists continue to take cytology during endometrial cancer staging, some have stopped doing so. And in Colombia, most of us are not performing pelvic cytology.”

Although some studies indicate that hysteroscopy may increase the rate of positive cytology, positive cytology may not be associated with worse oncological outcomes independent of other risk factors for recurrence, said Dr. Pareja.

So far, studies have been retrospective. Furthermore, the sensitivity and specificity of pelvic cytology tests are not 100%. “Should we continue performing pelvic cytology given the results of this and other studies?” Dr. Pareja asked.

Despite limited knowledge about this variable, physicians may want to be aware if a patient has positive cytology, Dr. Brito suggested. “At least it will give us some red flags so we can be attentive to these patients.”

If researchers were to design a prospective study that incorporates hysteroscopic variables, it could provide more complete answers about the relationship between hysteroscopy and peritoneal cytology and clarify the importance of positive cytology, Dr. Brito said.

Dr. Brito had no relevant disclosures. Dr. Pareja disclosed consulting for Johnson & Johnson.

jremaly@mdedge.com

SOURCE: Oliveira Brito LG et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.356.

Among women with type 2 endometrial cancer, diagnostic hysteroscopy may not be associated with increased odds of positive peritoneal cytology at the time of surgical staging or with decreased survival, according to a retrospective study of 127 patients.

Compared with another diagnostic method, dilation and curettage, hysteroscopy “might present equal safety” in this patient population, a researcher said at the meeting sponsored by AAGL, held virtually this year.
 

Possible associations between cytology and procedures

Prior research has found that positive peritoneal cytology may correlate with greater likelihood of death among patients with endometrial cancer, and researchers have wondered whether pressure on the uterine cavity during hysteroscopy increases the presence of positive peritoneal cytology. “According to some systematic reviews ... it seems that it does,” said study author Luiz Brito, MD, PhD, associate professor of obstetrics and gynecology at the University of Campinas in Brazil.

Nevertheless, research suggests that “most of the time hysteroscopy does not have a powerful impact on the prognosis of these patients,” he said.

Studies have tended to focus on patients with type 1 endometrial cancer, however. Type 2 endometrial cancer, which is more aggressive, “is scarcely studied,” Dr. Brito said. One retrospective study that focused on type 2 endometrial cancer included 140 patients. Among patients who underwent hysteroscopy, 30% had positive cytology. In comparison, 12% of patients in the curettage group had positive cytology. But the difference in disease-specific survival between groups was not statistically significant, and about 33% of the patients in each group developed a recurrence.

To examine associations between diagnostic methods and outcomes in another group of patients with type 2 endometrial cancer, Dr. Brito and colleagues analyzed data from a hospital registry in Brazil.

The database included 1,183 patients with endometrial cancer between 2002 and 2017, including 235 patients with type 2 endometrial cancer. After excluding patients with synchronous tumor and those who did not undergo surgery or did not have peritoneal cytology performed, 127 patients remained for the analysis. The study included follow-up to December 2019.

The researchers compared the prevalence of positive peritoneal cytology among 43 patients who underwent hysteroscopy with that among 84 patients who underwent curettage. The groups had similar baseline characteristics.

Positive peritoneal cytology was more common in the curettage group than in the hysteroscopy group (10.7% vs. 4.6%), although the difference was not statistically significant. Lymphovascular invasion and advanced surgical staging were more common in the curettage group.

In a multivariate analysis, older age and advanced cancer staging were the only factors associated with decreased disease-free survival. Age, advanced cancer staging, and vascular invasion were associated with decreased disease-specific survival.

The researchers also had considered factors such as peritoneal cytology, diagnostic method, age of menarche, menopause time, parity, comorbidities, smoking status, body mass index, abnormal uterine bleeding, histological type, and adjuvant treatment.

A limitation of the study is that it relied on data from a public health system that often has long wait times for diagnosis and treatment, Dr. Brito noted.
 

Some doctors may forgo cytology

The available research raises questions about the role and relevance of peritoneal cytology in caring for patients with endometrial cancer, René Pareja, MD, a gynecologic oncologist at Instituto Nacional de Cancerología, Bogotá, Colombia, said in a discussion following the presentation.

Peritoneal cytology has not been part of endometrial cancer staging since 2009, Dr. Pareja said. Still, guidelines recommend that surgeons collect cytology during surgical staging, with the idea that the results could inform adjuvant treatment decisions.

“Peritoneal cytology is recommended in the guidelines, but there are no recommendations on how to proceed if it is positive,” Dr. Pareja said. “While some gynecologic oncologists continue to take cytology during endometrial cancer staging, some have stopped doing so. And in Colombia, most of us are not performing pelvic cytology.”

Although some studies indicate that hysteroscopy may increase the rate of positive cytology, positive cytology may not be associated with worse oncological outcomes independent of other risk factors for recurrence, said Dr. Pareja.

So far, studies have been retrospective. Furthermore, the sensitivity and specificity of pelvic cytology tests are not 100%. “Should we continue performing pelvic cytology given the results of this and other studies?” Dr. Pareja asked.

Despite limited knowledge about this variable, physicians may want to be aware if a patient has positive cytology, Dr. Brito suggested. “At least it will give us some red flags so we can be attentive to these patients.”

If researchers were to design a prospective study that incorporates hysteroscopic variables, it could provide more complete answers about the relationship between hysteroscopy and peritoneal cytology and clarify the importance of positive cytology, Dr. Brito said.

Dr. Brito had no relevant disclosures. Dr. Pareja disclosed consulting for Johnson & Johnson.

jremaly@mdedge.com

SOURCE: Oliveira Brito LG et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.356.

Among women with type 2 endometrial cancer, diagnostic hysteroscopy may not be associated with increased odds of positive peritoneal cytology at the time of surgical staging or with decreased survival, according to a retrospective study of 127 patients.

Compared with another diagnostic method, dilation and curettage, hysteroscopy “might present equal safety” in this patient population, a researcher said at the meeting sponsored by AAGL, held virtually this year.
 

Possible associations between cytology and procedures

Prior research has found that positive peritoneal cytology may correlate with greater likelihood of death among patients with endometrial cancer, and researchers have wondered whether pressure on the uterine cavity during hysteroscopy increases the presence of positive peritoneal cytology. “According to some systematic reviews ... it seems that it does,” said study author Luiz Brito, MD, PhD, associate professor of obstetrics and gynecology at the University of Campinas in Brazil.

Nevertheless, research suggests that “most of the time hysteroscopy does not have a powerful impact on the prognosis of these patients,” he said.

Studies have tended to focus on patients with type 1 endometrial cancer, however. Type 2 endometrial cancer, which is more aggressive, “is scarcely studied,” Dr. Brito said. One retrospective study that focused on type 2 endometrial cancer included 140 patients. Among patients who underwent hysteroscopy, 30% had positive cytology. In comparison, 12% of patients in the curettage group had positive cytology. But the difference in disease-specific survival between groups was not statistically significant, and about 33% of the patients in each group developed a recurrence.

To examine associations between diagnostic methods and outcomes in another group of patients with type 2 endometrial cancer, Dr. Brito and colleagues analyzed data from a hospital registry in Brazil.

The database included 1,183 patients with endometrial cancer between 2002 and 2017, including 235 patients with type 2 endometrial cancer. After excluding patients with synchronous tumor and those who did not undergo surgery or did not have peritoneal cytology performed, 127 patients remained for the analysis. The study included follow-up to December 2019.

The researchers compared the prevalence of positive peritoneal cytology among 43 patients who underwent hysteroscopy with that among 84 patients who underwent curettage. The groups had similar baseline characteristics.

Positive peritoneal cytology was more common in the curettage group than in the hysteroscopy group (10.7% vs. 4.6%), although the difference was not statistically significant. Lymphovascular invasion and advanced surgical staging were more common in the curettage group.

In a multivariate analysis, older age and advanced cancer staging were the only factors associated with decreased disease-free survival. Age, advanced cancer staging, and vascular invasion were associated with decreased disease-specific survival.

The researchers also had considered factors such as peritoneal cytology, diagnostic method, age of menarche, menopause time, parity, comorbidities, smoking status, body mass index, abnormal uterine bleeding, histological type, and adjuvant treatment.

A limitation of the study is that it relied on data from a public health system that often has long wait times for diagnosis and treatment, Dr. Brito noted.
 

Some doctors may forgo cytology

The available research raises questions about the role and relevance of peritoneal cytology in caring for patients with endometrial cancer, René Pareja, MD, a gynecologic oncologist at Instituto Nacional de Cancerología, Bogotá, Colombia, said in a discussion following the presentation.

Peritoneal cytology has not been part of endometrial cancer staging since 2009, Dr. Pareja said. Still, guidelines recommend that surgeons collect cytology during surgical staging, with the idea that the results could inform adjuvant treatment decisions.

“Peritoneal cytology is recommended in the guidelines, but there are no recommendations on how to proceed if it is positive,” Dr. Pareja said. “While some gynecologic oncologists continue to take cytology during endometrial cancer staging, some have stopped doing so. And in Colombia, most of us are not performing pelvic cytology.”

Although some studies indicate that hysteroscopy may increase the rate of positive cytology, positive cytology may not be associated with worse oncological outcomes independent of other risk factors for recurrence, said Dr. Pareja.

So far, studies have been retrospective. Furthermore, the sensitivity and specificity of pelvic cytology tests are not 100%. “Should we continue performing pelvic cytology given the results of this and other studies?” Dr. Pareja asked.

Despite limited knowledge about this variable, physicians may want to be aware if a patient has positive cytology, Dr. Brito suggested. “At least it will give us some red flags so we can be attentive to these patients.”

If researchers were to design a prospective study that incorporates hysteroscopic variables, it could provide more complete answers about the relationship between hysteroscopy and peritoneal cytology and clarify the importance of positive cytology, Dr. Brito said.

Dr. Brito had no relevant disclosures. Dr. Pareja disclosed consulting for Johnson & Johnson.

jremaly@mdedge.com

SOURCE: Oliveira Brito LG et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.356.

Labor induction at 39 weeks instead of 41 weeks may have a positive impact on neonatal outcomes, Aaron B. Caughey, MD, PhD, said at the 2020 virtual meeting of the American College of Obstetricians and Gynecologists.

For much of the 20th century, term gestation has been defined as 37 weeks and beyond, said Dr. Caughey, of Oregon Health & Science University, Portland. He noted several studies showing a U-shaped distribution in neonatal outcomes during the period from 37 weeks to 41 weeks for some outcomes, including Apgar scores. However, respiratory outcomes in a study from 2008 showed an increase, with meconium stained amniotic fluid increasing from 2.27% at 37 weeks to 10.33% at 41 weeks, and meconium aspiration increasing from 0.07% at 37 weeks to 0.27% at 41 weeks.

Late-term induction may carry more risk

The study “that really got everyone’s attention” in terms of neonatal outcomes was published in 2009 in the New England Journal of Medicine. The cohort study included 24,077 elective cesarean deliveries between 37 and 42 weeks and reviewed a range of neonatal outcomes based on gestational age.

The rate of any adverse outcome decreased from 37 weeks to 39 weeks, “but then started going back up again,” Dr. Caughey said. He reviewed data from another study that factored in stillbirth and the risk of expectant management based on gestational age. A composite risk of perinatal death with expectant management was 15.4 deaths per 10,000 cases at 37 weeks and 39 weeks, but increased to 19.9 at 42 weeks.

“The morbidity appears to have a U-shaped distribution and the mortality seems to favor delivery at 39 weeks,” he said.

When it comes to induction of labor, medically indicated vs. nonmedically indicated does matter, Dr. Caughey said. Factors not considered a medical indication include impending macrosomia, increased risk for developing preeclampsia or intrauterine growth retardation, and a favorable cervix, he noted.

“For indicated induction of labor, the risks and benefits of induction of labor vs. expectant management have been considered and weighed in by the field of experts that care for pregnant women,” he said. With nonmedically indicated induction, experts “either decided that risks and benefits don’t favor induction of labor, or we haven’t come down hard on what the protocol might be.

“It is important to consider the risks and benefits,” said Dr. Caughey. The factors you want to include are neonatal outcomes, maternal preferences, and doctor preferences. However, “we want to be thoughtful about this intervention,” because of the association of higher costs and increased risk of cesarean with induction of labor.

As for timing of induction of labor, certain conditions favoring early-term induction include preeclampsia and gestational hypertension, chronic hypertension, diabetes, intrauterine growth restriction, nonreassuring fetal testing, cholestasis, placenta previa or accreta, and twins.
 

Data support value of 39 weeks

As for late-term induction of labor, “at 41 weeks it is pretty clear that neonatal outcomes would be improved by delivery,” he said. Historically, clinicians have raised concerns about the increased risk of cesarean delivery following induction of labor, but this risk has not been borne out in recent studies. Dr. Caughey said. However, in the findings from the ARRIVE trial, a large study of 6,106 women who were randomized to induction or labor or expectant management at 39 weeks, “they found a reduction in their risk of cesarean delivery compared to expectant management (18.6% vs. 22.2%). Rates of preeclampsia also were lower among induced women, while rate of chorioamnionitis, postpartum hemorrhage, and intensive care were similar between the groups. The researchers did not find significant differences in perinatal outcomes.

Dr. Caughey and colleagues conducted a systematic review of cesarean risk and induction of labor, and found a risk ratio of 0.83, similar to the ARRIVE trial. “The data suggest a consistently reduced risk for cesarean delivery with the induction of labor.”

However, “I would caution us to be thoughtful about research protocols vs. actual practice,” he said. “You must think about the environment.” The latent phase of labor can continue for a long time after induction, and patience is called for, he emphasized.

Dr. Caughey said that despite the ARRIVE trial and other studies, 39 weeks should not necessarily be the new standard for induction of labor. “The proportion of women impacted is dramatically different, if you would be inducing every woman at 39 weeks, that would be 60% to 70%,” which could have a great impact on resources.

Based on current research, early-term induction of labor at 37 weeks “is a bad idea without indication,” said Dr. Caughey. Induction at 41 weeks (sometimes considered post term) is the current ACOG recommendation and is associated with improved outcomes.

Induction of labor at full term (39-40 weeks) depends in part on the environment, and is not a violation of standard of care, he said. “Evidence is evolving, and individual hospitals are trying to figure this out.”

Cesarean data are convincing, at least in some settings, he said. However, “we need more global trials and different medical settings” to determine the optimal time for induction of labor.
 

Consider maternal preferences and characteristics

During a question-and-answer session, Dr. Caughey was asked whether all women should be offered induction of labor at 39 weeks.

“I think it is OK if your entire health system has agreed to offering, to have that shared medical decision making, but you need to have careful conversation to make sure you have the resources,” he noted. Also, he said he believed clinicians should respond to women as they request labor induction at 39 weeks.

In response to a question about induction of labor in obese women, he noted that women with a body mass index greater than 35 kg/m² are not equally successful with induction of labor. “We know they have a higher risk of cesarean delivery,” however, “it has been demonstrated that they have the same potential benefits of reduced risk of cesarean.”

As for factoring in the Bishop score to determine a favorable or unfavorable cervix, Dr. Caughey noted that women with a favorable cervix are more likely to go into labor on their own, while those with an unfavorable cervix may benefit from cervical ripening.

Dr. Caughey had no financial conflicts relevant to this talk, but disclosed serving as a medical adviser to Celmatix and Mindchild, as well as an endowment to his academic department from Bob’s Red Mill, an Oregon-based whole grain foods manufacturer.

Labor induction at 39 weeks instead of 41 weeks may have a positive impact on neonatal outcomes, Aaron B. Caughey, MD, PhD, said at the 2020 virtual meeting of the American College of Obstetricians and Gynecologists.

For much of the 20th century, term gestation has been defined as 37 weeks and beyond, said Dr. Caughey, of Oregon Health & Science University, Portland. He noted several studies showing a U-shaped distribution in neonatal outcomes during the period from 37 weeks to 41 weeks for some outcomes, including Apgar scores. However, respiratory outcomes in a study from 2008 showed an increase, with meconium stained amniotic fluid increasing from 2.27% at 37 weeks to 10.33% at 41 weeks, and meconium aspiration increasing from 0.07% at 37 weeks to 0.27% at 41 weeks.

Late-term induction may carry more risk

The study “that really got everyone’s attention” in terms of neonatal outcomes was published in 2009 in the New England Journal of Medicine. The cohort study included 24,077 elective cesarean deliveries between 37 and 42 weeks and reviewed a range of neonatal outcomes based on gestational age.

The rate of any adverse outcome decreased from 37 weeks to 39 weeks, “but then started going back up again,” Dr. Caughey said. He reviewed data from another study that factored in stillbirth and the risk of expectant management based on gestational age. A composite risk of perinatal death with expectant management was 15.4 deaths per 10,000 cases at 37 weeks and 39 weeks, but increased to 19.9 at 42 weeks.

“The morbidity appears to have a U-shaped distribution and the mortality seems to favor delivery at 39 weeks,” he said.

When it comes to induction of labor, medically indicated vs. nonmedically indicated does matter, Dr. Caughey said. Factors not considered a medical indication include impending macrosomia, increased risk for developing preeclampsia or intrauterine growth retardation, and a favorable cervix, he noted.

“For indicated induction of labor, the risks and benefits of induction of labor vs. expectant management have been considered and weighed in by the field of experts that care for pregnant women,” he said. With nonmedically indicated induction, experts “either decided that risks and benefits don’t favor induction of labor, or we haven’t come down hard on what the protocol might be.

“It is important to consider the risks and benefits,” said Dr. Caughey. The factors you want to include are neonatal outcomes, maternal preferences, and doctor preferences. However, “we want to be thoughtful about this intervention,” because of the association of higher costs and increased risk of cesarean with induction of labor.

As for timing of induction of labor, certain conditions favoring early-term induction include preeclampsia and gestational hypertension, chronic hypertension, diabetes, intrauterine growth restriction, nonreassuring fetal testing, cholestasis, placenta previa or accreta, and twins.
 

Data support value of 39 weeks

As for late-term induction of labor, “at 41 weeks it is pretty clear that neonatal outcomes would be improved by delivery,” he said. Historically, clinicians have raised concerns about the increased risk of cesarean delivery following induction of labor, but this risk has not been borne out in recent studies. Dr. Caughey said. However, in the findings from the ARRIVE trial, a large study of 6,106 women who were randomized to induction or labor or expectant management at 39 weeks, “they found a reduction in their risk of cesarean delivery compared to expectant management (18.6% vs. 22.2%). Rates of preeclampsia also were lower among induced women, while rate of chorioamnionitis, postpartum hemorrhage, and intensive care were similar between the groups. The researchers did not find significant differences in perinatal outcomes.

Dr. Caughey and colleagues conducted a systematic review of cesarean risk and induction of labor, and found a risk ratio of 0.83, similar to the ARRIVE trial. “The data suggest a consistently reduced risk for cesarean delivery with the induction of labor.”

However, “I would caution us to be thoughtful about research protocols vs. actual practice,” he said. “You must think about the environment.” The latent phase of labor can continue for a long time after induction, and patience is called for, he emphasized.

Dr. Caughey said that despite the ARRIVE trial and other studies, 39 weeks should not necessarily be the new standard for induction of labor. “The proportion of women impacted is dramatically different, if you would be inducing every woman at 39 weeks, that would be 60% to 70%,” which could have a great impact on resources.

Based on current research, early-term induction of labor at 37 weeks “is a bad idea without indication,” said Dr. Caughey. Induction at 41 weeks (sometimes considered post term) is the current ACOG recommendation and is associated with improved outcomes.

Induction of labor at full term (39-40 weeks) depends in part on the environment, and is not a violation of standard of care, he said. “Evidence is evolving, and individual hospitals are trying to figure this out.”

Cesarean data are convincing, at least in some settings, he said. However, “we need more global trials and different medical settings” to determine the optimal time for induction of labor.
 

Consider maternal preferences and characteristics

During a question-and-answer session, Dr. Caughey was asked whether all women should be offered induction of labor at 39 weeks.

“I think it is OK if your entire health system has agreed to offering, to have that shared medical decision making, but you need to have careful conversation to make sure you have the resources,” he noted. Also, he said he believed clinicians should respond to women as they request labor induction at 39 weeks.

In response to a question about induction of labor in obese women, he noted that women with a body mass index greater than 35 kg/m² are not equally successful with induction of labor. “We know they have a higher risk of cesarean delivery,” however, “it has been demonstrated that they have the same potential benefits of reduced risk of cesarean.”

As for factoring in the Bishop score to determine a favorable or unfavorable cervix, Dr. Caughey noted that women with a favorable cervix are more likely to go into labor on their own, while those with an unfavorable cervix may benefit from cervical ripening.

Dr. Caughey had no financial conflicts relevant to this talk, but disclosed serving as a medical adviser to Celmatix and Mindchild, as well as an endowment to his academic department from Bob’s Red Mill, an Oregon-based whole grain foods manufacturer.

Labor induction at 39 weeks instead of 41 weeks may have a positive impact on neonatal outcomes, Aaron B. Caughey, MD, PhD, said at the 2020 virtual meeting of the American College of Obstetricians and Gynecologists.

For much of the 20th century, term gestation has been defined as 37 weeks and beyond, said Dr. Caughey, of Oregon Health & Science University, Portland. He noted several studies showing a U-shaped distribution in neonatal outcomes during the period from 37 weeks to 41 weeks for some outcomes, including Apgar scores. However, respiratory outcomes in a study from 2008 showed an increase, with meconium stained amniotic fluid increasing from 2.27% at 37 weeks to 10.33% at 41 weeks, and meconium aspiration increasing from 0.07% at 37 weeks to 0.27% at 41 weeks.

Late-term induction may carry more risk

The study “that really got everyone’s attention” in terms of neonatal outcomes was published in 2009 in the New England Journal of Medicine. The cohort study included 24,077 elective cesarean deliveries between 37 and 42 weeks and reviewed a range of neonatal outcomes based on gestational age.

The rate of any adverse outcome decreased from 37 weeks to 39 weeks, “but then started going back up again,” Dr. Caughey said. He reviewed data from another study that factored in stillbirth and the risk of expectant management based on gestational age. A composite risk of perinatal death with expectant management was 15.4 deaths per 10,000 cases at 37 weeks and 39 weeks, but increased to 19.9 at 42 weeks.

“The morbidity appears to have a U-shaped distribution and the mortality seems to favor delivery at 39 weeks,” he said.

When it comes to induction of labor, medically indicated vs. nonmedically indicated does matter, Dr. Caughey said. Factors not considered a medical indication include impending macrosomia, increased risk for developing preeclampsia or intrauterine growth retardation, and a favorable cervix, he noted.

“For indicated induction of labor, the risks and benefits of induction of labor vs. expectant management have been considered and weighed in by the field of experts that care for pregnant women,” he said. With nonmedically indicated induction, experts “either decided that risks and benefits don’t favor induction of labor, or we haven’t come down hard on what the protocol might be.

“It is important to consider the risks and benefits,” said Dr. Caughey. The factors you want to include are neonatal outcomes, maternal preferences, and doctor preferences. However, “we want to be thoughtful about this intervention,” because of the association of higher costs and increased risk of cesarean with induction of labor.

As for timing of induction of labor, certain conditions favoring early-term induction include preeclampsia and gestational hypertension, chronic hypertension, diabetes, intrauterine growth restriction, nonreassuring fetal testing, cholestasis, placenta previa or accreta, and twins.
 

Data support value of 39 weeks

As for late-term induction of labor, “at 41 weeks it is pretty clear that neonatal outcomes would be improved by delivery,” he said. Historically, clinicians have raised concerns about the increased risk of cesarean delivery following induction of labor, but this risk has not been borne out in recent studies. Dr. Caughey said. However, in the findings from the ARRIVE trial, a large study of 6,106 women who were randomized to induction or labor or expectant management at 39 weeks, “they found a reduction in their risk of cesarean delivery compared to expectant management (18.6% vs. 22.2%). Rates of preeclampsia also were lower among induced women, while rate of chorioamnionitis, postpartum hemorrhage, and intensive care were similar between the groups. The researchers did not find significant differences in perinatal outcomes.

Dr. Caughey and colleagues conducted a systematic review of cesarean risk and induction of labor, and found a risk ratio of 0.83, similar to the ARRIVE trial. “The data suggest a consistently reduced risk for cesarean delivery with the induction of labor.”

However, “I would caution us to be thoughtful about research protocols vs. actual practice,” he said. “You must think about the environment.” The latent phase of labor can continue for a long time after induction, and patience is called for, he emphasized.

Dr. Caughey said that despite the ARRIVE trial and other studies, 39 weeks should not necessarily be the new standard for induction of labor. “The proportion of women impacted is dramatically different, if you would be inducing every woman at 39 weeks, that would be 60% to 70%,” which could have a great impact on resources.

Based on current research, early-term induction of labor at 37 weeks “is a bad idea without indication,” said Dr. Caughey. Induction at 41 weeks (sometimes considered post term) is the current ACOG recommendation and is associated with improved outcomes.

Induction of labor at full term (39-40 weeks) depends in part on the environment, and is not a violation of standard of care, he said. “Evidence is evolving, and individual hospitals are trying to figure this out.”

Cesarean data are convincing, at least in some settings, he said. However, “we need more global trials and different medical settings” to determine the optimal time for induction of labor.
 

Consider maternal preferences and characteristics

During a question-and-answer session, Dr. Caughey was asked whether all women should be offered induction of labor at 39 weeks.

“I think it is OK if your entire health system has agreed to offering, to have that shared medical decision making, but you need to have careful conversation to make sure you have the resources,” he noted. Also, he said he believed clinicians should respond to women as they request labor induction at 39 weeks.

In response to a question about induction of labor in obese women, he noted that women with a body mass index greater than 35 kg/m² are not equally successful with induction of labor. “We know they have a higher risk of cesarean delivery,” however, “it has been demonstrated that they have the same potential benefits of reduced risk of cesarean.”

As for factoring in the Bishop score to determine a favorable or unfavorable cervix, Dr. Caughey noted that women with a favorable cervix are more likely to go into labor on their own, while those with an unfavorable cervix may benefit from cervical ripening.

Dr. Caughey had no financial conflicts relevant to this talk, but disclosed serving as a medical adviser to Celmatix and Mindchild, as well as an endowment to his academic department from Bob’s Red Mill, an Oregon-based whole grain foods manufacturer.

Physicians who developed a protocol for treating hospitalized patients with COVID-19 they call MATH+ have now published a literature review with observational mortality rates in the Journal of Intensive Care Medicine (JICM) that they say supports the protocol’s use.

The physicians have been promoting their MATH+ protocol as a way to improve survival from severe COVID-19 since the spring, and this is the first time their protocol and any results have been published in a peer-reviewed journal. But because the paper contains only hospital-level mortality rates compared with previously published observational data and clinical trials (not data from a randomized controlled trial testing the protocol), experts remain unconvinced the protocol benefits patients.

“This is not a study by any stretch of the imagination,” Hugh Cassiere, MD, director of critical care medicine at North Shore University Hospital in Manhasset, New York, told Medscape Medical News via email. “It is comparative data which should never be used to make conclusions of one therapy over another.”

“It’s food for thought for those clinicians [treating COVID-19] and it gives them some options,” said Pierre Kory, MD, MPA, a pulmonary critical care specialist in Wisconsin and one of the protocol developers. “What we really emphasize for this disease is it has to be a combination therapy protocol.”

As Medscape previously reported, MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” includes additional therapies like vitamin D, zinc, melatonin, statins, and famotidine. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

The protocol evolved over a few weeks this spring as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action. In March, when Marik and his colleagues formalized the MATH+ protocol, healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients.

Determined to spread a different message, the MATH+ physicians began publicizing the protocol with a website and a small communications team. They tried to get their protocol in front of leading healthcare organizations, like the WHO, and Kory testified remotely in front of the Senate Homeland Security Committee in early May. (Kory testified in front of the committee again earlier this month about the use of ivermectin as a COVID-19 treatment. He told Medscape the MATH+ protocol has been updated to include ivermectin since the submission to JICM.)

The physicians have continued promoting the protocol in the summer and fall, even after the RECOVERY trial showed dexamethasone treatment decreased mortality in hospitalized patients with severe COVID-19 and the WHO and other organizations started recommending the drug.

In the newly published JICM article, the researchers describe a mix of randomized controlled trials, observational studies, and basic science research that inform each of the individual pieces of the MATH+ protocol. Some of the cited research pertains specifically to the treatment of COVID-19.

Other studies the authors use to support the protocol are based on data from other viral outbreaks, like H1N1 and SARS-CoV, as well as other medical conditions, like nonviral acute respiratory distress syndrome and sepsis. The researchers did not conduct a randomized controlled trial of MATH+ for patients with COVID-19 because, as they write in the article, they did not believe they had the clinical equipoise required for such a study.

“With respect to each of the individual ‘core’ therapies of MATH+, all authors felt the therapies either superior to any placebo or possessed evidence of minimal risk and cost compared to potential benefit,” they wrote in the paper.

“With a new disease, it is totally reasonable to take your best guess at a therapy,” wrote F. Perry Wilson, MD, MSCE, director of the Clinical and Translational Research Accelerator at Yale University School of Medicine, in an email to Medscape. “When there is limited information, you go with what you have. What I take issue with here is the authors’ implication that that’s where the scientific process stops. In my mind, it’s actually just the beginning.” Every investigator believes his or her intervention is beneficial but is not sure — that’s why they conduct a randomized controlled trial, Wilson said.

“Without robust trials, we are left with too many options on the table and no way to know what helps — leading to this ‘throw the book at them’ approach, where you just pick your favorite molecule and give it,” said Wilson. 

Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, echoed this sentiment: “Many of the individual components could be expected to provide benefit and combining therapies is something physicians often do,” Parnia said in an email to Medscape. “I think this is a promising approach; however, this ultimately needs to be studied.”

The article includes previously unpublished observational mortality rates from two hospitals where the physicians have used the protocol: United Memorial Hospital in Houston, Texas and Norfolk General Hospital in Norfolk, Virginia. At United Memorial, MATH+ was “systematically” followed for patients admitted to the hospital, and at Norfolk General it was followed for patients admitted to the ICU. The two hospitals treated 140 and 191 COVID-19 patients with MATH+, respectively, as of July 20.

The average observed hospital or 28-day mortality rate at United Memorial was 4.4% and at Norfolk General was 6.1%, for a combined mortality rate of 5.1%. The researchers compared this rate with reported outcomes from 10 studies of more than 400 hospitals in the United States (72 hospitals), the United Kingdom (386), and China (3). The mortality rate for COVID-19 patients at these hospitals ranged from 15.6% to 32%, for an average mortality rate of 22.9%.

The difference in average mortality rates represents a “more than 75% absolute risk reduction in mortality” with MATH+, according to the authors. The data from other hospitals were reported from January to early June, representative of death rates early in the pandemic and before the announcement of the RECOVERY trial results spurred increased use of dexamethasone. 

The new numbers may not be convincing to other physicians.

“The comparison of the outcomes in the two hospitals where this protocol is implemented vs mortality rates in other published studies is quite a stretch,” Wilson told Medscape. “Hospitals with robust research programs that publish large cohorts tend to be tertiary care centers where sick patients get referred. Without data on the baseline characteristics of the patients in these studies, it’s really not appropriate to draw apples-to-apples comparisons.”

“There are many factors that lead to different mortality rates [between hospitals] and it often reflects the quality of general ICU care,” said Parnia. For example, many ICUs were overwhelmed and stretched during the pandemic, while others were not.

“This protocol remains a hypothesis in need of a prospective clinical trial,” said Daniel Kaul, MD, professor of infectious diseases at the University of Michigan, Ann Arbor. “Comparing gross mortality rates from different centers at different times with different case mixes is at most hypothesis generating.”

“The use of comparative data is useless information…not based on true comparison of groups,” said Cassiere of the average mortality rates. Only a randomized, placebo-controlled trial can prove if a treatment is effective. “This protocol should be abandoned.”

“The MATH+ is based on negative evidence,” Cassiere told Medscape, pointing to trials that showed no effect for vitamin C (ascorbic acid) and thiamine in critical illnesses. And, given the “overwhelming positive data’’ for dexamethasone to treat patients with severe COVID-19, its exclusion from MATH+ in favor of a steroid that has not been extensively studied for COVID-19 is “reckless and irresponsible,” he said. 

Kory pushed back strongly against this assertion, pointing to the decades of research on methylprednisolone as a treatment for lung disease and ARDS outlined in the article. “It has far more evidence than dexamethasone,” he told Medscape over the phone.

“Our recommendation is based on a clear understanding of the pharmacological principle to guide prolonged glucocorticoid administration in ARDS and COVID-19,” wrote G. Umberto Meduri, MD, a MATH+ coauthor and professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Tennessee Health Science Center in Memphis.

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

Physicians who developed a protocol for treating hospitalized patients with COVID-19 they call MATH+ have now published a literature review with observational mortality rates in the Journal of Intensive Care Medicine (JICM) that they say supports the protocol’s use.

The physicians have been promoting their MATH+ protocol as a way to improve survival from severe COVID-19 since the spring, and this is the first time their protocol and any results have been published in a peer-reviewed journal. But because the paper contains only hospital-level mortality rates compared with previously published observational data and clinical trials (not data from a randomized controlled trial testing the protocol), experts remain unconvinced the protocol benefits patients.

“This is not a study by any stretch of the imagination,” Hugh Cassiere, MD, director of critical care medicine at North Shore University Hospital in Manhasset, New York, told Medscape Medical News via email. “It is comparative data which should never be used to make conclusions of one therapy over another.”

“It’s food for thought for those clinicians [treating COVID-19] and it gives them some options,” said Pierre Kory, MD, MPA, a pulmonary critical care specialist in Wisconsin and one of the protocol developers. “What we really emphasize for this disease is it has to be a combination therapy protocol.”

As Medscape previously reported, MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” includes additional therapies like vitamin D, zinc, melatonin, statins, and famotidine. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

The protocol evolved over a few weeks this spring as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action. In March, when Marik and his colleagues formalized the MATH+ protocol, healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients.

Determined to spread a different message, the MATH+ physicians began publicizing the protocol with a website and a small communications team. They tried to get their protocol in front of leading healthcare organizations, like the WHO, and Kory testified remotely in front of the Senate Homeland Security Committee in early May. (Kory testified in front of the committee again earlier this month about the use of ivermectin as a COVID-19 treatment. He told Medscape the MATH+ protocol has been updated to include ivermectin since the submission to JICM.)

The physicians have continued promoting the protocol in the summer and fall, even after the RECOVERY trial showed dexamethasone treatment decreased mortality in hospitalized patients with severe COVID-19 and the WHO and other organizations started recommending the drug.

In the newly published JICM article, the researchers describe a mix of randomized controlled trials, observational studies, and basic science research that inform each of the individual pieces of the MATH+ protocol. Some of the cited research pertains specifically to the treatment of COVID-19.

Other studies the authors use to support the protocol are based on data from other viral outbreaks, like H1N1 and SARS-CoV, as well as other medical conditions, like nonviral acute respiratory distress syndrome and sepsis. The researchers did not conduct a randomized controlled trial of MATH+ for patients with COVID-19 because, as they write in the article, they did not believe they had the clinical equipoise required for such a study.

“With respect to each of the individual ‘core’ therapies of MATH+, all authors felt the therapies either superior to any placebo or possessed evidence of minimal risk and cost compared to potential benefit,” they wrote in the paper.

“With a new disease, it is totally reasonable to take your best guess at a therapy,” wrote F. Perry Wilson, MD, MSCE, director of the Clinical and Translational Research Accelerator at Yale University School of Medicine, in an email to Medscape. “When there is limited information, you go with what you have. What I take issue with here is the authors’ implication that that’s where the scientific process stops. In my mind, it’s actually just the beginning.” Every investigator believes his or her intervention is beneficial but is not sure — that’s why they conduct a randomized controlled trial, Wilson said.

“Without robust trials, we are left with too many options on the table and no way to know what helps — leading to this ‘throw the book at them’ approach, where you just pick your favorite molecule and give it,” said Wilson. 

Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, echoed this sentiment: “Many of the individual components could be expected to provide benefit and combining therapies is something physicians often do,” Parnia said in an email to Medscape. “I think this is a promising approach; however, this ultimately needs to be studied.”

The article includes previously unpublished observational mortality rates from two hospitals where the physicians have used the protocol: United Memorial Hospital in Houston, Texas and Norfolk General Hospital in Norfolk, Virginia. At United Memorial, MATH+ was “systematically” followed for patients admitted to the hospital, and at Norfolk General it was followed for patients admitted to the ICU. The two hospitals treated 140 and 191 COVID-19 patients with MATH+, respectively, as of July 20.

The average observed hospital or 28-day mortality rate at United Memorial was 4.4% and at Norfolk General was 6.1%, for a combined mortality rate of 5.1%. The researchers compared this rate with reported outcomes from 10 studies of more than 400 hospitals in the United States (72 hospitals), the United Kingdom (386), and China (3). The mortality rate for COVID-19 patients at these hospitals ranged from 15.6% to 32%, for an average mortality rate of 22.9%.

The difference in average mortality rates represents a “more than 75% absolute risk reduction in mortality” with MATH+, according to the authors. The data from other hospitals were reported from January to early June, representative of death rates early in the pandemic and before the announcement of the RECOVERY trial results spurred increased use of dexamethasone. 

The new numbers may not be convincing to other physicians.

“The comparison of the outcomes in the two hospitals where this protocol is implemented vs mortality rates in other published studies is quite a stretch,” Wilson told Medscape. “Hospitals with robust research programs that publish large cohorts tend to be tertiary care centers where sick patients get referred. Without data on the baseline characteristics of the patients in these studies, it’s really not appropriate to draw apples-to-apples comparisons.”

“There are many factors that lead to different mortality rates [between hospitals] and it often reflects the quality of general ICU care,” said Parnia. For example, many ICUs were overwhelmed and stretched during the pandemic, while others were not.

“This protocol remains a hypothesis in need of a prospective clinical trial,” said Daniel Kaul, MD, professor of infectious diseases at the University of Michigan, Ann Arbor. “Comparing gross mortality rates from different centers at different times with different case mixes is at most hypothesis generating.”

“The use of comparative data is useless information…not based on true comparison of groups,” said Cassiere of the average mortality rates. Only a randomized, placebo-controlled trial can prove if a treatment is effective. “This protocol should be abandoned.”

“The MATH+ is based on negative evidence,” Cassiere told Medscape, pointing to trials that showed no effect for vitamin C (ascorbic acid) and thiamine in critical illnesses. And, given the “overwhelming positive data’’ for dexamethasone to treat patients with severe COVID-19, its exclusion from MATH+ in favor of a steroid that has not been extensively studied for COVID-19 is “reckless and irresponsible,” he said. 

Kory pushed back strongly against this assertion, pointing to the decades of research on methylprednisolone as a treatment for lung disease and ARDS outlined in the article. “It has far more evidence than dexamethasone,” he told Medscape over the phone.

“Our recommendation is based on a clear understanding of the pharmacological principle to guide prolonged glucocorticoid administration in ARDS and COVID-19,” wrote G. Umberto Meduri, MD, a MATH+ coauthor and professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Tennessee Health Science Center in Memphis.

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

Physicians who developed a protocol for treating hospitalized patients with COVID-19 they call MATH+ have now published a literature review with observational mortality rates in the Journal of Intensive Care Medicine (JICM) that they say supports the protocol’s use.

The physicians have been promoting their MATH+ protocol as a way to improve survival from severe COVID-19 since the spring, and this is the first time their protocol and any results have been published in a peer-reviewed journal. But because the paper contains only hospital-level mortality rates compared with previously published observational data and clinical trials (not data from a randomized controlled trial testing the protocol), experts remain unconvinced the protocol benefits patients.

“This is not a study by any stretch of the imagination,” Hugh Cassiere, MD, director of critical care medicine at North Shore University Hospital in Manhasset, New York, told Medscape Medical News via email. “It is comparative data which should never be used to make conclusions of one therapy over another.”

“It’s food for thought for those clinicians [treating COVID-19] and it gives them some options,” said Pierre Kory, MD, MPA, a pulmonary critical care specialist in Wisconsin and one of the protocol developers. “What we really emphasize for this disease is it has to be a combination therapy protocol.”

As Medscape previously reported, MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” includes additional therapies like vitamin D, zinc, melatonin, statins, and famotidine. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

The protocol evolved over a few weeks this spring as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action. In March, when Marik and his colleagues formalized the MATH+ protocol, healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients.

Determined to spread a different message, the MATH+ physicians began publicizing the protocol with a website and a small communications team. They tried to get their protocol in front of leading healthcare organizations, like the WHO, and Kory testified remotely in front of the Senate Homeland Security Committee in early May. (Kory testified in front of the committee again earlier this month about the use of ivermectin as a COVID-19 treatment. He told Medscape the MATH+ protocol has been updated to include ivermectin since the submission to JICM.)

The physicians have continued promoting the protocol in the summer and fall, even after the RECOVERY trial showed dexamethasone treatment decreased mortality in hospitalized patients with severe COVID-19 and the WHO and other organizations started recommending the drug.

In the newly published JICM article, the researchers describe a mix of randomized controlled trials, observational studies, and basic science research that inform each of the individual pieces of the MATH+ protocol. Some of the cited research pertains specifically to the treatment of COVID-19.

Other studies the authors use to support the protocol are based on data from other viral outbreaks, like H1N1 and SARS-CoV, as well as other medical conditions, like nonviral acute respiratory distress syndrome and sepsis. The researchers did not conduct a randomized controlled trial of MATH+ for patients with COVID-19 because, as they write in the article, they did not believe they had the clinical equipoise required for such a study.

“With respect to each of the individual ‘core’ therapies of MATH+, all authors felt the therapies either superior to any placebo or possessed evidence of minimal risk and cost compared to potential benefit,” they wrote in the paper.

“With a new disease, it is totally reasonable to take your best guess at a therapy,” wrote F. Perry Wilson, MD, MSCE, director of the Clinical and Translational Research Accelerator at Yale University School of Medicine, in an email to Medscape. “When there is limited information, you go with what you have. What I take issue with here is the authors’ implication that that’s where the scientific process stops. In my mind, it’s actually just the beginning.” Every investigator believes his or her intervention is beneficial but is not sure — that’s why they conduct a randomized controlled trial, Wilson said.

“Without robust trials, we are left with too many options on the table and no way to know what helps — leading to this ‘throw the book at them’ approach, where you just pick your favorite molecule and give it,” said Wilson. 

Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, echoed this sentiment: “Many of the individual components could be expected to provide benefit and combining therapies is something physicians often do,” Parnia said in an email to Medscape. “I think this is a promising approach; however, this ultimately needs to be studied.”

The article includes previously unpublished observational mortality rates from two hospitals where the physicians have used the protocol: United Memorial Hospital in Houston, Texas and Norfolk General Hospital in Norfolk, Virginia. At United Memorial, MATH+ was “systematically” followed for patients admitted to the hospital, and at Norfolk General it was followed for patients admitted to the ICU. The two hospitals treated 140 and 191 COVID-19 patients with MATH+, respectively, as of July 20.

The average observed hospital or 28-day mortality rate at United Memorial was 4.4% and at Norfolk General was 6.1%, for a combined mortality rate of 5.1%. The researchers compared this rate with reported outcomes from 10 studies of more than 400 hospitals in the United States (72 hospitals), the United Kingdom (386), and China (3). The mortality rate for COVID-19 patients at these hospitals ranged from 15.6% to 32%, for an average mortality rate of 22.9%.

The difference in average mortality rates represents a “more than 75% absolute risk reduction in mortality” with MATH+, according to the authors. The data from other hospitals were reported from January to early June, representative of death rates early in the pandemic and before the announcement of the RECOVERY trial results spurred increased use of dexamethasone. 

The new numbers may not be convincing to other physicians.

“The comparison of the outcomes in the two hospitals where this protocol is implemented vs mortality rates in other published studies is quite a stretch,” Wilson told Medscape. “Hospitals with robust research programs that publish large cohorts tend to be tertiary care centers where sick patients get referred. Without data on the baseline characteristics of the patients in these studies, it’s really not appropriate to draw apples-to-apples comparisons.”

“There are many factors that lead to different mortality rates [between hospitals] and it often reflects the quality of general ICU care,” said Parnia. For example, many ICUs were overwhelmed and stretched during the pandemic, while others were not.

“This protocol remains a hypothesis in need of a prospective clinical trial,” said Daniel Kaul, MD, professor of infectious diseases at the University of Michigan, Ann Arbor. “Comparing gross mortality rates from different centers at different times with different case mixes is at most hypothesis generating.”

“The use of comparative data is useless information…not based on true comparison of groups,” said Cassiere of the average mortality rates. Only a randomized, placebo-controlled trial can prove if a treatment is effective. “This protocol should be abandoned.”

“The MATH+ is based on negative evidence,” Cassiere told Medscape, pointing to trials that showed no effect for vitamin C (ascorbic acid) and thiamine in critical illnesses. And, given the “overwhelming positive data’’ for dexamethasone to treat patients with severe COVID-19, its exclusion from MATH+ in favor of a steroid that has not been extensively studied for COVID-19 is “reckless and irresponsible,” he said. 

Kory pushed back strongly against this assertion, pointing to the decades of research on methylprednisolone as a treatment for lung disease and ARDS outlined in the article. “It has far more evidence than dexamethasone,” he told Medscape over the phone.

“Our recommendation is based on a clear understanding of the pharmacological principle to guide prolonged glucocorticoid administration in ARDS and COVID-19,” wrote G. Umberto Meduri, MD, a MATH+ coauthor and professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Tennessee Health Science Center in Memphis.

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

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

RyanKing999/iStock/Getty Images

A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

RyanKing999/iStock/Getty Images

A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

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A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com