OBG Management

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

The medicated intrauterine devices (IUDs), including the levonorgestrel-releasing IUD (LNG-IUD) (Mirena, Kyleena, Skyla, and Liletta) and the copper IUD (Cu-IUD; Paragard), are remarkably effective contraceptives. For the 52-mg LNG-IUD (Mirena, Liletta) the pregnancy rate over 6 years of use averaged less than 0.2% per year.^1,2 For the Cu-IUD, the pregnancy rate over 10 years of use averaged 0.5% per year for the first 3 years of use and 0.2% per year over the following 7 years of use.³ IUD perforation of the uterus, expulsion, and malposition are recognized complications of IUD use. Our understanding of the prevalence and management of malpositioned IUDs is evolving and the main focus of this editorial.

Complete and partial uterus perforation

A complete uterine perforation occurs when the entire IUD is outside the walls of the uterus. A partial uterine perforation occurs when the IUD is outside the uterine cavity, but a portion of the IUD remains in the myometrium. When uterine perforation is suspected, ultrasound can determine if the IUD is properly sited within the uterus. If ultrasonography does not detect the IUD within the uterus, an x-ray of the pelvis and abdomen should be obtained to determine if the IUD is in the peritoneal cavity. If both an ultrasound and a pelvic-abdominal x-ray do not detect the IUD, the IUD was probably expelled from the patient.

Uterine perforation is uncommon and occurs once in every 500 to 1,000 insertions in non-breastfeeding women.^4-8 The most common symptoms reported by patients with a perforated IUD are pain and/or bleeding.⁸ Investigators in the European Active Surveillance Study on Intrauterine Devices (EURAS) enrolled more than 60,000 patients who had an IUD insertion and followed them for 12 months with more than 39,000 followed for up to 60 months.^7,8 The uterine perforation rate per 1,000 IUD insertions in non-breastfeeding women with 60 months of follow-up was 1.6 for the LNG-IUD and 0.8 for the Cu-IUD.⁸ The rate of uterine perforation was much higher in women who are breastfeeding or recently postpartum. In the EURAS study after 60 months of follow-up, the perforation rate per 1,000 insertions among breastfeeding women was 7.9 for the LNG-IUS and 4.7 for the Cu-IUD.⁸

Remarkably very few IUD perforations were detected at the time of insertion, including only 2% of the LNG-IUD insertions and 17% of the Cu-IUD insertions.⁸ Many perforations were not detected until more than 12 months following insertion, including 32% of the LNG-IUD insertions and 22% of the Cu-IUD insertions.⁸ Obviously, an IUD that has completely perforated the uterus and resides in the peritoneal cavity is not an effective contraceptive. For some patients, the IUD perforation was initially diagnosed after they became pregnant, and imaging studies to locate the IUD and assess the pregnancy were initiated. Complete perforation is usually treated with laparoscopy to remove the IUD and reduce the risk of injury to intra-abdominal organs.

Patients with an IUD partial perforation may present with pelvic pain or abnormal uterine bleeding.⁹ An ultrasound study to explore the cause of the presenting symptom may detect the partial perforation. It is estimated that approximately 20% of cases of IUD perforation are partial perforation.⁹ Over time, a partial perforation may progress to a complete perforation. In some cases of partial perforation, the IUD string may still be visible in the cervix, and the IUD may be removed by pulling on the strings.⁸ Hysteroscopy and/or laparoscopy may be needed to remove a partially perforated IUD. Following a partial or complete IUD perforation, if the patient desires to continue with IUD contraception, it would be wise to insert a new IUD under ultrasound guidance or assess proper placement with a postplacement ultrasound.

Continue to: Expulsion...

IUD expulsion occurs in approximately 3% to 11% of patients.^10-13 The age of the patient influences the rate of expulsion. In a study of 2,748 patients with a Cu-IUD, the rate of expulsion by age for patients <20 years, 20–24 years, 25–29 years, 30–34 years, and ≥35 years was 8.2%, 3.2%, 3.0%, 2.3%, and 1.8%, respectively.¹⁰ In this study, age did not influence the rate of IUD removal for pelvic pain or abnormal bleeding, which was 4% to 5% across all age groups.¹⁰ In a study of 5,403 patients with an IUD, the rate of IUD expulsion by age for patients <20 years, 20–29 years, and 30–45 years was 14.6%, 7.3%, and 7.2%, respectively.¹² In this study, the 3-year cumulative rate of expulsion was 10.2%.¹² There was no statistically significant difference in the 3-year cumulative rate of expulsion for the 52-mg LNG-IUD (10.1%) and Cu-IUD (10.7%).¹²

The majority of patients who have an IUD expulsion recognize the event and seek additional contraception care. A few patients first recognize the IUD expulsion when they become pregnant, and imaging studies detect no IUD in the uterus or the peritoneal cavity. In a study of more than 17,000 patients using an LNG-IUD, 108 pregnancies were reported. Seven pregnancies occurred in patients who did not realize their IUD was expelled.¹⁴ Patients who have had an IUD expulsion and receive a new IUD are at increased risk for re-expulsion. For these patients, reinsertion of an IUD could be performed under ultrasound guidance to ensure and document optimal initial IUD position within the uterus, or ultrasound can be obtained postinsertion to document appropriate IUD position.

Malposition—prevalence and management

Our understanding of the prevalence and management of a malpositioned IUD is evolving. For the purposes of this discussion a malpositioned IUD is defined as being in the uterus, but not properly positioned within the uterine cavity. Perforation into the peritoneal cavity and complete expulsion of an IUD are considered separate entities. However, a malpositioned IUD within the uterus may eventually perforate the uterus or be expelled from the body. For example, an IUD embedded in the uterine wall may eventually work its way through the wall and become perforated, residing in the peritoneal cavity. An IUD with the stem in the cervix below the internal os may eventually be expelled from the uterus and leave the body through the vagina.

High-quality ultrasonography, including 2-dimensional (2-D) ultrasound with videoclips or 3-dimensional (3-D) ultrasound with coronal views, has greatly advanced our understanding of the prevalence and characteristics of a malpositioned IUD.^15-18 Ultrasound features of an IUD correctly placed within the uterus include:

• the IUD is in the uterus
• the shaft is in the midline of the uterine cavity
• the shaft of the IUD is not in the endocervix
• the IUD arms are at a 90-degree angle from the shaft
• the top of the IUD is within 2 cm of the fundus
• the IUD is not rotated outside of the cornual plane, inverted or transverse.

Ultrasound imaging has identified multiple types of malpositioned IUDs, including:

• IUD embedded in the myometrium—a portion of the IUD is embedded in the uterine wall
• low-lying IUD—the IUD is low in the uterine cavity but not in the endocervix
• IUD in the endocervix—the stem is in the endocervical canal
• rotated—the IUD is rotated outside the cornual plane
• malpositioned arms—the arms are not at a 90-degree angle to the stem
• the IUD is inverted, transverse, or laterally displaced.

IUD malposition is highly prevalent and has been identified in 10% to 20% of convenience cohorts in which an ultrasound study was performed.^15-18

Benacerraf, Shipp, and Bromley were among the first experts to use ultrasound to detect the high prevalence of malpositioned IUDs among a convenience sample of 167 patients with an IUD undergoing ultrasound for a variety of indications. Using 3-D ultrasound, including reconstructed coronal views, they identified 28 patients (17%) with a malpositioned IUD based on the detection of the IUD “poking into the substance of the uterus or cervix.” Among the patients with a malpositioned IUD, the principal indication for the ultrasound study was pelvic pain (39%) or abnormal uterine bleeding (36%). Among women with a normally sited IUD, pelvic pain (19%) or abnormal uterine bleeding (15%) were less often the principal indication for the ultrasound.¹⁵ The malpositioned IUD was removed in 21 of the 28 cases and the symptoms of pelvic pain or abnormal bleeding resolved in 20 of the 21 patients.¹⁵

Other investigators have confirmed the observation that IUD malposition is common.^16-18 In a retrospective study of 1,748 pelvic ultrasounds performed for any indication where an IUD was present, after excluding 13 patients who were determined to have expelled their IUD (13) and 13 patients with a perforated IUD, 156 patients (8.9%) were diagnosed as having a malpositioned IUD.¹⁶ IUD malposition was diagnosed when the IUD was in the uterus but positioned in the lower uterine segment, cervix, rotated or embedded in the uterus. An IUD in the lower uterine segment or cervix was detected in 133 patients, representing 85% of cases. Among these cases, 29 IUDs were also embedded and/or rotated, indicating that some IUDs have multiple causes of the malposition. Twenty-one IUDs were near the fundus but embedded and/or rotated. Controls with a normally-sited IUD were selected for comparison to the case group. Among IUD users, the identification of suspected adenomyosis on the ultrasound was associated with an increased risk of IUD malposition (odds ratio [OR], 3.04; 95% confidence interval [CI], 1.08-8.52).¹⁶ In this study, removal of a malpositioned LNG-IUD, without initiating a highly reliable contraceptive was associated with an increased risk of pregnancy. It is important to initiate a highly reliable form of contraception if the plan is to remove a malpositioned IUD.^16,19

In a study of 1,253 pelvic ultrasounds performed for any indication where an IUD was identified in the uterus, 263 IUDs (19%) were determined to be malpositioned.¹⁷ In this study the location of the malpositioned IUDs included¹⁷:

• the lower uterine segment not extending into the cervix (38%)
• in the lower uterine segment extending into the cervix (22%)
• in the cervix (26%)
• rotated axis of the IUD (12%)
• other (2%).

Among the 236 malpositioned IUDs, 24% appeared to be embedded in the uterine wall.¹⁷ Compared with patients with a normally-sited IUD on ultrasound, patients with a malpositioned IUD more frequently reported vaginal bleeding (30% vs 19%; P<.005) and pelvic pain (43% vs 30%; P<.002), similar to the findings in the Benacerraf et al. study.¹⁴

Connolly and Fox¹⁸ designed an innovative study to determine the rate of malpositioned IUDs using 2-D ultrasound to ensure proper IUD placement at the time of insertion with a follow-up 3-D ultrasound 8 weeks after insertion to assess IUD position within the uterus. At the 8-week 3-D ultrasound, among 763 women, 16.6% of the IUDs were malpositioned.¹⁸ In this study, IUD position was determined to be correct if all the following features were identified:

• the IUD shaft was in the midline of the uterine cavity
• the IUD arms were at 90 degrees from the stem
• the top of the IUD was within 3 to 4 mm of the fundus
• the IUD was not rotated, inverted or transverse.

IUD malpositions were categorized as:

• embedded in the uterine wall
• low in the uterine cavity
• in the endocervical canal
• misaligned
• perforated
• expulsed.

At the 8-week follow-up, 636 patients (83.4%) had an IUD that was correctly positioned.¹⁸ In 127 patients (16.6%) IUD malposition was identified, with some patients having more than one type of malposition. The types of malposition identified were:

• embedded in the myometrium (54%)
• misaligned, including rotated, laterally displaced, inverted, transverse or arms not deployed (47%)
• low in the uterine cavity (39%)
• in the endocervical canal (14%)
• perforated (3%)
• expulsion (0%).

Recall that all of these patients had a 2-D ultrasound at the time of insertion that identified the IUD as correctly placed. This suggests that during the 8 weeks following IUD placement there were changes in the location of the IUD or that 2-D ultrasound has lower sensitivity than 3-D ultrasound to detect malposition. Of note, at the 8-week follow-up, bleeding or pain was reported by 36% of the patients with a malpositioned IUD and 20% of patients with a correctly positioned IUD.¹⁷ Sixty-seven of the 127 malpositioned IUDs “required” removal, but the precise reasons for the removals were not delineated. The investigators concluded that 3-D ultrasonography is useful for the detection of IUD malposition and could be considered as part of ongoing IUD care, if symptoms of pain or bleeding occur.¹⁸

Continue to: IUD malposition following postplacental insertion...

IUD malposition following postplacental insertion

IUD malposition is common in patients who have had a postplacental insertion. Ultrasound imaging plays an important role in detecting IUD expulsion and malposition in these cases. Postplacental IUD insertion is defined as the placement of an IUD within 10 minutes following delivery of the placenta. Postplacental IUD insertion can be performed following a vaginal or cesarean birth and with a Cu-IUD or LNG-IUD. The good news is that postplacental IUD insertion reduces the risk of unplanned pregnancy in the years following birth. However, postplacental IUD insertion is associated with a high rate of IUD malposition.

In a study of 162 patients who had postplacental insertion of a Cu-IUD following a vaginal birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 8%, partial expulsion in 16%, and malposition in 15%.²⁰ The IUD was correctly sited in 56% of patients. Seven patients (4%) had the IUD removed, and 1 patient had a perforated IUD. Among the 25 malpositioned IUDs, 14 were not within 1 cm of the fundus, and 11 were rotated outside of the axis of the cornuas. In this study partial expulsion was defined as an IUD protruding from the external cervical os on physical exam or demonstration of the distal tip of the IUD below the internal os of the cervix on ultrasound. Malposition was defined as an IUD that was >1 cm from the fundus or in an abnormal location or axis, but not partially expelled.

In a study of 69 patients who had postplacental insertion of a Cu-IUD following a cesarean birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 3%, partial expulsion (stem in the cervix below the internal os) in 4% and malposition in 30%.²⁰ The IUD was correctly positioned in 59% of the patients.²¹ The IUD had been electively removed in 3%. Among the 21 patients with a malpositioned IUD, 10 were rotated within the uterine cavity, 6 were inverted (upside down), 3 were low-lying, and 2 were transverse.²¹ Given the relatively high rate of IUD malposition following postplacental insertion, it may be useful to perform a pelvic ultrasound at a postpartum visit to assess the location of the IUD, if ultrasonography is available.

Management of the malpositioned IUD

There are no consensus guidelines on how to care for a patient with a malpositioned IUD. Clinicians need to use their best judgment and engage the patient in joint decision making when managing a malpositioned IUD. When an IUD is malpositioned and the patient has bothersome symptoms of pelvic pain or abnormal bleeding that have not responded to standard interventions, consideration may be given to a remove and replace strategy. When the stem of the IUD is below the level of the internal os on ultrasound or visible at the external os on physical examination, consideration should be given to removing and replacing the IUD. However, if the IUD is removed without replacement or the initiation of a highly reliable contraceptive, the risk of unplanned pregnancy is considerable.^16,19

IUD totally or partially within the cervix or low-lying. When an IUD is in the cervix, the contraceptive efficacy of the IUD may be diminished, especially with a Cu-IUD.²² In these cases, removing and replacing the IUD is an option. In a survey of 20 expert clinicians, >80% recommended replacing an IUD that was totally or partially in the cervical canal.²³ But most of the experts would not replace an IUD that was incidentally noted on ultrasound to be low-lying, being positioned more than 2 cm below the fundus, with no portion of the IUD in the cervical canal. In the same survey, for patients with a low-lying IUD and pelvic pain or bleeding, the majority of experts reported that they would explore other causes of bleeding and pelvic pain not related to the IUD itself and not replace the IUD, but 30% of the experts reported that they would remove and replace the device.²³

IUD embedded in the myometrium with pelvic pain. Based on my clinical experience, when a patient has persistent pelvic pain following the insertion of an IUD and the pain does not resolve with standard measures including medication, an ultrasound study is warranted to assess the position of the IUD. If the ultrasound demonstrates that an arm of the IUD is embedded in the myometrium, removal of the IUD may be associated with resolution of the pain. Reinsertion of an IUD under ultrasound guidance may result in a correctly-sited IUD with no recurrence of pelvic pain.

IUD rotated within the uterus with no pain or abnormal bleeding. For an IUD that is near the fundus and rotated on its axis within the uterus, if the patient has no symptoms of pain or abnormal bleeding, my recommendation to the patient would be to leave the device in situ.

Without available guidelines, engage in clinician-patient discussion

It is clear that IUD malposition is common, occurring in 10% to 20% of patients with an IUD. High-quality ultrasound imaging is helpful in detecting IUD malposition, including 2-D ultrasound with videoclips and/or 3-D ultrasound with coronal reconstruction. More data are needed to identify the best options for managing various types of malpositioned IUDs in patients with and without bothersome symptoms such as pain and bleeding. Until consensus guidelines are developed, clinicians need to engage the patient in a discussion of how to best manage the malpositioned IUD. Medicated IUDs and progestin subdermal implants are our two most effective reversible contraceptives. They are among the most important advances in health care over the past half-century. ●

The medicated intrauterine devices (IUDs), including the levonorgestrel-releasing IUD (LNG-IUD) (Mirena, Kyleena, Skyla, and Liletta) and the copper IUD (Cu-IUD; Paragard), are remarkably effective contraceptives. For the 52-mg LNG-IUD (Mirena, Liletta) the pregnancy rate over 6 years of use averaged less than 0.2% per year.^1,2 For the Cu-IUD, the pregnancy rate over 10 years of use averaged 0.5% per year for the first 3 years of use and 0.2% per year over the following 7 years of use.³ IUD perforation of the uterus, expulsion, and malposition are recognized complications of IUD use. Our understanding of the prevalence and management of malpositioned IUDs is evolving and the main focus of this editorial.

Complete and partial uterus perforation

A complete uterine perforation occurs when the entire IUD is outside the walls of the uterus. A partial uterine perforation occurs when the IUD is outside the uterine cavity, but a portion of the IUD remains in the myometrium. When uterine perforation is suspected, ultrasound can determine if the IUD is properly sited within the uterus. If ultrasonography does not detect the IUD within the uterus, an x-ray of the pelvis and abdomen should be obtained to determine if the IUD is in the peritoneal cavity. If both an ultrasound and a pelvic-abdominal x-ray do not detect the IUD, the IUD was probably expelled from the patient.

Uterine perforation is uncommon and occurs once in every 500 to 1,000 insertions in non-breastfeeding women.^4-8 The most common symptoms reported by patients with a perforated IUD are pain and/or bleeding.⁸ Investigators in the European Active Surveillance Study on Intrauterine Devices (EURAS) enrolled more than 60,000 patients who had an IUD insertion and followed them for 12 months with more than 39,000 followed for up to 60 months.^7,8 The uterine perforation rate per 1,000 IUD insertions in non-breastfeeding women with 60 months of follow-up was 1.6 for the LNG-IUD and 0.8 for the Cu-IUD.⁸ The rate of uterine perforation was much higher in women who are breastfeeding or recently postpartum. In the EURAS study after 60 months of follow-up, the perforation rate per 1,000 insertions among breastfeeding women was 7.9 for the LNG-IUS and 4.7 for the Cu-IUD.⁸

Remarkably very few IUD perforations were detected at the time of insertion, including only 2% of the LNG-IUD insertions and 17% of the Cu-IUD insertions.⁸ Many perforations were not detected until more than 12 months following insertion, including 32% of the LNG-IUD insertions and 22% of the Cu-IUD insertions.⁸ Obviously, an IUD that has completely perforated the uterus and resides in the peritoneal cavity is not an effective contraceptive. For some patients, the IUD perforation was initially diagnosed after they became pregnant, and imaging studies to locate the IUD and assess the pregnancy were initiated. Complete perforation is usually treated with laparoscopy to remove the IUD and reduce the risk of injury to intra-abdominal organs.

Patients with an IUD partial perforation may present with pelvic pain or abnormal uterine bleeding.⁹ An ultrasound study to explore the cause of the presenting symptom may detect the partial perforation. It is estimated that approximately 20% of cases of IUD perforation are partial perforation.⁹ Over time, a partial perforation may progress to a complete perforation. In some cases of partial perforation, the IUD string may still be visible in the cervix, and the IUD may be removed by pulling on the strings.⁸ Hysteroscopy and/or laparoscopy may be needed to remove a partially perforated IUD. Following a partial or complete IUD perforation, if the patient desires to continue with IUD contraception, it would be wise to insert a new IUD under ultrasound guidance or assess proper placement with a postplacement ultrasound.

Continue to: Expulsion...

IUD expulsion occurs in approximately 3% to 11% of patients.^10-13 The age of the patient influences the rate of expulsion. In a study of 2,748 patients with a Cu-IUD, the rate of expulsion by age for patients <20 years, 20–24 years, 25–29 years, 30–34 years, and ≥35 years was 8.2%, 3.2%, 3.0%, 2.3%, and 1.8%, respectively.¹⁰ In this study, age did not influence the rate of IUD removal for pelvic pain or abnormal bleeding, which was 4% to 5% across all age groups.¹⁰ In a study of 5,403 patients with an IUD, the rate of IUD expulsion by age for patients <20 years, 20–29 years, and 30–45 years was 14.6%, 7.3%, and 7.2%, respectively.¹² In this study, the 3-year cumulative rate of expulsion was 10.2%.¹² There was no statistically significant difference in the 3-year cumulative rate of expulsion for the 52-mg LNG-IUD (10.1%) and Cu-IUD (10.7%).¹²

The majority of patients who have an IUD expulsion recognize the event and seek additional contraception care. A few patients first recognize the IUD expulsion when they become pregnant, and imaging studies detect no IUD in the uterus or the peritoneal cavity. In a study of more than 17,000 patients using an LNG-IUD, 108 pregnancies were reported. Seven pregnancies occurred in patients who did not realize their IUD was expelled.¹⁴ Patients who have had an IUD expulsion and receive a new IUD are at increased risk for re-expulsion. For these patients, reinsertion of an IUD could be performed under ultrasound guidance to ensure and document optimal initial IUD position within the uterus, or ultrasound can be obtained postinsertion to document appropriate IUD position.

Malposition—prevalence and management

Our understanding of the prevalence and management of a malpositioned IUD is evolving. For the purposes of this discussion a malpositioned IUD is defined as being in the uterus, but not properly positioned within the uterine cavity. Perforation into the peritoneal cavity and complete expulsion of an IUD are considered separate entities. However, a malpositioned IUD within the uterus may eventually perforate the uterus or be expelled from the body. For example, an IUD embedded in the uterine wall may eventually work its way through the wall and become perforated, residing in the peritoneal cavity. An IUD with the stem in the cervix below the internal os may eventually be expelled from the uterus and leave the body through the vagina.

High-quality ultrasonography, including 2-dimensional (2-D) ultrasound with videoclips or 3-dimensional (3-D) ultrasound with coronal views, has greatly advanced our understanding of the prevalence and characteristics of a malpositioned IUD.^15-18 Ultrasound features of an IUD correctly placed within the uterus include:

• the IUD is in the uterus
• the shaft is in the midline of the uterine cavity
• the shaft of the IUD is not in the endocervix
• the IUD arms are at a 90-degree angle from the shaft
• the top of the IUD is within 2 cm of the fundus
• the IUD is not rotated outside of the cornual plane, inverted or transverse.

Ultrasound imaging has identified multiple types of malpositioned IUDs, including:

• IUD embedded in the myometrium—a portion of the IUD is embedded in the uterine wall
• low-lying IUD—the IUD is low in the uterine cavity but not in the endocervix
• IUD in the endocervix—the stem is in the endocervical canal
• rotated—the IUD is rotated outside the cornual plane
• malpositioned arms—the arms are not at a 90-degree angle to the stem
• the IUD is inverted, transverse, or laterally displaced.

IUD malposition is highly prevalent and has been identified in 10% to 20% of convenience cohorts in which an ultrasound study was performed.^15-18

Benacerraf, Shipp, and Bromley were among the first experts to use ultrasound to detect the high prevalence of malpositioned IUDs among a convenience sample of 167 patients with an IUD undergoing ultrasound for a variety of indications. Using 3-D ultrasound, including reconstructed coronal views, they identified 28 patients (17%) with a malpositioned IUD based on the detection of the IUD “poking into the substance of the uterus or cervix.” Among the patients with a malpositioned IUD, the principal indication for the ultrasound study was pelvic pain (39%) or abnormal uterine bleeding (36%). Among women with a normally sited IUD, pelvic pain (19%) or abnormal uterine bleeding (15%) were less often the principal indication for the ultrasound.¹⁵ The malpositioned IUD was removed in 21 of the 28 cases and the symptoms of pelvic pain or abnormal bleeding resolved in 20 of the 21 patients.¹⁵

Other investigators have confirmed the observation that IUD malposition is common.^16-18 In a retrospective study of 1,748 pelvic ultrasounds performed for any indication where an IUD was present, after excluding 13 patients who were determined to have expelled their IUD (13) and 13 patients with a perforated IUD, 156 patients (8.9%) were diagnosed as having a malpositioned IUD.¹⁶ IUD malposition was diagnosed when the IUD was in the uterus but positioned in the lower uterine segment, cervix, rotated or embedded in the uterus. An IUD in the lower uterine segment or cervix was detected in 133 patients, representing 85% of cases. Among these cases, 29 IUDs were also embedded and/or rotated, indicating that some IUDs have multiple causes of the malposition. Twenty-one IUDs were near the fundus but embedded and/or rotated. Controls with a normally-sited IUD were selected for comparison to the case group. Among IUD users, the identification of suspected adenomyosis on the ultrasound was associated with an increased risk of IUD malposition (odds ratio [OR], 3.04; 95% confidence interval [CI], 1.08-8.52).¹⁶ In this study, removal of a malpositioned LNG-IUD, without initiating a highly reliable contraceptive was associated with an increased risk of pregnancy. It is important to initiate a highly reliable form of contraception if the plan is to remove a malpositioned IUD.^16,19

In a study of 1,253 pelvic ultrasounds performed for any indication where an IUD was identified in the uterus, 263 IUDs (19%) were determined to be malpositioned.¹⁷ In this study the location of the malpositioned IUDs included¹⁷:

• the lower uterine segment not extending into the cervix (38%)
• in the lower uterine segment extending into the cervix (22%)
• in the cervix (26%)
• rotated axis of the IUD (12%)
• other (2%).

Among the 236 malpositioned IUDs, 24% appeared to be embedded in the uterine wall.¹⁷ Compared with patients with a normally-sited IUD on ultrasound, patients with a malpositioned IUD more frequently reported vaginal bleeding (30% vs 19%; P<.005) and pelvic pain (43% vs 30%; P<.002), similar to the findings in the Benacerraf et al. study.¹⁴

Connolly and Fox¹⁸ designed an innovative study to determine the rate of malpositioned IUDs using 2-D ultrasound to ensure proper IUD placement at the time of insertion with a follow-up 3-D ultrasound 8 weeks after insertion to assess IUD position within the uterus. At the 8-week 3-D ultrasound, among 763 women, 16.6% of the IUDs were malpositioned.¹⁸ In this study, IUD position was determined to be correct if all the following features were identified:

• the IUD shaft was in the midline of the uterine cavity
• the IUD arms were at 90 degrees from the stem
• the top of the IUD was within 3 to 4 mm of the fundus
• the IUD was not rotated, inverted or transverse.

IUD malpositions were categorized as:

• embedded in the uterine wall
• low in the uterine cavity
• in the endocervical canal
• misaligned
• perforated
• expulsed.

At the 8-week follow-up, 636 patients (83.4%) had an IUD that was correctly positioned.¹⁸ In 127 patients (16.6%) IUD malposition was identified, with some patients having more than one type of malposition. The types of malposition identified were:

• embedded in the myometrium (54%)
• misaligned, including rotated, laterally displaced, inverted, transverse or arms not deployed (47%)
• low in the uterine cavity (39%)
• in the endocervical canal (14%)
• perforated (3%)
• expulsion (0%).

Recall that all of these patients had a 2-D ultrasound at the time of insertion that identified the IUD as correctly placed. This suggests that during the 8 weeks following IUD placement there were changes in the location of the IUD or that 2-D ultrasound has lower sensitivity than 3-D ultrasound to detect malposition. Of note, at the 8-week follow-up, bleeding or pain was reported by 36% of the patients with a malpositioned IUD and 20% of patients with a correctly positioned IUD.¹⁷ Sixty-seven of the 127 malpositioned IUDs “required” removal, but the precise reasons for the removals were not delineated. The investigators concluded that 3-D ultrasonography is useful for the detection of IUD malposition and could be considered as part of ongoing IUD care, if symptoms of pain or bleeding occur.¹⁸

Continue to: IUD malposition following postplacental insertion...

IUD malposition following postplacental insertion

IUD malposition is common in patients who have had a postplacental insertion. Ultrasound imaging plays an important role in detecting IUD expulsion and malposition in these cases. Postplacental IUD insertion is defined as the placement of an IUD within 10 minutes following delivery of the placenta. Postplacental IUD insertion can be performed following a vaginal or cesarean birth and with a Cu-IUD or LNG-IUD. The good news is that postplacental IUD insertion reduces the risk of unplanned pregnancy in the years following birth. However, postplacental IUD insertion is associated with a high rate of IUD malposition.

In a study of 162 patients who had postplacental insertion of a Cu-IUD following a vaginal birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 8%, partial expulsion in 16%, and malposition in 15%.²⁰ The IUD was correctly sited in 56% of patients. Seven patients (4%) had the IUD removed, and 1 patient had a perforated IUD. Among the 25 malpositioned IUDs, 14 were not within 1 cm of the fundus, and 11 were rotated outside of the axis of the cornuas. In this study partial expulsion was defined as an IUD protruding from the external cervical os on physical exam or demonstration of the distal tip of the IUD below the internal os of the cervix on ultrasound. Malposition was defined as an IUD that was >1 cm from the fundus or in an abnormal location or axis, but not partially expelled.

In a study of 69 patients who had postplacental insertion of a Cu-IUD following a cesarean birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 3%, partial expulsion (stem in the cervix below the internal os) in 4% and malposition in 30%.²⁰ The IUD was correctly positioned in 59% of the patients.²¹ The IUD had been electively removed in 3%. Among the 21 patients with a malpositioned IUD, 10 were rotated within the uterine cavity, 6 were inverted (upside down), 3 were low-lying, and 2 were transverse.²¹ Given the relatively high rate of IUD malposition following postplacental insertion, it may be useful to perform a pelvic ultrasound at a postpartum visit to assess the location of the IUD, if ultrasonography is available.

Management of the malpositioned IUD

There are no consensus guidelines on how to care for a patient with a malpositioned IUD. Clinicians need to use their best judgment and engage the patient in joint decision making when managing a malpositioned IUD. When an IUD is malpositioned and the patient has bothersome symptoms of pelvic pain or abnormal bleeding that have not responded to standard interventions, consideration may be given to a remove and replace strategy. When the stem of the IUD is below the level of the internal os on ultrasound or visible at the external os on physical examination, consideration should be given to removing and replacing the IUD. However, if the IUD is removed without replacement or the initiation of a highly reliable contraceptive, the risk of unplanned pregnancy is considerable.^16,19

IUD totally or partially within the cervix or low-lying. When an IUD is in the cervix, the contraceptive efficacy of the IUD may be diminished, especially with a Cu-IUD.²² In these cases, removing and replacing the IUD is an option. In a survey of 20 expert clinicians, >80% recommended replacing an IUD that was totally or partially in the cervical canal.²³ But most of the experts would not replace an IUD that was incidentally noted on ultrasound to be low-lying, being positioned more than 2 cm below the fundus, with no portion of the IUD in the cervical canal. In the same survey, for patients with a low-lying IUD and pelvic pain or bleeding, the majority of experts reported that they would explore other causes of bleeding and pelvic pain not related to the IUD itself and not replace the IUD, but 30% of the experts reported that they would remove and replace the device.²³

IUD embedded in the myometrium with pelvic pain. Based on my clinical experience, when a patient has persistent pelvic pain following the insertion of an IUD and the pain does not resolve with standard measures including medication, an ultrasound study is warranted to assess the position of the IUD. If the ultrasound demonstrates that an arm of the IUD is embedded in the myometrium, removal of the IUD may be associated with resolution of the pain. Reinsertion of an IUD under ultrasound guidance may result in a correctly-sited IUD with no recurrence of pelvic pain.

IUD rotated within the uterus with no pain or abnormal bleeding. For an IUD that is near the fundus and rotated on its axis within the uterus, if the patient has no symptoms of pain or abnormal bleeding, my recommendation to the patient would be to leave the device in situ.

Without available guidelines, engage in clinician-patient discussion

It is clear that IUD malposition is common, occurring in 10% to 20% of patients with an IUD. High-quality ultrasound imaging is helpful in detecting IUD malposition, including 2-D ultrasound with videoclips and/or 3-D ultrasound with coronal reconstruction. More data are needed to identify the best options for managing various types of malpositioned IUDs in patients with and without bothersome symptoms such as pain and bleeding. Until consensus guidelines are developed, clinicians need to engage the patient in a discussion of how to best manage the malpositioned IUD. Medicated IUDs and progestin subdermal implants are our two most effective reversible contraceptives. They are among the most important advances in health care over the past half-century. ●

The medicated intrauterine devices (IUDs), including the levonorgestrel-releasing IUD (LNG-IUD) (Mirena, Kyleena, Skyla, and Liletta) and the copper IUD (Cu-IUD; Paragard), are remarkably effective contraceptives. For the 52-mg LNG-IUD (Mirena, Liletta) the pregnancy rate over 6 years of use averaged less than 0.2% per year.^1,2 For the Cu-IUD, the pregnancy rate over 10 years of use averaged 0.5% per year for the first 3 years of use and 0.2% per year over the following 7 years of use.³ IUD perforation of the uterus, expulsion, and malposition are recognized complications of IUD use. Our understanding of the prevalence and management of malpositioned IUDs is evolving and the main focus of this editorial.

Complete and partial uterus perforation

A complete uterine perforation occurs when the entire IUD is outside the walls of the uterus. A partial uterine perforation occurs when the IUD is outside the uterine cavity, but a portion of the IUD remains in the myometrium. When uterine perforation is suspected, ultrasound can determine if the IUD is properly sited within the uterus. If ultrasonography does not detect the IUD within the uterus, an x-ray of the pelvis and abdomen should be obtained to determine if the IUD is in the peritoneal cavity. If both an ultrasound and a pelvic-abdominal x-ray do not detect the IUD, the IUD was probably expelled from the patient.

Uterine perforation is uncommon and occurs once in every 500 to 1,000 insertions in non-breastfeeding women.^4-8 The most common symptoms reported by patients with a perforated IUD are pain and/or bleeding.⁸ Investigators in the European Active Surveillance Study on Intrauterine Devices (EURAS) enrolled more than 60,000 patients who had an IUD insertion and followed them for 12 months with more than 39,000 followed for up to 60 months.^7,8 The uterine perforation rate per 1,000 IUD insertions in non-breastfeeding women with 60 months of follow-up was 1.6 for the LNG-IUD and 0.8 for the Cu-IUD.⁸ The rate of uterine perforation was much higher in women who are breastfeeding or recently postpartum. In the EURAS study after 60 months of follow-up, the perforation rate per 1,000 insertions among breastfeeding women was 7.9 for the LNG-IUS and 4.7 for the Cu-IUD.⁸

Remarkably very few IUD perforations were detected at the time of insertion, including only 2% of the LNG-IUD insertions and 17% of the Cu-IUD insertions.⁸ Many perforations were not detected until more than 12 months following insertion, including 32% of the LNG-IUD insertions and 22% of the Cu-IUD insertions.⁸ Obviously, an IUD that has completely perforated the uterus and resides in the peritoneal cavity is not an effective contraceptive. For some patients, the IUD perforation was initially diagnosed after they became pregnant, and imaging studies to locate the IUD and assess the pregnancy were initiated. Complete perforation is usually treated with laparoscopy to remove the IUD and reduce the risk of injury to intra-abdominal organs.

Patients with an IUD partial perforation may present with pelvic pain or abnormal uterine bleeding.⁹ An ultrasound study to explore the cause of the presenting symptom may detect the partial perforation. It is estimated that approximately 20% of cases of IUD perforation are partial perforation.⁹ Over time, a partial perforation may progress to a complete perforation. In some cases of partial perforation, the IUD string may still be visible in the cervix, and the IUD may be removed by pulling on the strings.⁸ Hysteroscopy and/or laparoscopy may be needed to remove a partially perforated IUD. Following a partial or complete IUD perforation, if the patient desires to continue with IUD contraception, it would be wise to insert a new IUD under ultrasound guidance or assess proper placement with a postplacement ultrasound.

Continue to: Expulsion...

IUD expulsion occurs in approximately 3% to 11% of patients.^10-13 The age of the patient influences the rate of expulsion. In a study of 2,748 patients with a Cu-IUD, the rate of expulsion by age for patients <20 years, 20–24 years, 25–29 years, 30–34 years, and ≥35 years was 8.2%, 3.2%, 3.0%, 2.3%, and 1.8%, respectively.¹⁰ In this study, age did not influence the rate of IUD removal for pelvic pain or abnormal bleeding, which was 4% to 5% across all age groups.¹⁰ In a study of 5,403 patients with an IUD, the rate of IUD expulsion by age for patients <20 years, 20–29 years, and 30–45 years was 14.6%, 7.3%, and 7.2%, respectively.¹² In this study, the 3-year cumulative rate of expulsion was 10.2%.¹² There was no statistically significant difference in the 3-year cumulative rate of expulsion for the 52-mg LNG-IUD (10.1%) and Cu-IUD (10.7%).¹²

The majority of patients who have an IUD expulsion recognize the event and seek additional contraception care. A few patients first recognize the IUD expulsion when they become pregnant, and imaging studies detect no IUD in the uterus or the peritoneal cavity. In a study of more than 17,000 patients using an LNG-IUD, 108 pregnancies were reported. Seven pregnancies occurred in patients who did not realize their IUD was expelled.¹⁴ Patients who have had an IUD expulsion and receive a new IUD are at increased risk for re-expulsion. For these patients, reinsertion of an IUD could be performed under ultrasound guidance to ensure and document optimal initial IUD position within the uterus, or ultrasound can be obtained postinsertion to document appropriate IUD position.

Malposition—prevalence and management

Our understanding of the prevalence and management of a malpositioned IUD is evolving. For the purposes of this discussion a malpositioned IUD is defined as being in the uterus, but not properly positioned within the uterine cavity. Perforation into the peritoneal cavity and complete expulsion of an IUD are considered separate entities. However, a malpositioned IUD within the uterus may eventually perforate the uterus or be expelled from the body. For example, an IUD embedded in the uterine wall may eventually work its way through the wall and become perforated, residing in the peritoneal cavity. An IUD with the stem in the cervix below the internal os may eventually be expelled from the uterus and leave the body through the vagina.

High-quality ultrasonography, including 2-dimensional (2-D) ultrasound with videoclips or 3-dimensional (3-D) ultrasound with coronal views, has greatly advanced our understanding of the prevalence and characteristics of a malpositioned IUD.^15-18 Ultrasound features of an IUD correctly placed within the uterus include:

• the IUD is in the uterus
• the shaft is in the midline of the uterine cavity
• the shaft of the IUD is not in the endocervix
• the IUD arms are at a 90-degree angle from the shaft
• the top of the IUD is within 2 cm of the fundus
• the IUD is not rotated outside of the cornual plane, inverted or transverse.

Ultrasound imaging has identified multiple types of malpositioned IUDs, including:

• IUD embedded in the myometrium—a portion of the IUD is embedded in the uterine wall
• low-lying IUD—the IUD is low in the uterine cavity but not in the endocervix
• IUD in the endocervix—the stem is in the endocervical canal
• rotated—the IUD is rotated outside the cornual plane
• malpositioned arms—the arms are not at a 90-degree angle to the stem
• the IUD is inverted, transverse, or laterally displaced.

IUD malposition is highly prevalent and has been identified in 10% to 20% of convenience cohorts in which an ultrasound study was performed.^15-18

Benacerraf, Shipp, and Bromley were among the first experts to use ultrasound to detect the high prevalence of malpositioned IUDs among a convenience sample of 167 patients with an IUD undergoing ultrasound for a variety of indications. Using 3-D ultrasound, including reconstructed coronal views, they identified 28 patients (17%) with a malpositioned IUD based on the detection of the IUD “poking into the substance of the uterus or cervix.” Among the patients with a malpositioned IUD, the principal indication for the ultrasound study was pelvic pain (39%) or abnormal uterine bleeding (36%). Among women with a normally sited IUD, pelvic pain (19%) or abnormal uterine bleeding (15%) were less often the principal indication for the ultrasound.¹⁵ The malpositioned IUD was removed in 21 of the 28 cases and the symptoms of pelvic pain or abnormal bleeding resolved in 20 of the 21 patients.¹⁵

Other investigators have confirmed the observation that IUD malposition is common.^16-18 In a retrospective study of 1,748 pelvic ultrasounds performed for any indication where an IUD was present, after excluding 13 patients who were determined to have expelled their IUD (13) and 13 patients with a perforated IUD, 156 patients (8.9%) were diagnosed as having a malpositioned IUD.¹⁶ IUD malposition was diagnosed when the IUD was in the uterus but positioned in the lower uterine segment, cervix, rotated or embedded in the uterus. An IUD in the lower uterine segment or cervix was detected in 133 patients, representing 85% of cases. Among these cases, 29 IUDs were also embedded and/or rotated, indicating that some IUDs have multiple causes of the malposition. Twenty-one IUDs were near the fundus but embedded and/or rotated. Controls with a normally-sited IUD were selected for comparison to the case group. Among IUD users, the identification of suspected adenomyosis on the ultrasound was associated with an increased risk of IUD malposition (odds ratio [OR], 3.04; 95% confidence interval [CI], 1.08-8.52).¹⁶ In this study, removal of a malpositioned LNG-IUD, without initiating a highly reliable contraceptive was associated with an increased risk of pregnancy. It is important to initiate a highly reliable form of contraception if the plan is to remove a malpositioned IUD.^16,19

In a study of 1,253 pelvic ultrasounds performed for any indication where an IUD was identified in the uterus, 263 IUDs (19%) were determined to be malpositioned.¹⁷ In this study the location of the malpositioned IUDs included¹⁷:

• the lower uterine segment not extending into the cervix (38%)
• in the lower uterine segment extending into the cervix (22%)
• in the cervix (26%)
• rotated axis of the IUD (12%)
• other (2%).

Among the 236 malpositioned IUDs, 24% appeared to be embedded in the uterine wall.¹⁷ Compared with patients with a normally-sited IUD on ultrasound, patients with a malpositioned IUD more frequently reported vaginal bleeding (30% vs 19%; P<.005) and pelvic pain (43% vs 30%; P<.002), similar to the findings in the Benacerraf et al. study.¹⁴

Connolly and Fox¹⁸ designed an innovative study to determine the rate of malpositioned IUDs using 2-D ultrasound to ensure proper IUD placement at the time of insertion with a follow-up 3-D ultrasound 8 weeks after insertion to assess IUD position within the uterus. At the 8-week 3-D ultrasound, among 763 women, 16.6% of the IUDs were malpositioned.¹⁸ In this study, IUD position was determined to be correct if all the following features were identified:

• the IUD shaft was in the midline of the uterine cavity
• the IUD arms were at 90 degrees from the stem
• the top of the IUD was within 3 to 4 mm of the fundus
• the IUD was not rotated, inverted or transverse.

IUD malpositions were categorized as:

• embedded in the uterine wall
• low in the uterine cavity
• in the endocervical canal
• misaligned
• perforated
• expulsed.

At the 8-week follow-up, 636 patients (83.4%) had an IUD that was correctly positioned.¹⁸ In 127 patients (16.6%) IUD malposition was identified, with some patients having more than one type of malposition. The types of malposition identified were:

• embedded in the myometrium (54%)
• misaligned, including rotated, laterally displaced, inverted, transverse or arms not deployed (47%)
• low in the uterine cavity (39%)
• in the endocervical canal (14%)
• perforated (3%)
• expulsion (0%).

Recall that all of these patients had a 2-D ultrasound at the time of insertion that identified the IUD as correctly placed. This suggests that during the 8 weeks following IUD placement there were changes in the location of the IUD or that 2-D ultrasound has lower sensitivity than 3-D ultrasound to detect malposition. Of note, at the 8-week follow-up, bleeding or pain was reported by 36% of the patients with a malpositioned IUD and 20% of patients with a correctly positioned IUD.¹⁷ Sixty-seven of the 127 malpositioned IUDs “required” removal, but the precise reasons for the removals were not delineated. The investigators concluded that 3-D ultrasonography is useful for the detection of IUD malposition and could be considered as part of ongoing IUD care, if symptoms of pain or bleeding occur.¹⁸

Continue to: IUD malposition following postplacental insertion...

IUD malposition following postplacental insertion

IUD malposition is common in patients who have had a postplacental insertion. Ultrasound imaging plays an important role in detecting IUD expulsion and malposition in these cases. Postplacental IUD insertion is defined as the placement of an IUD within 10 minutes following delivery of the placenta. Postplacental IUD insertion can be performed following a vaginal or cesarean birth and with a Cu-IUD or LNG-IUD. The good news is that postplacental IUD insertion reduces the risk of unplanned pregnancy in the years following birth. However, postplacental IUD insertion is associated with a high rate of IUD malposition.

In a study of 162 patients who had postplacental insertion of a Cu-IUD following a vaginal birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 8%, partial expulsion in 16%, and malposition in 15%.²⁰ The IUD was correctly sited in 56% of patients. Seven patients (4%) had the IUD removed, and 1 patient had a perforated IUD. Among the 25 malpositioned IUDs, 14 were not within 1 cm of the fundus, and 11 were rotated outside of the axis of the cornuas. In this study partial expulsion was defined as an IUD protruding from the external cervical os on physical exam or demonstration of the distal tip of the IUD below the internal os of the cervix on ultrasound. Malposition was defined as an IUD that was >1 cm from the fundus or in an abnormal location or axis, but not partially expelled.

In a study of 69 patients who had postplacental insertion of a Cu-IUD following a cesarean birth, ultrasound and physical examination at 6 months demonstrated complete IUD expulsion in 3%, partial expulsion (stem in the cervix below the internal os) in 4% and malposition in 30%.²⁰ The IUD was correctly positioned in 59% of the patients.²¹ The IUD had been electively removed in 3%. Among the 21 patients with a malpositioned IUD, 10 were rotated within the uterine cavity, 6 were inverted (upside down), 3 were low-lying, and 2 were transverse.²¹ Given the relatively high rate of IUD malposition following postplacental insertion, it may be useful to perform a pelvic ultrasound at a postpartum visit to assess the location of the IUD, if ultrasonography is available.

Management of the malpositioned IUD

There are no consensus guidelines on how to care for a patient with a malpositioned IUD. Clinicians need to use their best judgment and engage the patient in joint decision making when managing a malpositioned IUD. When an IUD is malpositioned and the patient has bothersome symptoms of pelvic pain or abnormal bleeding that have not responded to standard interventions, consideration may be given to a remove and replace strategy. When the stem of the IUD is below the level of the internal os on ultrasound or visible at the external os on physical examination, consideration should be given to removing and replacing the IUD. However, if the IUD is removed without replacement or the initiation of a highly reliable contraceptive, the risk of unplanned pregnancy is considerable.^16,19

IUD totally or partially within the cervix or low-lying. When an IUD is in the cervix, the contraceptive efficacy of the IUD may be diminished, especially with a Cu-IUD.²² In these cases, removing and replacing the IUD is an option. In a survey of 20 expert clinicians, >80% recommended replacing an IUD that was totally or partially in the cervical canal.²³ But most of the experts would not replace an IUD that was incidentally noted on ultrasound to be low-lying, being positioned more than 2 cm below the fundus, with no portion of the IUD in the cervical canal. In the same survey, for patients with a low-lying IUD and pelvic pain or bleeding, the majority of experts reported that they would explore other causes of bleeding and pelvic pain not related to the IUD itself and not replace the IUD, but 30% of the experts reported that they would remove and replace the device.²³

IUD embedded in the myometrium with pelvic pain. Based on my clinical experience, when a patient has persistent pelvic pain following the insertion of an IUD and the pain does not resolve with standard measures including medication, an ultrasound study is warranted to assess the position of the IUD. If the ultrasound demonstrates that an arm of the IUD is embedded in the myometrium, removal of the IUD may be associated with resolution of the pain. Reinsertion of an IUD under ultrasound guidance may result in a correctly-sited IUD with no recurrence of pelvic pain.

IUD rotated within the uterus with no pain or abnormal bleeding. For an IUD that is near the fundus and rotated on its axis within the uterus, if the patient has no symptoms of pain or abnormal bleeding, my recommendation to the patient would be to leave the device in situ.

Without available guidelines, engage in clinician-patient discussion

It is clear that IUD malposition is common, occurring in 10% to 20% of patients with an IUD. High-quality ultrasound imaging is helpful in detecting IUD malposition, including 2-D ultrasound with videoclips and/or 3-D ultrasound with coronal reconstruction. More data are needed to identify the best options for managing various types of malpositioned IUDs in patients with and without bothersome symptoms such as pain and bleeding. Until consensus guidelines are developed, clinicians need to engage the patient in a discussion of how to best manage the malpositioned IUD. Medicated IUDs and progestin subdermal implants are our two most effective reversible contraceptives. They are among the most important advances in health care over the past half-century. ●

UTIs IN PREGNANCY: MANAGING URETHRITIS, ASYMPTOMATIC BACTERIURIA, CYSTITIS, AND PYELONEPHRITIS

PATRICK DUFF, MD (JANUARY 2022)

Clarification on UTI issues

Regarding the article on urinary tract infections (UTIs) in pregnancy, I have 3 points of clarification. First, in 27 years of practice in which I universally performed screening urine cultures on prenatal patients plus all of those with symptoms, I have seen a total of 2 cultures with Staphylococcus saprophyticus. I see this organism listed in references as a major UTI causative, but is that the case? Second, the clinical case and symptoms discussed are accurate, but costovertebral angle tenderness or fever of 101 °F or higher indicate pyelonephritis and should be treated aggressively. Many of these patients will have nausea and vomiting and will be dehydrated. This decreases urine flow, allowing progressive bacterial growth in renal parenchyma. An initial bolus of intravenous fluids, at least 2 L wide open through a large-bore catheter, rapidly decreases fever, flushes the urinary tract, and improves nausea, headaches, and malaise. Finally, nitrofurantoin is excreted in the urine so rapidly that it does not achieve adequate tissue levels, and it should never be used to treat pyelonephritis or, for that matter, any infection other than uncomplicated cystitis/urethritis.

David Janowitz, MD

Houston, Texas

Dr. Duff responds

I appreciate Dr. Janowitz’s interest and thoughtful comments. The patient presented in the case study has acute cystitis, characterized by a low-grade fever, suprapubic pain, dysuria, frequency, and hesitancy. Patients with pyelonephritis typically have a higher fever and significant costovertebral angle pain and tenderness. I agree completely with Dr. Janowitz’s observations about the seriousness of pyelonephritis in pregnancy. Pyelonephritis is an important cause of preterm labor, bacteremia, and even septic shock. As I point out in the article, women with moderate to severe kidney infections should be hospitalized and treated with intravenous fluids, antipyretics, antiemetics, and intravenous antibiotics. My usual recommendation is ceftriaxone. Intravenous antibiotics should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. Once patients improve, they can be transitioned to oral antibiotics to complete a 10-day course of therapy. Again, I agree with Dr. Janowitz’s statement that nitrofurantoin is not an appropriate drug for treatment of pyelonephritis because it does not reach acceptable concentrations in either the blood or the renal parenchyma. Rather, amoxicillin-clavulanate and trimethoprim-sulfamethoxazole are much better choices for oral therapy. However, once the infection is cleared, nitrofurantoin is an excellent agent for suppression of recurrent infection.

Finally, there is no doubt that the principal pathogens that cause UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, and Proteus species. However, 3 aerobic Gram-positive cocci do, in fact, cause a small percentage of infections: group B streptococci, enterococci, and Staphylococcus saprophyticus. When the latter bacterium is identified as a single organism in high colony count, particularly in a catheterized urine specimen, it should be considered a true pathogen and not simply a contaminant.

CAN WE RETURN TO THE ABCs OF CRAFTING A MEDICAL RECORD NOTE?

ROBERT L. BARBIERI, MD (OCTOBER 2021)

Another suggestion for reducing note bloat in the EMR

Thank you for picking up a topic that is important for all physicians and one that has been annoying me since the introduction of electronic medical records (EMRs). I like the APSO approach, that works well. My idea for reducing “note bloat” is to eliminate all normal and routine findings and to hide them behind a hyperlink or behind a QR code. This would give you a truly short note and, should you need or want more details, you could always scan the QR code for access to the complete (and bloated) note. I would also recommend hiding all details that do not contribute to the immediate pressing issue at hand (for example, routine depression screening) behind a hyperlink or QR code. The same principle should apply to sending faxes to other physicians’ offices. I “love” receiving a chart an inch thick, only to discover that the whole pile of paper could be reduced to a single page of true information. Too few people speak up about this major time and productivity thief. Thank you!

Matthias Muenzer, MD

Rochester, New Hampshire

Dr. Barbieri responds

I thank Dr. Muenzer for his innovative suggestions for improving medical record notes. We spend many hours per week crafting notes in the medical record. Yet, very little attention is given to the development of best practices for improving the value and effectiveness of our notes for our patients and colleagues.

UTIs IN PREGNANCY: MANAGING URETHRITIS, ASYMPTOMATIC BACTERIURIA, CYSTITIS, AND PYELONEPHRITIS

PATRICK DUFF, MD (JANUARY 2022)

Clarification on UTI issues

Regarding the article on urinary tract infections (UTIs) in pregnancy, I have 3 points of clarification. First, in 27 years of practice in which I universally performed screening urine cultures on prenatal patients plus all of those with symptoms, I have seen a total of 2 cultures with Staphylococcus saprophyticus. I see this organism listed in references as a major UTI causative, but is that the case? Second, the clinical case and symptoms discussed are accurate, but costovertebral angle tenderness or fever of 101 °F or higher indicate pyelonephritis and should be treated aggressively. Many of these patients will have nausea and vomiting and will be dehydrated. This decreases urine flow, allowing progressive bacterial growth in renal parenchyma. An initial bolus of intravenous fluids, at least 2 L wide open through a large-bore catheter, rapidly decreases fever, flushes the urinary tract, and improves nausea, headaches, and malaise. Finally, nitrofurantoin is excreted in the urine so rapidly that it does not achieve adequate tissue levels, and it should never be used to treat pyelonephritis or, for that matter, any infection other than uncomplicated cystitis/urethritis.

David Janowitz, MD

Houston, Texas

Dr. Duff responds

I appreciate Dr. Janowitz’s interest and thoughtful comments. The patient presented in the case study has acute cystitis, characterized by a low-grade fever, suprapubic pain, dysuria, frequency, and hesitancy. Patients with pyelonephritis typically have a higher fever and significant costovertebral angle pain and tenderness. I agree completely with Dr. Janowitz’s observations about the seriousness of pyelonephritis in pregnancy. Pyelonephritis is an important cause of preterm labor, bacteremia, and even septic shock. As I point out in the article, women with moderate to severe kidney infections should be hospitalized and treated with intravenous fluids, antipyretics, antiemetics, and intravenous antibiotics. My usual recommendation is ceftriaxone. Intravenous antibiotics should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. Once patients improve, they can be transitioned to oral antibiotics to complete a 10-day course of therapy. Again, I agree with Dr. Janowitz’s statement that nitrofurantoin is not an appropriate drug for treatment of pyelonephritis because it does not reach acceptable concentrations in either the blood or the renal parenchyma. Rather, amoxicillin-clavulanate and trimethoprim-sulfamethoxazole are much better choices for oral therapy. However, once the infection is cleared, nitrofurantoin is an excellent agent for suppression of recurrent infection.

Finally, there is no doubt that the principal pathogens that cause UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, and Proteus species. However, 3 aerobic Gram-positive cocci do, in fact, cause a small percentage of infections: group B streptococci, enterococci, and Staphylococcus saprophyticus. When the latter bacterium is identified as a single organism in high colony count, particularly in a catheterized urine specimen, it should be considered a true pathogen and not simply a contaminant.

CAN WE RETURN TO THE ABCs OF CRAFTING A MEDICAL RECORD NOTE?

ROBERT L. BARBIERI, MD (OCTOBER 2021)

Another suggestion for reducing note bloat in the EMR

Thank you for picking up a topic that is important for all physicians and one that has been annoying me since the introduction of electronic medical records (EMRs). I like the APSO approach, that works well. My idea for reducing “note bloat” is to eliminate all normal and routine findings and to hide them behind a hyperlink or behind a QR code. This would give you a truly short note and, should you need or want more details, you could always scan the QR code for access to the complete (and bloated) note. I would also recommend hiding all details that do not contribute to the immediate pressing issue at hand (for example, routine depression screening) behind a hyperlink or QR code. The same principle should apply to sending faxes to other physicians’ offices. I “love” receiving a chart an inch thick, only to discover that the whole pile of paper could be reduced to a single page of true information. Too few people speak up about this major time and productivity thief. Thank you!

Matthias Muenzer, MD

Rochester, New Hampshire

Dr. Barbieri responds

I thank Dr. Muenzer for his innovative suggestions for improving medical record notes. We spend many hours per week crafting notes in the medical record. Yet, very little attention is given to the development of best practices for improving the value and effectiveness of our notes for our patients and colleagues.

UTIs IN PREGNANCY: MANAGING URETHRITIS, ASYMPTOMATIC BACTERIURIA, CYSTITIS, AND PYELONEPHRITIS

PATRICK DUFF, MD (JANUARY 2022)

Clarification on UTI issues

Regarding the article on urinary tract infections (UTIs) in pregnancy, I have 3 points of clarification. First, in 27 years of practice in which I universally performed screening urine cultures on prenatal patients plus all of those with symptoms, I have seen a total of 2 cultures with Staphylococcus saprophyticus. I see this organism listed in references as a major UTI causative, but is that the case? Second, the clinical case and symptoms discussed are accurate, but costovertebral angle tenderness or fever of 101 °F or higher indicate pyelonephritis and should be treated aggressively. Many of these patients will have nausea and vomiting and will be dehydrated. This decreases urine flow, allowing progressive bacterial growth in renal parenchyma. An initial bolus of intravenous fluids, at least 2 L wide open through a large-bore catheter, rapidly decreases fever, flushes the urinary tract, and improves nausea, headaches, and malaise. Finally, nitrofurantoin is excreted in the urine so rapidly that it does not achieve adequate tissue levels, and it should never be used to treat pyelonephritis or, for that matter, any infection other than uncomplicated cystitis/urethritis.

David Janowitz, MD

Houston, Texas

Dr. Duff responds

I appreciate Dr. Janowitz’s interest and thoughtful comments. The patient presented in the case study has acute cystitis, characterized by a low-grade fever, suprapubic pain, dysuria, frequency, and hesitancy. Patients with pyelonephritis typically have a higher fever and significant costovertebral angle pain and tenderness. I agree completely with Dr. Janowitz’s observations about the seriousness of pyelonephritis in pregnancy. Pyelonephritis is an important cause of preterm labor, bacteremia, and even septic shock. As I point out in the article, women with moderate to severe kidney infections should be hospitalized and treated with intravenous fluids, antipyretics, antiemetics, and intravenous antibiotics. My usual recommendation is ceftriaxone. Intravenous antibiotics should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. Once patients improve, they can be transitioned to oral antibiotics to complete a 10-day course of therapy. Again, I agree with Dr. Janowitz’s statement that nitrofurantoin is not an appropriate drug for treatment of pyelonephritis because it does not reach acceptable concentrations in either the blood or the renal parenchyma. Rather, amoxicillin-clavulanate and trimethoprim-sulfamethoxazole are much better choices for oral therapy. However, once the infection is cleared, nitrofurantoin is an excellent agent for suppression of recurrent infection.

Finally, there is no doubt that the principal pathogens that cause UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, and Proteus species. However, 3 aerobic Gram-positive cocci do, in fact, cause a small percentage of infections: group B streptococci, enterococci, and Staphylococcus saprophyticus. When the latter bacterium is identified as a single organism in high colony count, particularly in a catheterized urine specimen, it should be considered a true pathogen and not simply a contaminant.

CAN WE RETURN TO THE ABCs OF CRAFTING A MEDICAL RECORD NOTE?

ROBERT L. BARBIERI, MD (OCTOBER 2021)

Another suggestion for reducing note bloat in the EMR

Thank you for picking up a topic that is important for all physicians and one that has been annoying me since the introduction of electronic medical records (EMRs). I like the APSO approach, that works well. My idea for reducing “note bloat” is to eliminate all normal and routine findings and to hide them behind a hyperlink or behind a QR code. This would give you a truly short note and, should you need or want more details, you could always scan the QR code for access to the complete (and bloated) note. I would also recommend hiding all details that do not contribute to the immediate pressing issue at hand (for example, routine depression screening) behind a hyperlink or QR code. The same principle should apply to sending faxes to other physicians’ offices. I “love” receiving a chart an inch thick, only to discover that the whole pile of paper could be reduced to a single page of true information. Too few people speak up about this major time and productivity thief. Thank you!

Matthias Muenzer, MD

Rochester, New Hampshire

Dr. Barbieri responds

I thank Dr. Muenzer for his innovative suggestions for improving medical record notes. We spend many hours per week crafting notes in the medical record. Yet, very little attention is given to the development of best practices for improving the value and effectiveness of our notes for our patients and colleagues.

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●