Women's Health

The country’s top medical organizations condemned the overturning of Roe v. Wade, saying the removal of federal protections for women to access abortion services marks a “dark day.”

“It is unfathomable. It is unfair. It is wrong,” said the President of the American College of Obstetricians and Gynecologists (ACOG) Iffath Abbasi Hoskins, MD.

“Today is a very dark day in health care. It is a dark day, indeed, for the tens of millions of patients who have suddenly and unfairly lost access to safe legal and evidence-based abortion care,” Dr. Hoskins said at a press conference June 24 sponsored by ACOG. 

“It is dark for the thousands of clinicians who now, instead of focusing on providing health care to their patients, have to live with the threats of legal, civil, and even professional penalties,” Dr. Hoskins added.

ACOG has 62,000 members and is the leading group of doctors that provides obstetric and gynecologic care.
 

Dilemma for some doctors?

“I’d like to take a moment to talk about the future of the medical profession,” said ACOG Chief Executive Officer Maureen G. Phipps, MD, MPH. “[The] decision is, as Dr. Hoskins clearly said, a tragic one for our patients in states across the country, but the harm does not end there.”

Dr. Phipps described overturning Roe v. Wade as “the boldest act of legislative interference that we have seen in this country. It will allow state legislators to tell physicians what care they can and cannot provide to their patients.”

“It will leave physicians looking over our shoulders, wondering if a patient is in enough of a crisis to permit an exception to a law,” Dr. Phipps added. “This is an affront to all that drew my colleagues and me into medicine.”

Although the impact on doctor training remains to be seen, she said 44% of ob.gyn. residents are trained in states now empowered to ban abortions.

The effect of the Supreme Court decision on miscarriage management is another unknown.

“It’s going to be very difficult for us, the clinicians, to manage miscarriage,” Dr. Hoskins said. “Many miscarriages could be what we call ‘incomplete’ in the beginning,” where there is still a heartbeat and the patient is cramping and/or bleeding.

In that instance, Dr. Hoskins said, clinicians may be thinking that they have to wait.

“They may be needing to get additional opinions, whether it’s a legal opinion ... or another medical opinion.”

“It’s going to have a devastating effect on every aspect of a woman’s health care, including if she is spontaneously miscarrying,” Dr. Hoskins predicted.

Physician protect thyself?

To what extent doctors can shield themselves from potential prosecution “is a hard question to answer,” Molly Meegan, JD, ACOG’s chief legal officer and general counsel, said.

Ms. Meegan recommended members speak to the risk managers at their individual institutions for guidance.

“It is a real patchwork [of laws] out there, she said. “And that patchwork itself is a danger to people as they seek essential reproductive health care.”

Also, she added, “If a doctor can’t tell what the law is at the time they’re trying to provide the care, it has a terribly chilling effect on medical care.”

Another potential threat to doctors in states that still allow abortion services is action from a neighboring state.

“We are going to be advocating very strongly that states do not have extra-territorial jurisdiction to reach beyond the edges of their state.”

The worry is if a doctor in New Mexico, where abortion is legal, performs an abortion for a person from Texas, where it will soon be illegal, is then prosecuted by Texas, for example.
 

Medication abortion

Asked about any potential effects on medication abortions, ACOG’s Jen Villavicencio, MD, said it remains to be seen.

“Certainly many of the laws that we have seen, including trigger ban laws, encompass medication abortion,” she said. Several states have these so-called trigger laws, which put into effect laws passed to ban abortion in case Roe was overturned.

This means, she said, that any abortion option, whether it’s procedural or medication, could be and will be banned in some of these states.

Ms. Meegan added that ACOG will continue to support access to medication abortion and that it should be decided by the U.S. Food and Drug Administration and not individual states.
 

Maternal mortality may rise

“Maternal mortality in and of itself is a very difficult topic,” Dr. Hoskins said, but [the] decision amplifies the implications. “I think of the patients who will have to manage severe complications and mental health challenges while they are carrying a pregnancy that they are forced to carry.”

“I also think of the patients who need to end their pregnancies in order to save their own lives,” Dr. Hoskins added.

Dr. Hoskins said the United States already has a high maternal mortality rate. This new law, she added, could force women into higher-risk situations if they experience high blood pressure, preeclampsia, or bleeding after the birth of the baby.
 

Growing inequality possible?

“The grievous inequities that exist in this country will grow and expand unchecked without safe access to legal abortion,” Dr. Phipps said.

She noted that women, based on location, will continue “to have protected access to safe evidence-based abortion. Others will have the means and resources and opportunities to secure the care.”

But the same may not be true for women in underserved or disadvantaged communities, Dr. Phipps added.
 

American Medical Association

ACOG was not the only group to react. “The American Medical Association is deeply disturbed by the U.S. Supreme Court’s decision to overturn nearly a half century of precedent protecting patients’ right to critical reproductive health care,” President Jack Resneck Jr., MD, said in a statement.

The decision represents “an egregious allowance of government intrusion into the medical examination room, a direct attack on the practice of medicine and the patient-physician relationship, and a brazen violation of patients’ rights to evidence-based reproductive health services.”

American Academy of Family Physicians

“The American Academy of Family Physicians is disappointed and disheartened by the Supreme Court’s decision to strike down longstanding protections afforded by Roe v. Wade and Planned Parenthood v. Casey,” President Sterling N. Ransone Jr., MD, said in a statement.

The organization has 127,600 physician and medical student members.

“This decision negatively impacts our practices and our patients by undermining the patient-physician relationship and potentially criminalizing evidence-based medical care,” added Dr. Ransone.
 

American College of Physicians

“A patient’s decision about whether to continue a pregnancy should be a private decision made in consultation with a physician or other health care professional, without interference from the government,” President Ryan D. Mire, MD, said in a statement. “We strongly oppose medically unnecessary government restrictions on any health care services,” added Dr. Mire on behalf of the group’s 161,000 members.

American Academy of Pediatrics

“This decision carries grave consequences for our adolescent patients, who already face many more barriers than adults in accessing comprehensive reproductive health care services and abortion care,” President Moira Szilagyi, MD, PhD, said in a statement. 

“In the wake of this ruling, the American Academy of Pediatrics will continue to support our chapters as states consider policies affecting access to abortion care, and pediatricians will continue to support our patients,” Dr. Szilagyi added.
 

American Public Health Association

The court’s decision “is a catastrophic judicial failure that will reverberate differently in each state and portends to jeopardize the health and lives of all Americans,” Executive Director Georges C. Benjamin, MD, said in a statement.

American Urogynecologic Society

“The American Urogynecologic Society opposes any ruling that restricts a person’s access to health care and criminalizes the practice of medicine,” the group said in a statement. “This ruling ultimately poses a serious threat to the patient-provider relationship and subsequent decisionmaking necessary to ensure optimal outcomes for patients. As practitioners, we should be free to provide what is in the best interest of our patients.”

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

The country’s top medical organizations condemned the overturning of Roe v. Wade, saying the removal of federal protections for women to access abortion services marks a “dark day.”

“It is unfathomable. It is unfair. It is wrong,” said the President of the American College of Obstetricians and Gynecologists (ACOG) Iffath Abbasi Hoskins, MD.

“Today is a very dark day in health care. It is a dark day, indeed, for the tens of millions of patients who have suddenly and unfairly lost access to safe legal and evidence-based abortion care,” Dr. Hoskins said at a press conference June 24 sponsored by ACOG. 

“It is dark for the thousands of clinicians who now, instead of focusing on providing health care to their patients, have to live with the threats of legal, civil, and even professional penalties,” Dr. Hoskins added.

ACOG has 62,000 members and is the leading group of doctors that provides obstetric and gynecologic care.
 

Dilemma for some doctors?

“I’d like to take a moment to talk about the future of the medical profession,” said ACOG Chief Executive Officer Maureen G. Phipps, MD, MPH. “[The] decision is, as Dr. Hoskins clearly said, a tragic one for our patients in states across the country, but the harm does not end there.”

Dr. Phipps described overturning Roe v. Wade as “the boldest act of legislative interference that we have seen in this country. It will allow state legislators to tell physicians what care they can and cannot provide to their patients.”

“It will leave physicians looking over our shoulders, wondering if a patient is in enough of a crisis to permit an exception to a law,” Dr. Phipps added. “This is an affront to all that drew my colleagues and me into medicine.”

Although the impact on doctor training remains to be seen, she said 44% of ob.gyn. residents are trained in states now empowered to ban abortions.

The effect of the Supreme Court decision on miscarriage management is another unknown.

“It’s going to be very difficult for us, the clinicians, to manage miscarriage,” Dr. Hoskins said. “Many miscarriages could be what we call ‘incomplete’ in the beginning,” where there is still a heartbeat and the patient is cramping and/or bleeding.

In that instance, Dr. Hoskins said, clinicians may be thinking that they have to wait.

“They may be needing to get additional opinions, whether it’s a legal opinion ... or another medical opinion.”

“It’s going to have a devastating effect on every aspect of a woman’s health care, including if she is spontaneously miscarrying,” Dr. Hoskins predicted.

Physician protect thyself?

To what extent doctors can shield themselves from potential prosecution “is a hard question to answer,” Molly Meegan, JD, ACOG’s chief legal officer and general counsel, said.

Ms. Meegan recommended members speak to the risk managers at their individual institutions for guidance.

“It is a real patchwork [of laws] out there, she said. “And that patchwork itself is a danger to people as they seek essential reproductive health care.”

Also, she added, “If a doctor can’t tell what the law is at the time they’re trying to provide the care, it has a terribly chilling effect on medical care.”

Another potential threat to doctors in states that still allow abortion services is action from a neighboring state.

“We are going to be advocating very strongly that states do not have extra-territorial jurisdiction to reach beyond the edges of their state.”

The worry is if a doctor in New Mexico, where abortion is legal, performs an abortion for a person from Texas, where it will soon be illegal, is then prosecuted by Texas, for example.
 

Medication abortion

Asked about any potential effects on medication abortions, ACOG’s Jen Villavicencio, MD, said it remains to be seen.

“Certainly many of the laws that we have seen, including trigger ban laws, encompass medication abortion,” she said. Several states have these so-called trigger laws, which put into effect laws passed to ban abortion in case Roe was overturned.

This means, she said, that any abortion option, whether it’s procedural or medication, could be and will be banned in some of these states.

Ms. Meegan added that ACOG will continue to support access to medication abortion and that it should be decided by the U.S. Food and Drug Administration and not individual states.
 

Maternal mortality may rise

“Maternal mortality in and of itself is a very difficult topic,” Dr. Hoskins said, but [the] decision amplifies the implications. “I think of the patients who will have to manage severe complications and mental health challenges while they are carrying a pregnancy that they are forced to carry.”

“I also think of the patients who need to end their pregnancies in order to save their own lives,” Dr. Hoskins added.

Dr. Hoskins said the United States already has a high maternal mortality rate. This new law, she added, could force women into higher-risk situations if they experience high blood pressure, preeclampsia, or bleeding after the birth of the baby.
 

Growing inequality possible?

“The grievous inequities that exist in this country will grow and expand unchecked without safe access to legal abortion,” Dr. Phipps said.

She noted that women, based on location, will continue “to have protected access to safe evidence-based abortion. Others will have the means and resources and opportunities to secure the care.”

But the same may not be true for women in underserved or disadvantaged communities, Dr. Phipps added.
 

American Medical Association

ACOG was not the only group to react. “The American Medical Association is deeply disturbed by the U.S. Supreme Court’s decision to overturn nearly a half century of precedent protecting patients’ right to critical reproductive health care,” President Jack Resneck Jr., MD, said in a statement.

The decision represents “an egregious allowance of government intrusion into the medical examination room, a direct attack on the practice of medicine and the patient-physician relationship, and a brazen violation of patients’ rights to evidence-based reproductive health services.”

American Academy of Family Physicians

“The American Academy of Family Physicians is disappointed and disheartened by the Supreme Court’s decision to strike down longstanding protections afforded by Roe v. Wade and Planned Parenthood v. Casey,” President Sterling N. Ransone Jr., MD, said in a statement.

The organization has 127,600 physician and medical student members.

“This decision negatively impacts our practices and our patients by undermining the patient-physician relationship and potentially criminalizing evidence-based medical care,” added Dr. Ransone.
 

American College of Physicians

“A patient’s decision about whether to continue a pregnancy should be a private decision made in consultation with a physician or other health care professional, without interference from the government,” President Ryan D. Mire, MD, said in a statement. “We strongly oppose medically unnecessary government restrictions on any health care services,” added Dr. Mire on behalf of the group’s 161,000 members.

American Academy of Pediatrics

“This decision carries grave consequences for our adolescent patients, who already face many more barriers than adults in accessing comprehensive reproductive health care services and abortion care,” President Moira Szilagyi, MD, PhD, said in a statement. 

“In the wake of this ruling, the American Academy of Pediatrics will continue to support our chapters as states consider policies affecting access to abortion care, and pediatricians will continue to support our patients,” Dr. Szilagyi added.
 

American Public Health Association

The court’s decision “is a catastrophic judicial failure that will reverberate differently in each state and portends to jeopardize the health and lives of all Americans,” Executive Director Georges C. Benjamin, MD, said in a statement.

American Urogynecologic Society

“The American Urogynecologic Society opposes any ruling that restricts a person’s access to health care and criminalizes the practice of medicine,” the group said in a statement. “This ruling ultimately poses a serious threat to the patient-provider relationship and subsequent decisionmaking necessary to ensure optimal outcomes for patients. As practitioners, we should be free to provide what is in the best interest of our patients.”

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

The country’s top medical organizations condemned the overturning of Roe v. Wade, saying the removal of federal protections for women to access abortion services marks a “dark day.”

“It is unfathomable. It is unfair. It is wrong,” said the President of the American College of Obstetricians and Gynecologists (ACOG) Iffath Abbasi Hoskins, MD.

“Today is a very dark day in health care. It is a dark day, indeed, for the tens of millions of patients who have suddenly and unfairly lost access to safe legal and evidence-based abortion care,” Dr. Hoskins said at a press conference June 24 sponsored by ACOG. 

“It is dark for the thousands of clinicians who now, instead of focusing on providing health care to their patients, have to live with the threats of legal, civil, and even professional penalties,” Dr. Hoskins added.

ACOG has 62,000 members and is the leading group of doctors that provides obstetric and gynecologic care.
 

Dilemma for some doctors?

“I’d like to take a moment to talk about the future of the medical profession,” said ACOG Chief Executive Officer Maureen G. Phipps, MD, MPH. “[The] decision is, as Dr. Hoskins clearly said, a tragic one for our patients in states across the country, but the harm does not end there.”

Dr. Phipps described overturning Roe v. Wade as “the boldest act of legislative interference that we have seen in this country. It will allow state legislators to tell physicians what care they can and cannot provide to their patients.”

“It will leave physicians looking over our shoulders, wondering if a patient is in enough of a crisis to permit an exception to a law,” Dr. Phipps added. “This is an affront to all that drew my colleagues and me into medicine.”

Although the impact on doctor training remains to be seen, she said 44% of ob.gyn. residents are trained in states now empowered to ban abortions.

The effect of the Supreme Court decision on miscarriage management is another unknown.

“It’s going to be very difficult for us, the clinicians, to manage miscarriage,” Dr. Hoskins said. “Many miscarriages could be what we call ‘incomplete’ in the beginning,” where there is still a heartbeat and the patient is cramping and/or bleeding.

In that instance, Dr. Hoskins said, clinicians may be thinking that they have to wait.

“They may be needing to get additional opinions, whether it’s a legal opinion ... or another medical opinion.”

“It’s going to have a devastating effect on every aspect of a woman’s health care, including if she is spontaneously miscarrying,” Dr. Hoskins predicted.

Physician protect thyself?

To what extent doctors can shield themselves from potential prosecution “is a hard question to answer,” Molly Meegan, JD, ACOG’s chief legal officer and general counsel, said.

Ms. Meegan recommended members speak to the risk managers at their individual institutions for guidance.

“It is a real patchwork [of laws] out there, she said. “And that patchwork itself is a danger to people as they seek essential reproductive health care.”

Also, she added, “If a doctor can’t tell what the law is at the time they’re trying to provide the care, it has a terribly chilling effect on medical care.”

Another potential threat to doctors in states that still allow abortion services is action from a neighboring state.

“We are going to be advocating very strongly that states do not have extra-territorial jurisdiction to reach beyond the edges of their state.”

The worry is if a doctor in New Mexico, where abortion is legal, performs an abortion for a person from Texas, where it will soon be illegal, is then prosecuted by Texas, for example.
 

Medication abortion

Asked about any potential effects on medication abortions, ACOG’s Jen Villavicencio, MD, said it remains to be seen.

“Certainly many of the laws that we have seen, including trigger ban laws, encompass medication abortion,” she said. Several states have these so-called trigger laws, which put into effect laws passed to ban abortion in case Roe was overturned.

This means, she said, that any abortion option, whether it’s procedural or medication, could be and will be banned in some of these states.

Ms. Meegan added that ACOG will continue to support access to medication abortion and that it should be decided by the U.S. Food and Drug Administration and not individual states.
 

Maternal mortality may rise

“Maternal mortality in and of itself is a very difficult topic,” Dr. Hoskins said, but [the] decision amplifies the implications. “I think of the patients who will have to manage severe complications and mental health challenges while they are carrying a pregnancy that they are forced to carry.”

“I also think of the patients who need to end their pregnancies in order to save their own lives,” Dr. Hoskins added.

Dr. Hoskins said the United States already has a high maternal mortality rate. This new law, she added, could force women into higher-risk situations if they experience high blood pressure, preeclampsia, or bleeding after the birth of the baby.
 

Growing inequality possible?

“The grievous inequities that exist in this country will grow and expand unchecked without safe access to legal abortion,” Dr. Phipps said.

She noted that women, based on location, will continue “to have protected access to safe evidence-based abortion. Others will have the means and resources and opportunities to secure the care.”

But the same may not be true for women in underserved or disadvantaged communities, Dr. Phipps added.
 

American Medical Association

ACOG was not the only group to react. “The American Medical Association is deeply disturbed by the U.S. Supreme Court’s decision to overturn nearly a half century of precedent protecting patients’ right to critical reproductive health care,” President Jack Resneck Jr., MD, said in a statement.

The decision represents “an egregious allowance of government intrusion into the medical examination room, a direct attack on the practice of medicine and the patient-physician relationship, and a brazen violation of patients’ rights to evidence-based reproductive health services.”

American Academy of Family Physicians

“The American Academy of Family Physicians is disappointed and disheartened by the Supreme Court’s decision to strike down longstanding protections afforded by Roe v. Wade and Planned Parenthood v. Casey,” President Sterling N. Ransone Jr., MD, said in a statement.

The organization has 127,600 physician and medical student members.

“This decision negatively impacts our practices and our patients by undermining the patient-physician relationship and potentially criminalizing evidence-based medical care,” added Dr. Ransone.
 

American College of Physicians

“A patient’s decision about whether to continue a pregnancy should be a private decision made in consultation with a physician or other health care professional, without interference from the government,” President Ryan D. Mire, MD, said in a statement. “We strongly oppose medically unnecessary government restrictions on any health care services,” added Dr. Mire on behalf of the group’s 161,000 members.

American Academy of Pediatrics

“This decision carries grave consequences for our adolescent patients, who already face many more barriers than adults in accessing comprehensive reproductive health care services and abortion care,” President Moira Szilagyi, MD, PhD, said in a statement. 

“In the wake of this ruling, the American Academy of Pediatrics will continue to support our chapters as states consider policies affecting access to abortion care, and pediatricians will continue to support our patients,” Dr. Szilagyi added.
 

American Public Health Association

The court’s decision “is a catastrophic judicial failure that will reverberate differently in each state and portends to jeopardize the health and lives of all Americans,” Executive Director Georges C. Benjamin, MD, said in a statement.

American Urogynecologic Society

“The American Urogynecologic Society opposes any ruling that restricts a person’s access to health care and criminalizes the practice of medicine,” the group said in a statement. “This ruling ultimately poses a serious threat to the patient-provider relationship and subsequent decisionmaking necessary to ensure optimal outcomes for patients. As practitioners, we should be free to provide what is in the best interest of our patients.”

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

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Children born to mothers who take antibiotics during pregnancy may be at an increased risk of developing pediatric asthma and other diseases involved in the atopic march, a systematic review and meta-analysis reports.

“Antibiotic use during pregnancy is significantly associated with the development of asthma in children. Additionally prenatal antibiotic exposure is also associated with disorders present in the atopic march including atopic sensitization, dermatitis/eczema, food allergy, allergic rhinitis, and wheeze,” lead study author Alissa Cait, PhD, of Malaghan Institute of Medical Research in Wellington, New Zealand, and colleagues write in Allergy.

“Antibiotics account for 80% of prescribed medications during pregnancy, and it is estimated that 20%-25% of pregnant women receive at least one course of an antibiotic during this time period,” they add.

The researchers evaluated prenatal antibiotic exposure and the risk for childhood wheeze or asthma, as well as for diseases associated with the atopic march, by searching standard medical databases for controlled trials in English, German, French, Dutch, or Arabic involving the use of any antibiotic at any time during pregnancy and for atopic disease incidence in children with asthma or wheeze as primary outcome. They excluded reviews, preclinical data, and descriptive studies.

From the 6,060 citations the search returned, 11 prospective and 16 retrospective studies met the authors’ selection criteria. For each study, they evaluated risk of bias using the Newcastle-Ottawa Quality Assessment Scale, and they rated certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) protocol.

The studies, published between 2002 and 2020, were conducted in Europe, North America, Asia, and South America. Exposure to antibiotics during the prenatal period was assessed through unsupervised questionnaires, interviews by medical professionals, or extraction from official medical databases.

The results showed that:

• Antibiotic use during pregnancy was linked with increased relative risk of developing wheeze (relative risk, 1.51; 95% confidence interval, 1.17-1.94) or asthma (RR, 1.28; 95% CI, 1.22-1.34) during childhood.
• Antibiotic use during pregnancy also increased a child’s risk for eczema or dermatitis (RR, 1.28; 95% CI, 1.06-1.53) and allergic rhinitis (RR, 1.13; 95% CI, 1.02-1.25).
• Food allergy increased in one study (RR, 1.81; 95% CI, 1.11-2.95).

Quality of studies

“These results have importance for antibiotic stewardship throughout the prenatal period,” the authors write. However, due to issues including high heterogeneity, publication bias, and lack of population numbers in some studies, the overall quality of the evidence presented in the studies was low. Other limitations include mainly White and European study populations, underpowered studies, and study protocol inconsistencies.

“Though there is evidence that antibiotic treatment during pregnancy is a driver of the atopic march, due to a large heterogeneity between studies more research is needed to draw firm conclusions on this matter,” the authors add. “Future studies should employ and report more direct and objective measurement methods rather than self-reported questionnaires.”

Dustin D. Flannery, DO, MSCE, a neonatologist and clinical researcher in perinatal infectious diseases and neonatal antimicrobial resistance and stewardship at Children’s Hospital of Philadelphia, said in an email that the study was well done.

He noted, though, that “although the study reports an association, it cannot prove causation. The relationship between prenatal antibiotics and childhood allergic disorders is likely multifactorial and quite complex.”

He joins the authors in recommending further related research. “Due to the variation in how exposures and outcomes were defined across the studies, more rigorous research will be needed in this area.”

Despite the study’s limitations, “given that some studies have found associations between prenatal antibiotic exposure and childhood atopic and allergic disorders, including asthma, while other studies have not, this systematic review and meta-analysis asks an important question,” Dr. Flannery, who was not involved in the study, said in an interview.

“Investigators found a strong association between prenatal antibiotic exposure and risk of childhood asthma and other disorders,” he said. “This finding supports efforts to safely reduce antibiotic use during pregnancy.”

The study was supported by the Deutsche Forschungsgemeinschaft and by the Konrad Adenauer Foundation. The authors and Dr. Flannery have disclosed no relevant financial relationships.

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

Children born to mothers who take antibiotics during pregnancy may be at an increased risk of developing pediatric asthma and other diseases involved in the atopic march, a systematic review and meta-analysis reports.

“Antibiotic use during pregnancy is significantly associated with the development of asthma in children. Additionally prenatal antibiotic exposure is also associated with disorders present in the atopic march including atopic sensitization, dermatitis/eczema, food allergy, allergic rhinitis, and wheeze,” lead study author Alissa Cait, PhD, of Malaghan Institute of Medical Research in Wellington, New Zealand, and colleagues write in Allergy.

“Antibiotics account for 80% of prescribed medications during pregnancy, and it is estimated that 20%-25% of pregnant women receive at least one course of an antibiotic during this time period,” they add.

The researchers evaluated prenatal antibiotic exposure and the risk for childhood wheeze or asthma, as well as for diseases associated with the atopic march, by searching standard medical databases for controlled trials in English, German, French, Dutch, or Arabic involving the use of any antibiotic at any time during pregnancy and for atopic disease incidence in children with asthma or wheeze as primary outcome. They excluded reviews, preclinical data, and descriptive studies.

From the 6,060 citations the search returned, 11 prospective and 16 retrospective studies met the authors’ selection criteria. For each study, they evaluated risk of bias using the Newcastle-Ottawa Quality Assessment Scale, and they rated certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) protocol.

The studies, published between 2002 and 2020, were conducted in Europe, North America, Asia, and South America. Exposure to antibiotics during the prenatal period was assessed through unsupervised questionnaires, interviews by medical professionals, or extraction from official medical databases.

The results showed that:

• Antibiotic use during pregnancy was linked with increased relative risk of developing wheeze (relative risk, 1.51; 95% confidence interval, 1.17-1.94) or asthma (RR, 1.28; 95% CI, 1.22-1.34) during childhood.
• Antibiotic use during pregnancy also increased a child’s risk for eczema or dermatitis (RR, 1.28; 95% CI, 1.06-1.53) and allergic rhinitis (RR, 1.13; 95% CI, 1.02-1.25).
• Food allergy increased in one study (RR, 1.81; 95% CI, 1.11-2.95).

Quality of studies

“These results have importance for antibiotic stewardship throughout the prenatal period,” the authors write. However, due to issues including high heterogeneity, publication bias, and lack of population numbers in some studies, the overall quality of the evidence presented in the studies was low. Other limitations include mainly White and European study populations, underpowered studies, and study protocol inconsistencies.

“Though there is evidence that antibiotic treatment during pregnancy is a driver of the atopic march, due to a large heterogeneity between studies more research is needed to draw firm conclusions on this matter,” the authors add. “Future studies should employ and report more direct and objective measurement methods rather than self-reported questionnaires.”

Dustin D. Flannery, DO, MSCE, a neonatologist and clinical researcher in perinatal infectious diseases and neonatal antimicrobial resistance and stewardship at Children’s Hospital of Philadelphia, said in an email that the study was well done.

He noted, though, that “although the study reports an association, it cannot prove causation. The relationship between prenatal antibiotics and childhood allergic disorders is likely multifactorial and quite complex.”

He joins the authors in recommending further related research. “Due to the variation in how exposures and outcomes were defined across the studies, more rigorous research will be needed in this area.”

Despite the study’s limitations, “given that some studies have found associations between prenatal antibiotic exposure and childhood atopic and allergic disorders, including asthma, while other studies have not, this systematic review and meta-analysis asks an important question,” Dr. Flannery, who was not involved in the study, said in an interview.

“Investigators found a strong association between prenatal antibiotic exposure and risk of childhood asthma and other disorders,” he said. “This finding supports efforts to safely reduce antibiotic use during pregnancy.”

The study was supported by the Deutsche Forschungsgemeinschaft and by the Konrad Adenauer Foundation. The authors and Dr. Flannery have disclosed no relevant financial relationships.

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

Children born to mothers who take antibiotics during pregnancy may be at an increased risk of developing pediatric asthma and other diseases involved in the atopic march, a systematic review and meta-analysis reports.

“Antibiotic use during pregnancy is significantly associated with the development of asthma in children. Additionally prenatal antibiotic exposure is also associated with disorders present in the atopic march including atopic sensitization, dermatitis/eczema, food allergy, allergic rhinitis, and wheeze,” lead study author Alissa Cait, PhD, of Malaghan Institute of Medical Research in Wellington, New Zealand, and colleagues write in Allergy.

“Antibiotics account for 80% of prescribed medications during pregnancy, and it is estimated that 20%-25% of pregnant women receive at least one course of an antibiotic during this time period,” they add.

The researchers evaluated prenatal antibiotic exposure and the risk for childhood wheeze or asthma, as well as for diseases associated with the atopic march, by searching standard medical databases for controlled trials in English, German, French, Dutch, or Arabic involving the use of any antibiotic at any time during pregnancy and for atopic disease incidence in children with asthma or wheeze as primary outcome. They excluded reviews, preclinical data, and descriptive studies.

From the 6,060 citations the search returned, 11 prospective and 16 retrospective studies met the authors’ selection criteria. For each study, they evaluated risk of bias using the Newcastle-Ottawa Quality Assessment Scale, and they rated certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) protocol.

The studies, published between 2002 and 2020, were conducted in Europe, North America, Asia, and South America. Exposure to antibiotics during the prenatal period was assessed through unsupervised questionnaires, interviews by medical professionals, or extraction from official medical databases.

The results showed that:

• Antibiotic use during pregnancy was linked with increased relative risk of developing wheeze (relative risk, 1.51; 95% confidence interval, 1.17-1.94) or asthma (RR, 1.28; 95% CI, 1.22-1.34) during childhood.
• Antibiotic use during pregnancy also increased a child’s risk for eczema or dermatitis (RR, 1.28; 95% CI, 1.06-1.53) and allergic rhinitis (RR, 1.13; 95% CI, 1.02-1.25).
• Food allergy increased in one study (RR, 1.81; 95% CI, 1.11-2.95).

Quality of studies

“These results have importance for antibiotic stewardship throughout the prenatal period,” the authors write. However, due to issues including high heterogeneity, publication bias, and lack of population numbers in some studies, the overall quality of the evidence presented in the studies was low. Other limitations include mainly White and European study populations, underpowered studies, and study protocol inconsistencies.

“Though there is evidence that antibiotic treatment during pregnancy is a driver of the atopic march, due to a large heterogeneity between studies more research is needed to draw firm conclusions on this matter,” the authors add. “Future studies should employ and report more direct and objective measurement methods rather than self-reported questionnaires.”

Dustin D. Flannery, DO, MSCE, a neonatologist and clinical researcher in perinatal infectious diseases and neonatal antimicrobial resistance and stewardship at Children’s Hospital of Philadelphia, said in an email that the study was well done.

He noted, though, that “although the study reports an association, it cannot prove causation. The relationship between prenatal antibiotics and childhood allergic disorders is likely multifactorial and quite complex.”

He joins the authors in recommending further related research. “Due to the variation in how exposures and outcomes were defined across the studies, more rigorous research will be needed in this area.”

Despite the study’s limitations, “given that some studies have found associations between prenatal antibiotic exposure and childhood atopic and allergic disorders, including asthma, while other studies have not, this systematic review and meta-analysis asks an important question,” Dr. Flannery, who was not involved in the study, said in an interview.

“Investigators found a strong association between prenatal antibiotic exposure and risk of childhood asthma and other disorders,” he said. “This finding supports efforts to safely reduce antibiotic use during pregnancy.”

The study was supported by the Deutsche Forschungsgemeinschaft and by the Konrad Adenauer Foundation. The authors and Dr. Flannery have disclosed no relevant financial relationships.

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

Women for whom an intrauterine device is inserted from 4 days to 6 weeks after giving birth, as well as those who are breastfeeding, are at higher risk of the contraceptive device puncturing their uterus, new research shows.

The risk of perforation was nearly seven times higher for patients who received an IUD within that window than for those with an IUD who’d never given birth or who were more than a year out from delivery, the researchers found. Health care providers should make patients aware of the heightened risk and should monitor these patients more closely, according to Susan Reed, MD, an ob.gyn. at the University of Washington, Seattle, lead author of the new study.

“I’m a surgeon, and I like to be able to give people good information and good data about risks and benefits for their choices,” Dr. Reed told this news organization. “Uterine perforations related to IUDs are exceedingly rare, and to get good data or known risk factors, you need huge studies. This was the largest study done that really provided accurate information for patients and providers.” The new study, which appears in a recent issue of The Lancet, also found that the risk of uterine perforation was lower if an IUD had been inserted immediately after delivery.

Dr. Reed and colleagues analyzed data from the health records of 326,658 women younger than 50 years for whom an IUD was inserted between 2001 and 2018 at four health care systems. Nearly 30% of these patients received an IUD after giving birth.

The researchers identified a total of 1,008 uterine perforations, for a cumulative incidence at 5 years of 0.6%. The cumulative incidence of uterine perforations was lowest in the group of women who were considered “nonpostpartum”; these women either received an IUD a full year after giving birth or had not given birth during the study period (0.29%; 95% confidence interval, 0.26-0.34).

Women who received an IUD during the 3 days after delivery had a nearly threefold increased risk of an IUD perforation over nonpostpartum women.

In addition, the cumulative incidence of perforation was almost double among breastfeeding women, compared with women who were not breastfeeding. However, Dr. Reed and coauthors noted that breastfeeding is highly beneficial for babies and that the risk of IUD perforation is relatively small.

Among the women who received an IUD following birth, Dr. Reed’s group found that 673 uterine perforations – of which 62% were complete – occurred in breastfeeding individuals, 37% more than for those who did not breastfeed.

Dr. Reed said the study provided some clarity on previous notions that women who’d never given birth were possibly at higher risk for uterine perforation because of smaller uteruses.

“We used to be concerned that women who had never had a pregnancy at all might be at higher risk because their uterus was smaller, the cervix was tighter, and therefore perhaps they might have greater risks,” Dr. Reed said in an interview. “As a clinician and as a provider, it’s pretty exciting to me to be able to tell our younger women who have never had a pregnancy that indeed their risk is lower than anybody else’s.”

The findings help women to make informed decisions, but overall, the benefits of IUDs outweigh the risks, said Monica V. Dragoman, MD, assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai, New York.

“The likelihood of anyone experiencing these types of complications of that population level remains really low,” Dr. Dragoman said.

The findings also provide guidance for providers as to which patients should come in for additional follow-up visits following insertion, Dr. Reed said.

“These are small risks, but it does tell us where we need to consider if there’s a challenging insertion,” Dr. Reed said. “You’re going to look with the ultrasound and make sure the placement looks right. You’re going to give instructions that if the woman has pain or a change in her bleeding pattern, you want to see her back.”

Patients should be aware of the symptoms of uterine perforation – an abrupt change in bleeding pattern and pelvic pain. Perforation correction typically consists of a minimally invasive surgical procedure.

The study was conducted as a result of an order from the Food and Drug Administration to Bayer Pharmaceuticals to evaluate risks of uterine perforation for women who’d received the company’s Mirena IUD. The findings led the company to update the language on the packaging of the device so as to specify the main symptoms of uterine perforations.

The study authors received research funding from Bayer. Multiple authors are employees of Bayer. One study author has in the past received funding from CooperSurgical, Bayer Healthcare Pharmaceutical, and Merck. Bayer was provided the opportunity to review the manuscript before submission, and comments were advisory only.

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

Women for whom an intrauterine device is inserted from 4 days to 6 weeks after giving birth, as well as those who are breastfeeding, are at higher risk of the contraceptive device puncturing their uterus, new research shows.

The risk of perforation was nearly seven times higher for patients who received an IUD within that window than for those with an IUD who’d never given birth or who were more than a year out from delivery, the researchers found. Health care providers should make patients aware of the heightened risk and should monitor these patients more closely, according to Susan Reed, MD, an ob.gyn. at the University of Washington, Seattle, lead author of the new study.

“I’m a surgeon, and I like to be able to give people good information and good data about risks and benefits for their choices,” Dr. Reed told this news organization. “Uterine perforations related to IUDs are exceedingly rare, and to get good data or known risk factors, you need huge studies. This was the largest study done that really provided accurate information for patients and providers.” The new study, which appears in a recent issue of The Lancet, also found that the risk of uterine perforation was lower if an IUD had been inserted immediately after delivery.

Dr. Reed and colleagues analyzed data from the health records of 326,658 women younger than 50 years for whom an IUD was inserted between 2001 and 2018 at four health care systems. Nearly 30% of these patients received an IUD after giving birth.

The researchers identified a total of 1,008 uterine perforations, for a cumulative incidence at 5 years of 0.6%. The cumulative incidence of uterine perforations was lowest in the group of women who were considered “nonpostpartum”; these women either received an IUD a full year after giving birth or had not given birth during the study period (0.29%; 95% confidence interval, 0.26-0.34).

Women who received an IUD during the 3 days after delivery had a nearly threefold increased risk of an IUD perforation over nonpostpartum women.

In addition, the cumulative incidence of perforation was almost double among breastfeeding women, compared with women who were not breastfeeding. However, Dr. Reed and coauthors noted that breastfeeding is highly beneficial for babies and that the risk of IUD perforation is relatively small.

Among the women who received an IUD following birth, Dr. Reed’s group found that 673 uterine perforations – of which 62% were complete – occurred in breastfeeding individuals, 37% more than for those who did not breastfeed.

Dr. Reed said the study provided some clarity on previous notions that women who’d never given birth were possibly at higher risk for uterine perforation because of smaller uteruses.

“We used to be concerned that women who had never had a pregnancy at all might be at higher risk because their uterus was smaller, the cervix was tighter, and therefore perhaps they might have greater risks,” Dr. Reed said in an interview. “As a clinician and as a provider, it’s pretty exciting to me to be able to tell our younger women who have never had a pregnancy that indeed their risk is lower than anybody else’s.”

The findings help women to make informed decisions, but overall, the benefits of IUDs outweigh the risks, said Monica V. Dragoman, MD, assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai, New York.

“The likelihood of anyone experiencing these types of complications of that population level remains really low,” Dr. Dragoman said.

The findings also provide guidance for providers as to which patients should come in for additional follow-up visits following insertion, Dr. Reed said.

“These are small risks, but it does tell us where we need to consider if there’s a challenging insertion,” Dr. Reed said. “You’re going to look with the ultrasound and make sure the placement looks right. You’re going to give instructions that if the woman has pain or a change in her bleeding pattern, you want to see her back.”

Patients should be aware of the symptoms of uterine perforation – an abrupt change in bleeding pattern and pelvic pain. Perforation correction typically consists of a minimally invasive surgical procedure.

The study was conducted as a result of an order from the Food and Drug Administration to Bayer Pharmaceuticals to evaluate risks of uterine perforation for women who’d received the company’s Mirena IUD. The findings led the company to update the language on the packaging of the device so as to specify the main symptoms of uterine perforations.

The study authors received research funding from Bayer. Multiple authors are employees of Bayer. One study author has in the past received funding from CooperSurgical, Bayer Healthcare Pharmaceutical, and Merck. Bayer was provided the opportunity to review the manuscript before submission, and comments were advisory only.

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

Women for whom an intrauterine device is inserted from 4 days to 6 weeks after giving birth, as well as those who are breastfeeding, are at higher risk of the contraceptive device puncturing their uterus, new research shows.

The risk of perforation was nearly seven times higher for patients who received an IUD within that window than for those with an IUD who’d never given birth or who were more than a year out from delivery, the researchers found. Health care providers should make patients aware of the heightened risk and should monitor these patients more closely, according to Susan Reed, MD, an ob.gyn. at the University of Washington, Seattle, lead author of the new study.

“I’m a surgeon, and I like to be able to give people good information and good data about risks and benefits for their choices,” Dr. Reed told this news organization. “Uterine perforations related to IUDs are exceedingly rare, and to get good data or known risk factors, you need huge studies. This was the largest study done that really provided accurate information for patients and providers.” The new study, which appears in a recent issue of The Lancet, also found that the risk of uterine perforation was lower if an IUD had been inserted immediately after delivery.

Dr. Reed and colleagues analyzed data from the health records of 326,658 women younger than 50 years for whom an IUD was inserted between 2001 and 2018 at four health care systems. Nearly 30% of these patients received an IUD after giving birth.

The researchers identified a total of 1,008 uterine perforations, for a cumulative incidence at 5 years of 0.6%. The cumulative incidence of uterine perforations was lowest in the group of women who were considered “nonpostpartum”; these women either received an IUD a full year after giving birth or had not given birth during the study period (0.29%; 95% confidence interval, 0.26-0.34).

Women who received an IUD during the 3 days after delivery had a nearly threefold increased risk of an IUD perforation over nonpostpartum women.

In addition, the cumulative incidence of perforation was almost double among breastfeeding women, compared with women who were not breastfeeding. However, Dr. Reed and coauthors noted that breastfeeding is highly beneficial for babies and that the risk of IUD perforation is relatively small.

Among the women who received an IUD following birth, Dr. Reed’s group found that 673 uterine perforations – of which 62% were complete – occurred in breastfeeding individuals, 37% more than for those who did not breastfeed.

Dr. Reed said the study provided some clarity on previous notions that women who’d never given birth were possibly at higher risk for uterine perforation because of smaller uteruses.

“We used to be concerned that women who had never had a pregnancy at all might be at higher risk because their uterus was smaller, the cervix was tighter, and therefore perhaps they might have greater risks,” Dr. Reed said in an interview. “As a clinician and as a provider, it’s pretty exciting to me to be able to tell our younger women who have never had a pregnancy that indeed their risk is lower than anybody else’s.”

The findings help women to make informed decisions, but overall, the benefits of IUDs outweigh the risks, said Monica V. Dragoman, MD, assistant professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai, New York.

“The likelihood of anyone experiencing these types of complications of that population level remains really low,” Dr. Dragoman said.

The findings also provide guidance for providers as to which patients should come in for additional follow-up visits following insertion, Dr. Reed said.

“These are small risks, but it does tell us where we need to consider if there’s a challenging insertion,” Dr. Reed said. “You’re going to look with the ultrasound and make sure the placement looks right. You’re going to give instructions that if the woman has pain or a change in her bleeding pattern, you want to see her back.”

Patients should be aware of the symptoms of uterine perforation – an abrupt change in bleeding pattern and pelvic pain. Perforation correction typically consists of a minimally invasive surgical procedure.

The study was conducted as a result of an order from the Food and Drug Administration to Bayer Pharmaceuticals to evaluate risks of uterine perforation for women who’d received the company’s Mirena IUD. The findings led the company to update the language on the packaging of the device so as to specify the main symptoms of uterine perforations.

The study authors received research funding from Bayer. Multiple authors are employees of Bayer. One study author has in the past received funding from CooperSurgical, Bayer Healthcare Pharmaceutical, and Merck. Bayer was provided the opportunity to review the manuscript before submission, and comments were advisory only.

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

Endometrial cancer (EC) is the most common gynecologic malignancy and is the fourth most common cancer seen in U.S. women. It is the only major cancer that has continued to see a rise in incidence and mortality for the past 2 decades, and it is anticipated that nearly 66,000 new cases of EC will be diagnosed this year with 12,550 deaths.¹ Given that the well-established risk factors for developing EC including obesity, diabetes, and insulin resistance, the obesity epidemic is indisputably playing a significant role in the increasing incidence.

Historically, White women were thought to have the highest incidence of EC; however, this incidence rate did not account for hysterectomy prevalence, which can vary widely by numerous factors including age, race, ethnicity, and geographic region. When correcting EC incidence rates for prevalence of hysterectomy, Black women have had the highest incidence of EC since 2007, and rates continue to climb.² In fact, the average annual percent change (APC) in EC incidence from 2000 to 2015 was stable for White women at 0.2% while Black women had a near order of magnitude greater APC at 2.1%.²

Differing incidence rates of EC can also be seen by histologic subtype. Endometrioid EC is the more common and less lethal histology of EC that often coincides with the type I classification of EC. These tumors are estrogen driven; therefore, they are associated with conditions resulting in excess estrogen (for example, anovulation, obesity, and hyperlipidemia). Nonendometrioid histologies, primarily composed of serous tumors, are more rare, are typically more aggressive, are not estrogen driven, and are commonly classified as type II tumors. Racial differences between type I and type II tumors are seen with White women more commonly being diagnosed with type I tumors while Black women more typically have type II tumors. White women have the greatest incidence rate of endometrioid EC with an APC that remained relatively unchanged from 2000 to 2015. Black women’s APC in incidence rate of endometrioid EC has increased during this same period at 1.3%. For nonendometrioid tumors, an increasing incidence is seen in all races and ethnicities; however, Black women have a much higher incidence of these tumors, with a rate that continues to increase at an APC of 3.2%.²

EC incidence is increasing with a particularly concerning rise in those who report Black race, but are these same disparities being seen in EC mortality? Unfortunately, drastic disparities are seen in survival data for Black women afflicted with EC. Black patients are more likely to be diagnosed with advanced or metastatic EC and less likely to be diagnosed with localized tumors. While being diagnosed with a more advanced stage of disease does affect survival in EC, Black patients have worse survival regardless of stage of disease at the time of diagnosis.¹ As discussed earlier, the more aggressive type II tumors are composed of nonendometrioid histologies and are more common in Black women. This could lead to the false assumption that these higher-risk tumors are why Black women are disproportionately dying from EC; however, when examining survival by histologic subtype, Black women are more frequently dying from the lower-risk endometrioid EC regardless of stage of disease. The same disparate survival outcomes are also seen in nonendometrioid histologies.² Thus, Black patients have the lowest survival rates irrespective of stage at diagnosis or histologic subtype.

The disparities seen in EC mortality are not new. They can be seen in data for over 30 years and are only widening. While there has been an increase in mortality rates from EC across all races and ethnicities from 2015 to 2019 compared with 1990 to 1994, the mortality rate ratio for Black women compared with White women has increased from 1.83 in 1990-1994 to 1.98 in 2015-2019.³ In the early 1990s, the risk of death from ovarian cancer was twice that of EC. The mortality of EC is now similar to that of ovarian cancer. This threshold in mortality ratio of EC to ovarian cancer has already been seen in Black women, who have experienced greater mortality in EC compared with ovarian cancer since 2005. In fact, the EC mortality of Black women in 2019 was similar to the mortality of White women with ovarian cancer nearly 30 years ago.³

Decades of data have demonstrated the glaring racial disparities seen in EC, and yet, no significant progress has been made in addressing this inequity. Oncology research is now beginning to move beyond describing these differences to a strategy of achieving equitable cancer care. While the study frameworks and novel investigations aimed at addressing the disparities in EC is outside the scope of this article, disparities in clinical trial enrollment continue to exist.

A recent example can be seen in the practice-changing KEYNOTE-775 trial, which led to the Food and Drug Administration approval of lenvatinib plus pembrolizumab in EC treatment.⁴ A total of 827 patients with EC that progressed or recurred following treatment with platinum-based chemotherapy were enrolled in this multinational, multicenter trial. Thirty-one (3.7%) of the patients enrolled were Black. Of those who were enrolled in the United States, 14% were Black. The authors report that this proportion of Black patients in the United States is consistent with 2020 census data, which reported 13.4% of people identified as Black. However, using census data as a benchmark for equitable enrollment is inappropriate. Certain demographic groups are historically more difficult to count, and the COVID-19 pandemic exacerbated the challenge in obtaining an accurate count through job loss, government distrust, and access restrictions resulting in an estimated net undercount of 2.45% in those who report Black race.⁵ Composition of trial enrollment should mirror the population that will be affected by the study results. As advanced EC disproportionately affects Black patients, their enrollment must be higher in these pivotal trials. How else are we to know if these novel therapeutics will work in the population that is most afflicted by EC?

Future studies must account for socioeconomic factors while acknowledging the role of social determinants of health. It is imperative that we use the knowledge that race is a social construct created to control access to power and that there are biologic responses to environmental stresses, including that of racism, affecting health and disease. Changes at every level, from individual practitioners up to federal policies, will need to be enacted or else the unacceptable status quo will continue.
 

Dr. Burkett is a clinical fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina at Chapel Hill.

References

1. Siegel RL et al. CA Cancer J Clin. 2022;72:7-33.

2. Clarke MA et al. J Clin Oncol. 2019;37:1895-908.

3. Giaquinto AN et al. Obstet Gynecol. 2022;139:440-2.

4. Makker V et al. N Engl J Med. 2022;386:437-48.

5. Elliott D et al. Simulating the 2020 Census: Miscounts and the fairness of outcomes. Urban Institute; 2021.

Endometrial cancer (EC) is the most common gynecologic malignancy and is the fourth most common cancer seen in U.S. women. It is the only major cancer that has continued to see a rise in incidence and mortality for the past 2 decades, and it is anticipated that nearly 66,000 new cases of EC will be diagnosed this year with 12,550 deaths.¹ Given that the well-established risk factors for developing EC including obesity, diabetes, and insulin resistance, the obesity epidemic is indisputably playing a significant role in the increasing incidence.

Historically, White women were thought to have the highest incidence of EC; however, this incidence rate did not account for hysterectomy prevalence, which can vary widely by numerous factors including age, race, ethnicity, and geographic region. When correcting EC incidence rates for prevalence of hysterectomy, Black women have had the highest incidence of EC since 2007, and rates continue to climb.² In fact, the average annual percent change (APC) in EC incidence from 2000 to 2015 was stable for White women at 0.2% while Black women had a near order of magnitude greater APC at 2.1%.²

Differing incidence rates of EC can also be seen by histologic subtype. Endometrioid EC is the more common and less lethal histology of EC that often coincides with the type I classification of EC. These tumors are estrogen driven; therefore, they are associated with conditions resulting in excess estrogen (for example, anovulation, obesity, and hyperlipidemia). Nonendometrioid histologies, primarily composed of serous tumors, are more rare, are typically more aggressive, are not estrogen driven, and are commonly classified as type II tumors. Racial differences between type I and type II tumors are seen with White women more commonly being diagnosed with type I tumors while Black women more typically have type II tumors. White women have the greatest incidence rate of endometrioid EC with an APC that remained relatively unchanged from 2000 to 2015. Black women’s APC in incidence rate of endometrioid EC has increased during this same period at 1.3%. For nonendometrioid tumors, an increasing incidence is seen in all races and ethnicities; however, Black women have a much higher incidence of these tumors, with a rate that continues to increase at an APC of 3.2%.²

EC incidence is increasing with a particularly concerning rise in those who report Black race, but are these same disparities being seen in EC mortality? Unfortunately, drastic disparities are seen in survival data for Black women afflicted with EC. Black patients are more likely to be diagnosed with advanced or metastatic EC and less likely to be diagnosed with localized tumors. While being diagnosed with a more advanced stage of disease does affect survival in EC, Black patients have worse survival regardless of stage of disease at the time of diagnosis.¹ As discussed earlier, the more aggressive type II tumors are composed of nonendometrioid histologies and are more common in Black women. This could lead to the false assumption that these higher-risk tumors are why Black women are disproportionately dying from EC; however, when examining survival by histologic subtype, Black women are more frequently dying from the lower-risk endometrioid EC regardless of stage of disease. The same disparate survival outcomes are also seen in nonendometrioid histologies.² Thus, Black patients have the lowest survival rates irrespective of stage at diagnosis or histologic subtype.

The disparities seen in EC mortality are not new. They can be seen in data for over 30 years and are only widening. While there has been an increase in mortality rates from EC across all races and ethnicities from 2015 to 2019 compared with 1990 to 1994, the mortality rate ratio for Black women compared with White women has increased from 1.83 in 1990-1994 to 1.98 in 2015-2019.³ In the early 1990s, the risk of death from ovarian cancer was twice that of EC. The mortality of EC is now similar to that of ovarian cancer. This threshold in mortality ratio of EC to ovarian cancer has already been seen in Black women, who have experienced greater mortality in EC compared with ovarian cancer since 2005. In fact, the EC mortality of Black women in 2019 was similar to the mortality of White women with ovarian cancer nearly 30 years ago.³

Decades of data have demonstrated the glaring racial disparities seen in EC, and yet, no significant progress has been made in addressing this inequity. Oncology research is now beginning to move beyond describing these differences to a strategy of achieving equitable cancer care. While the study frameworks and novel investigations aimed at addressing the disparities in EC is outside the scope of this article, disparities in clinical trial enrollment continue to exist.

A recent example can be seen in the practice-changing KEYNOTE-775 trial, which led to the Food and Drug Administration approval of lenvatinib plus pembrolizumab in EC treatment.⁴ A total of 827 patients with EC that progressed or recurred following treatment with platinum-based chemotherapy were enrolled in this multinational, multicenter trial. Thirty-one (3.7%) of the patients enrolled were Black. Of those who were enrolled in the United States, 14% were Black. The authors report that this proportion of Black patients in the United States is consistent with 2020 census data, which reported 13.4% of people identified as Black. However, using census data as a benchmark for equitable enrollment is inappropriate. Certain demographic groups are historically more difficult to count, and the COVID-19 pandemic exacerbated the challenge in obtaining an accurate count through job loss, government distrust, and access restrictions resulting in an estimated net undercount of 2.45% in those who report Black race.⁵ Composition of trial enrollment should mirror the population that will be affected by the study results. As advanced EC disproportionately affects Black patients, their enrollment must be higher in these pivotal trials. How else are we to know if these novel therapeutics will work in the population that is most afflicted by EC?

Future studies must account for socioeconomic factors while acknowledging the role of social determinants of health. It is imperative that we use the knowledge that race is a social construct created to control access to power and that there are biologic responses to environmental stresses, including that of racism, affecting health and disease. Changes at every level, from individual practitioners up to federal policies, will need to be enacted or else the unacceptable status quo will continue.
 

Dr. Burkett is a clinical fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina at Chapel Hill.

References

1. Siegel RL et al. CA Cancer J Clin. 2022;72:7-33.

2. Clarke MA et al. J Clin Oncol. 2019;37:1895-908.

3. Giaquinto AN et al. Obstet Gynecol. 2022;139:440-2.

4. Makker V et al. N Engl J Med. 2022;386:437-48.

5. Elliott D et al. Simulating the 2020 Census: Miscounts and the fairness of outcomes. Urban Institute; 2021.

Endometrial cancer (EC) is the most common gynecologic malignancy and is the fourth most common cancer seen in U.S. women. It is the only major cancer that has continued to see a rise in incidence and mortality for the past 2 decades, and it is anticipated that nearly 66,000 new cases of EC will be diagnosed this year with 12,550 deaths.¹ Given that the well-established risk factors for developing EC including obesity, diabetes, and insulin resistance, the obesity epidemic is indisputably playing a significant role in the increasing incidence.

Historically, White women were thought to have the highest incidence of EC; however, this incidence rate did not account for hysterectomy prevalence, which can vary widely by numerous factors including age, race, ethnicity, and geographic region. When correcting EC incidence rates for prevalence of hysterectomy, Black women have had the highest incidence of EC since 2007, and rates continue to climb.² In fact, the average annual percent change (APC) in EC incidence from 2000 to 2015 was stable for White women at 0.2% while Black women had a near order of magnitude greater APC at 2.1%.²

Differing incidence rates of EC can also be seen by histologic subtype. Endometrioid EC is the more common and less lethal histology of EC that often coincides with the type I classification of EC. These tumors are estrogen driven; therefore, they are associated with conditions resulting in excess estrogen (for example, anovulation, obesity, and hyperlipidemia). Nonendometrioid histologies, primarily composed of serous tumors, are more rare, are typically more aggressive, are not estrogen driven, and are commonly classified as type II tumors. Racial differences between type I and type II tumors are seen with White women more commonly being diagnosed with type I tumors while Black women more typically have type II tumors. White women have the greatest incidence rate of endometrioid EC with an APC that remained relatively unchanged from 2000 to 2015. Black women’s APC in incidence rate of endometrioid EC has increased during this same period at 1.3%. For nonendometrioid tumors, an increasing incidence is seen in all races and ethnicities; however, Black women have a much higher incidence of these tumors, with a rate that continues to increase at an APC of 3.2%.²

EC incidence is increasing with a particularly concerning rise in those who report Black race, but are these same disparities being seen in EC mortality? Unfortunately, drastic disparities are seen in survival data for Black women afflicted with EC. Black patients are more likely to be diagnosed with advanced or metastatic EC and less likely to be diagnosed with localized tumors. While being diagnosed with a more advanced stage of disease does affect survival in EC, Black patients have worse survival regardless of stage of disease at the time of diagnosis.¹ As discussed earlier, the more aggressive type II tumors are composed of nonendometrioid histologies and are more common in Black women. This could lead to the false assumption that these higher-risk tumors are why Black women are disproportionately dying from EC; however, when examining survival by histologic subtype, Black women are more frequently dying from the lower-risk endometrioid EC regardless of stage of disease. The same disparate survival outcomes are also seen in nonendometrioid histologies.² Thus, Black patients have the lowest survival rates irrespective of stage at diagnosis or histologic subtype.

The disparities seen in EC mortality are not new. They can be seen in data for over 30 years and are only widening. While there has been an increase in mortality rates from EC across all races and ethnicities from 2015 to 2019 compared with 1990 to 1994, the mortality rate ratio for Black women compared with White women has increased from 1.83 in 1990-1994 to 1.98 in 2015-2019.³ In the early 1990s, the risk of death from ovarian cancer was twice that of EC. The mortality of EC is now similar to that of ovarian cancer. This threshold in mortality ratio of EC to ovarian cancer has already been seen in Black women, who have experienced greater mortality in EC compared with ovarian cancer since 2005. In fact, the EC mortality of Black women in 2019 was similar to the mortality of White women with ovarian cancer nearly 30 years ago.³

Decades of data have demonstrated the glaring racial disparities seen in EC, and yet, no significant progress has been made in addressing this inequity. Oncology research is now beginning to move beyond describing these differences to a strategy of achieving equitable cancer care. While the study frameworks and novel investigations aimed at addressing the disparities in EC is outside the scope of this article, disparities in clinical trial enrollment continue to exist.

A recent example can be seen in the practice-changing KEYNOTE-775 trial, which led to the Food and Drug Administration approval of lenvatinib plus pembrolizumab in EC treatment.⁴ A total of 827 patients with EC that progressed or recurred following treatment with platinum-based chemotherapy were enrolled in this multinational, multicenter trial. Thirty-one (3.7%) of the patients enrolled were Black. Of those who were enrolled in the United States, 14% were Black. The authors report that this proportion of Black patients in the United States is consistent with 2020 census data, which reported 13.4% of people identified as Black. However, using census data as a benchmark for equitable enrollment is inappropriate. Certain demographic groups are historically more difficult to count, and the COVID-19 pandemic exacerbated the challenge in obtaining an accurate count through job loss, government distrust, and access restrictions resulting in an estimated net undercount of 2.45% in those who report Black race.⁵ Composition of trial enrollment should mirror the population that will be affected by the study results. As advanced EC disproportionately affects Black patients, their enrollment must be higher in these pivotal trials. How else are we to know if these novel therapeutics will work in the population that is most afflicted by EC?

Future studies must account for socioeconomic factors while acknowledging the role of social determinants of health. It is imperative that we use the knowledge that race is a social construct created to control access to power and that there are biologic responses to environmental stresses, including that of racism, affecting health and disease. Changes at every level, from individual practitioners up to federal policies, will need to be enacted or else the unacceptable status quo will continue.
 

Dr. Burkett is a clinical fellow in the division of gynecologic oncology, department of obstetrics and gynecology, at the University of North Carolina at Chapel Hill.

References

1. Siegel RL et al. CA Cancer J Clin. 2022;72:7-33.

2. Clarke MA et al. J Clin Oncol. 2019;37:1895-908.

3. Giaquinto AN et al. Obstet Gynecol. 2022;139:440-2.

4. Makker V et al. N Engl J Med. 2022;386:437-48.

5. Elliott D et al. Simulating the 2020 Census: Miscounts and the fairness of outcomes. Urban Institute; 2021.

Hypertensive disorders of pregnancy (HDP) are associated with a greater than twofold risk of developing hypertension a decade later, new research suggests.

Investigators prospectively studied patients who had and who had not experienced HDP 10 years earlier; most self-identified as Black. They found that those with a history of HDP had a 2.4-fold higher risk for new hypertension than those without such a history.

Patients who developed hypertension showed greater left ventricular (LV) remodeling (including greater relative wall thickness), worse diastolic function, more abnormal longitudinal strain, and higher effective arterial elastance than those without hypertension, regardless of the presence or absence of an HDP history.

“We know that patients with preeclampsia are at a higher risk for heart disease later in life, and it seems to be driven by the development of new hypertension,” lead author Lisa Levine, MD, MSCE, director, pregnancy and heart disease program, Hospital of the University of Pennsylvania, Philadelphia, told this news organization.

It is critically important to “study a more diverse population, including a larger percentage of Black patients, since HDP and CVD both disproportionately affect Black women,” Dr. Levine said. “And it is important to screen patients for hypertension, getting them into primary care for visits, getting them diagnosed sooner, and treating them early for hypertension.”

The study was published in the Journal of the American College of Cardiology.
 

Understudied population

HDP includes gestational hypertension and preeclampsia, Dr. Levine explained. “We already know that patients who have had preeclampsia are at higher risk for stroke, heart failure [HF], and myocardial infarction later in life,” she said. The goal of this study was to see whether, instead of waiting 20-30 years, they could look only 10 years later to see which patients would be at highest risk for future heart disease, Dr. Levine said.

In particular, it’s known that cardiovascular disease (CVD) and HDP “disproportionately affect Black women,” Dr. Levine continued. “What makes our study different from other studies is that we focused predominantly on the Black African American population, since it’s understudied and also at highest risk for preeclampsia and heart disease,” she said.

They set out to “evaluate differences in CV risk factors as well as subclinical CVD among a well-characterized group of racially diverse patients with and without a history of HDP 10 years earlier,” the authors state.

To investigate the question, the researchers performed a prospective, cross-sectional study between April 2016 and December 2019 of patients with and without a diagnosis of HDP during a previous pregnancy at least 10 years earlier (from 2005 to 2007). Patients were drawn from a parent cohort in a previously performed observational study of patients with preeclampsia or HDP and normotensive control subjects.

The current study focused on 135 patients (85% Black), 84 with a history of HDP and 51 without. Of the Black patients, 91.7% had a history of HDP, compared with 8.3% of the White patients.

During an in-person visit, the researchers assessed participants’ blood pressure and other clinical risk factors for CVD, including fasting glucose and lipids. They also used noninvasive means to measure cardiac and vascular structure and function.
 

Importance of routine screening

The risk for new hypertension was 2.4 times higher in patients with a history of HDP than in those without HDP, with stage 2 hypertension noted in 56.0% of patients with and in 23.5% without HDP (P < .001). This equates to a relative risk of 2.4 (95% confidence interval, 1.39-4.14), even after adjustment for race, maternal age, body mass index, and history of preterm birth.

“Importantly, 18% of patients with a history of HDP met criteria for a new diagnosis of hypertension identified through the study visit,” the authors report.

There were no differences in many cardiac measures (left ventricular (LV) structure, global longitudinal strain, diastolic function, arterial stiffness, or endothelial function) between patients with and without a history of HDP.

However, patients with chronic hypertension (CHTN), regardless of HDP history, had other cardiac abnormalities, including greater LV remodeling, worse diastolic function, and higher effective arterial elastance.

“The data regarding increased risk of hypertension after HDP is not a novel finding, however our cohort is unique in the high baseline rate of stage 2 hypertension, even among patients without a history of HDP,” the authors comment.

In fact, when they looked at the diagnosis of either stage 1 or stage 2 hypertension, they found that more than 80% of patients with and 60% of patients without a history of HDP had hypertension. Notably, among patients with a history of HDP, only 39% had a formal diagnosis of either stage 1 or stage 2 hypertension, further highlighting “the importance of routine screening for CHTN in this population,” they state.

“Further studies should evaluate the optimal time period to screen for postpartum hypertension and a monitoring plan for these at-risk women,” Dr. Levine added.
 

‘Opportunity of a lifetime’

Commenting for this news organization, Malamo Countouris, MD, MS, assistant professor of medicine and codirector, postpartum hypertension program, University of Pittsburgh Medical Center, said hypertension is “underrecognized and undertreated among young, premenopausal, Black women.”

Pregnancy “gives us a clue, through HDP, as to who is high risk to develop chronic hypertension and subsequent subclinical structural cardiac changes in the decade after delivery,” said Dr. Countouris, who was not involved with the study.

“The jury is still out on whether HDP contributes independently to cardiovascular changes in the years after delivery. Ongoing research is needed to clarify the unique or compounding contributions of pregnancy complications and hypertension,” she added.

In an accompanying editorial , Josephine Chou, MD, MS, director of cardio-obstetrics and codirector of maternal cardiology, Yale University, New Haven, Conn., called the study a “laudable contribution to understanding of HDP and hypertension within the first decade after pregnancy,” saying that it “paves the way for future efforts to improve postpartum CV care, enabling us to grasp this opportunity of a lifetime to ultimately reduce maternal and pregnancy-related morbidity and mortality.”

This study was supported by the National Institutes of Health, the National Heart, Lung, and Blood Institute, and the American Association of Obstetricians and Gynecologists Foundation. Dr. Levine reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Countouris reports receiving funding from the American Heart Association. Dr. Chou reports no relevant financial relationships.

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

Hypertensive disorders of pregnancy (HDP) are associated with a greater than twofold risk of developing hypertension a decade later, new research suggests.

Investigators prospectively studied patients who had and who had not experienced HDP 10 years earlier; most self-identified as Black. They found that those with a history of HDP had a 2.4-fold higher risk for new hypertension than those without such a history.

Patients who developed hypertension showed greater left ventricular (LV) remodeling (including greater relative wall thickness), worse diastolic function, more abnormal longitudinal strain, and higher effective arterial elastance than those without hypertension, regardless of the presence or absence of an HDP history.

“We know that patients with preeclampsia are at a higher risk for heart disease later in life, and it seems to be driven by the development of new hypertension,” lead author Lisa Levine, MD, MSCE, director, pregnancy and heart disease program, Hospital of the University of Pennsylvania, Philadelphia, told this news organization.

It is critically important to “study a more diverse population, including a larger percentage of Black patients, since HDP and CVD both disproportionately affect Black women,” Dr. Levine said. “And it is important to screen patients for hypertension, getting them into primary care for visits, getting them diagnosed sooner, and treating them early for hypertension.”

The study was published in the Journal of the American College of Cardiology.
 

Understudied population

HDP includes gestational hypertension and preeclampsia, Dr. Levine explained. “We already know that patients who have had preeclampsia are at higher risk for stroke, heart failure [HF], and myocardial infarction later in life,” she said. The goal of this study was to see whether, instead of waiting 20-30 years, they could look only 10 years later to see which patients would be at highest risk for future heart disease, Dr. Levine said.

In particular, it’s known that cardiovascular disease (CVD) and HDP “disproportionately affect Black women,” Dr. Levine continued. “What makes our study different from other studies is that we focused predominantly on the Black African American population, since it’s understudied and also at highest risk for preeclampsia and heart disease,” she said.

They set out to “evaluate differences in CV risk factors as well as subclinical CVD among a well-characterized group of racially diverse patients with and without a history of HDP 10 years earlier,” the authors state.

To investigate the question, the researchers performed a prospective, cross-sectional study between April 2016 and December 2019 of patients with and without a diagnosis of HDP during a previous pregnancy at least 10 years earlier (from 2005 to 2007). Patients were drawn from a parent cohort in a previously performed observational study of patients with preeclampsia or HDP and normotensive control subjects.

The current study focused on 135 patients (85% Black), 84 with a history of HDP and 51 without. Of the Black patients, 91.7% had a history of HDP, compared with 8.3% of the White patients.

During an in-person visit, the researchers assessed participants’ blood pressure and other clinical risk factors for CVD, including fasting glucose and lipids. They also used noninvasive means to measure cardiac and vascular structure and function.
 

Importance of routine screening

The risk for new hypertension was 2.4 times higher in patients with a history of HDP than in those without HDP, with stage 2 hypertension noted in 56.0% of patients with and in 23.5% without HDP (P < .001). This equates to a relative risk of 2.4 (95% confidence interval, 1.39-4.14), even after adjustment for race, maternal age, body mass index, and history of preterm birth.

“Importantly, 18% of patients with a history of HDP met criteria for a new diagnosis of hypertension identified through the study visit,” the authors report.

There were no differences in many cardiac measures (left ventricular (LV) structure, global longitudinal strain, diastolic function, arterial stiffness, or endothelial function) between patients with and without a history of HDP.

However, patients with chronic hypertension (CHTN), regardless of HDP history, had other cardiac abnormalities, including greater LV remodeling, worse diastolic function, and higher effective arterial elastance.

“The data regarding increased risk of hypertension after HDP is not a novel finding, however our cohort is unique in the high baseline rate of stage 2 hypertension, even among patients without a history of HDP,” the authors comment.

In fact, when they looked at the diagnosis of either stage 1 or stage 2 hypertension, they found that more than 80% of patients with and 60% of patients without a history of HDP had hypertension. Notably, among patients with a history of HDP, only 39% had a formal diagnosis of either stage 1 or stage 2 hypertension, further highlighting “the importance of routine screening for CHTN in this population,” they state.

“Further studies should evaluate the optimal time period to screen for postpartum hypertension and a monitoring plan for these at-risk women,” Dr. Levine added.
 

‘Opportunity of a lifetime’

Commenting for this news organization, Malamo Countouris, MD, MS, assistant professor of medicine and codirector, postpartum hypertension program, University of Pittsburgh Medical Center, said hypertension is “underrecognized and undertreated among young, premenopausal, Black women.”

Pregnancy “gives us a clue, through HDP, as to who is high risk to develop chronic hypertension and subsequent subclinical structural cardiac changes in the decade after delivery,” said Dr. Countouris, who was not involved with the study.

“The jury is still out on whether HDP contributes independently to cardiovascular changes in the years after delivery. Ongoing research is needed to clarify the unique or compounding contributions of pregnancy complications and hypertension,” she added.

In an accompanying editorial , Josephine Chou, MD, MS, director of cardio-obstetrics and codirector of maternal cardiology, Yale University, New Haven, Conn., called the study a “laudable contribution to understanding of HDP and hypertension within the first decade after pregnancy,” saying that it “paves the way for future efforts to improve postpartum CV care, enabling us to grasp this opportunity of a lifetime to ultimately reduce maternal and pregnancy-related morbidity and mortality.”

This study was supported by the National Institutes of Health, the National Heart, Lung, and Blood Institute, and the American Association of Obstetricians and Gynecologists Foundation. Dr. Levine reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Countouris reports receiving funding from the American Heart Association. Dr. Chou reports no relevant financial relationships.

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

Hypertensive disorders of pregnancy (HDP) are associated with a greater than twofold risk of developing hypertension a decade later, new research suggests.

Investigators prospectively studied patients who had and who had not experienced HDP 10 years earlier; most self-identified as Black. They found that those with a history of HDP had a 2.4-fold higher risk for new hypertension than those without such a history.

Patients who developed hypertension showed greater left ventricular (LV) remodeling (including greater relative wall thickness), worse diastolic function, more abnormal longitudinal strain, and higher effective arterial elastance than those without hypertension, regardless of the presence or absence of an HDP history.

“We know that patients with preeclampsia are at a higher risk for heart disease later in life, and it seems to be driven by the development of new hypertension,” lead author Lisa Levine, MD, MSCE, director, pregnancy and heart disease program, Hospital of the University of Pennsylvania, Philadelphia, told this news organization.

It is critically important to “study a more diverse population, including a larger percentage of Black patients, since HDP and CVD both disproportionately affect Black women,” Dr. Levine said. “And it is important to screen patients for hypertension, getting them into primary care for visits, getting them diagnosed sooner, and treating them early for hypertension.”

The study was published in the Journal of the American College of Cardiology.
 

Understudied population

HDP includes gestational hypertension and preeclampsia, Dr. Levine explained. “We already know that patients who have had preeclampsia are at higher risk for stroke, heart failure [HF], and myocardial infarction later in life,” she said. The goal of this study was to see whether, instead of waiting 20-30 years, they could look only 10 years later to see which patients would be at highest risk for future heart disease, Dr. Levine said.

In particular, it’s known that cardiovascular disease (CVD) and HDP “disproportionately affect Black women,” Dr. Levine continued. “What makes our study different from other studies is that we focused predominantly on the Black African American population, since it’s understudied and also at highest risk for preeclampsia and heart disease,” she said.

They set out to “evaluate differences in CV risk factors as well as subclinical CVD among a well-characterized group of racially diverse patients with and without a history of HDP 10 years earlier,” the authors state.

To investigate the question, the researchers performed a prospective, cross-sectional study between April 2016 and December 2019 of patients with and without a diagnosis of HDP during a previous pregnancy at least 10 years earlier (from 2005 to 2007). Patients were drawn from a parent cohort in a previously performed observational study of patients with preeclampsia or HDP and normotensive control subjects.

The current study focused on 135 patients (85% Black), 84 with a history of HDP and 51 without. Of the Black patients, 91.7% had a history of HDP, compared with 8.3% of the White patients.

During an in-person visit, the researchers assessed participants’ blood pressure and other clinical risk factors for CVD, including fasting glucose and lipids. They also used noninvasive means to measure cardiac and vascular structure and function.
 

Importance of routine screening

The risk for new hypertension was 2.4 times higher in patients with a history of HDP than in those without HDP, with stage 2 hypertension noted in 56.0% of patients with and in 23.5% without HDP (P < .001). This equates to a relative risk of 2.4 (95% confidence interval, 1.39-4.14), even after adjustment for race, maternal age, body mass index, and history of preterm birth.

“Importantly, 18% of patients with a history of HDP met criteria for a new diagnosis of hypertension identified through the study visit,” the authors report.

There were no differences in many cardiac measures (left ventricular (LV) structure, global longitudinal strain, diastolic function, arterial stiffness, or endothelial function) between patients with and without a history of HDP.

However, patients with chronic hypertension (CHTN), regardless of HDP history, had other cardiac abnormalities, including greater LV remodeling, worse diastolic function, and higher effective arterial elastance.

“The data regarding increased risk of hypertension after HDP is not a novel finding, however our cohort is unique in the high baseline rate of stage 2 hypertension, even among patients without a history of HDP,” the authors comment.

In fact, when they looked at the diagnosis of either stage 1 or stage 2 hypertension, they found that more than 80% of patients with and 60% of patients without a history of HDP had hypertension. Notably, among patients with a history of HDP, only 39% had a formal diagnosis of either stage 1 or stage 2 hypertension, further highlighting “the importance of routine screening for CHTN in this population,” they state.

“Further studies should evaluate the optimal time period to screen for postpartum hypertension and a monitoring plan for these at-risk women,” Dr. Levine added.
 

‘Opportunity of a lifetime’

Commenting for this news organization, Malamo Countouris, MD, MS, assistant professor of medicine and codirector, postpartum hypertension program, University of Pittsburgh Medical Center, said hypertension is “underrecognized and undertreated among young, premenopausal, Black women.”

Pregnancy “gives us a clue, through HDP, as to who is high risk to develop chronic hypertension and subsequent subclinical structural cardiac changes in the decade after delivery,” said Dr. Countouris, who was not involved with the study.

“The jury is still out on whether HDP contributes independently to cardiovascular changes in the years after delivery. Ongoing research is needed to clarify the unique or compounding contributions of pregnancy complications and hypertension,” she added.

In an accompanying editorial , Josephine Chou, MD, MS, director of cardio-obstetrics and codirector of maternal cardiology, Yale University, New Haven, Conn., called the study a “laudable contribution to understanding of HDP and hypertension within the first decade after pregnancy,” saying that it “paves the way for future efforts to improve postpartum CV care, enabling us to grasp this opportunity of a lifetime to ultimately reduce maternal and pregnancy-related morbidity and mortality.”

This study was supported by the National Institutes of Health, the National Heart, Lung, and Blood Institute, and the American Association of Obstetricians and Gynecologists Foundation. Dr. Levine reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Dr. Countouris reports receiving funding from the American Heart Association. Dr. Chou reports no relevant financial relationships.

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

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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

ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.

Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.

The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.

Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.

“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.

It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.

Lisa Nainggolan/MDedge News

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”

Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”

But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
 

‘Experiment of nature’ revealed invisible effect of pandemic stress

The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.

Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.

Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.

There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m² (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.

More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).

The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).

Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.  

The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.

And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).

Employment changes, caring responsibilities, and worry likely causes

The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.

“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.

Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.

“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.

Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.

“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.

Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”

Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.

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

Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.

However, new evidence suggests that HPV vaccination makes women more susceptible than their nonvaccinated peers to HPV genotypes not covered by the vaccine.

An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.

The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.

After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.

The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.

Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.

The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.

The findings were published online in The Lancet Oncology.

The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.

This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
 

Highlighting a need for caution

The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.

He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.

The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).

There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.

There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.

“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.

These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.

“There might be a little problem if we stop too early,” he said.
 

Study details

During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.

In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.

There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.

Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.

There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.

Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.

The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.

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

Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.

However, new evidence suggests that HPV vaccination makes women more susceptible than their nonvaccinated peers to HPV genotypes not covered by the vaccine.

An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.

The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.

After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.

The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.

Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.

The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.

The findings were published online in The Lancet Oncology.

The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.

This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
 

Highlighting a need for caution

The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.

He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.

The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).

There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.

There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.

“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.

These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.

“There might be a little problem if we stop too early,” he said.
 

Study details

During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.

In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.

There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.

Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.

There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.

Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.

The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.

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

Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.

However, new evidence suggests that HPV vaccination makes women more susceptible than their nonvaccinated peers to HPV genotypes not covered by the vaccine.

An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.

The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.

After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.

The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.

Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.

The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.

The findings were published online in The Lancet Oncology.

The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.

This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
 

Highlighting a need for caution

The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.

He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.

The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).

There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.

There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.

“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.

These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.

“There might be a little problem if we stop too early,” he said.
 

Study details

During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.

In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.

There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.

Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.

There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.

Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.

The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.

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