OBG Management

Updated option for breast biopsy

Hologic announces updates to its Brevera^® Breast Biopsy System with CorLumina^® Imaging Technology. The Brevera system is designed for use with the manufacturer’s Affirm^® Prone biopsy guidance system. 

For more information, visit https://www.hologic.com.

“Mini-sponge” device shows potential to treat PPH

During a pilot study, reports Obstetrx, 9 patients, treated at the University Teaching Hospital in Lusaka, Zambia, did not respond to conventional PPH management options after vaginal birth but did respond, with bleeding resolved in 60 seconds and no adverse events, to the XSTAT device. The device was left in place for a mean time of 1 hour, and none of the patients required further surgical procedures or blood transfusions. The initial placement time of XSTAT (mean time to placement, 62 seconds) was faster than times reported for balloon uterine tamponade devices. The pilot study results were published in Obstetrics & Gynecology.

XSTAT is US Food and Drug Administration–approved to treat high-flow arterial bleeding in prehospital trauma settings, and Obstetrx is planning to submit for 510k clearance in 2022, after the conclusion of a follow-up PPH trial in 2021.

For more information, visit: https://www.obstetrx.com/.

Continue to: AI and ovulation prediction...

A woman’s fertility window is typically the 5 days leading up to ovulation, with peak fertility in the 2 to 3 days before ovulation. There are other options for measuring that fertile window, including luteinizing hormone (LH) tests; however, Prima-Temp reports that Priya predicts the fertile window an average of 2.6 days before tests for LH. Utilizing continuous core body temperature measurement, Priya detects subtle changes in temperature patterns that occur prior to ovulation. The app portion of the technology stores and analyzes the temperature measurements, for a high-tech fertility alert system that also offers clinical diagnostic support. Potential users of the Priya system are able to sign up to receive it through the product’s website.

For more information, visit: https://www.priyafertility.com.

Updated option for breast biopsy

Hologic announces updates to its Brevera^® Breast Biopsy System with CorLumina^® Imaging Technology. The Brevera system is designed for use with the manufacturer’s Affirm^® Prone biopsy guidance system. 

For more information, visit https://www.hologic.com.

“Mini-sponge” device shows potential to treat PPH

During a pilot study, reports Obstetrx, 9 patients, treated at the University Teaching Hospital in Lusaka, Zambia, did not respond to conventional PPH management options after vaginal birth but did respond, with bleeding resolved in 60 seconds and no adverse events, to the XSTAT device. The device was left in place for a mean time of 1 hour, and none of the patients required further surgical procedures or blood transfusions. The initial placement time of XSTAT (mean time to placement, 62 seconds) was faster than times reported for balloon uterine tamponade devices. The pilot study results were published in Obstetrics & Gynecology.

XSTAT is US Food and Drug Administration–approved to treat high-flow arterial bleeding in prehospital trauma settings, and Obstetrx is planning to submit for 510k clearance in 2022, after the conclusion of a follow-up PPH trial in 2021.

For more information, visit: https://www.obstetrx.com/.

Continue to: AI and ovulation prediction...

A woman’s fertility window is typically the 5 days leading up to ovulation, with peak fertility in the 2 to 3 days before ovulation. There are other options for measuring that fertile window, including luteinizing hormone (LH) tests; however, Prima-Temp reports that Priya predicts the fertile window an average of 2.6 days before tests for LH. Utilizing continuous core body temperature measurement, Priya detects subtle changes in temperature patterns that occur prior to ovulation. The app portion of the technology stores and analyzes the temperature measurements, for a high-tech fertility alert system that also offers clinical diagnostic support. Potential users of the Priya system are able to sign up to receive it through the product’s website.

For more information, visit: https://www.priyafertility.com.

Updated option for breast biopsy

Hologic announces updates to its Brevera^® Breast Biopsy System with CorLumina^® Imaging Technology. The Brevera system is designed for use with the manufacturer’s Affirm^® Prone biopsy guidance system. 

For more information, visit https://www.hologic.com.

“Mini-sponge” device shows potential to treat PPH

During a pilot study, reports Obstetrx, 9 patients, treated at the University Teaching Hospital in Lusaka, Zambia, did not respond to conventional PPH management options after vaginal birth but did respond, with bleeding resolved in 60 seconds and no adverse events, to the XSTAT device. The device was left in place for a mean time of 1 hour, and none of the patients required further surgical procedures or blood transfusions. The initial placement time of XSTAT (mean time to placement, 62 seconds) was faster than times reported for balloon uterine tamponade devices. The pilot study results were published in Obstetrics & Gynecology.

XSTAT is US Food and Drug Administration–approved to treat high-flow arterial bleeding in prehospital trauma settings, and Obstetrx is planning to submit for 510k clearance in 2022, after the conclusion of a follow-up PPH trial in 2021.

For more information, visit: https://www.obstetrx.com/.

Continue to: AI and ovulation prediction...

A woman’s fertility window is typically the 5 days leading up to ovulation, with peak fertility in the 2 to 3 days before ovulation. There are other options for measuring that fertile window, including luteinizing hormone (LH) tests; however, Prima-Temp reports that Priya predicts the fertile window an average of 2.6 days before tests for LH. Utilizing continuous core body temperature measurement, Priya detects subtle changes in temperature patterns that occur prior to ovulation. The app portion of the technology stores and analyzes the temperature measurements, for a high-tech fertility alert system that also offers clinical diagnostic support. Potential users of the Priya system are able to sign up to receive it through the product’s website.

For more information, visit: https://www.priyafertility.com.

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

In their column, “Physician leadership: Racial disparities and racism. Where do we go from here?” (August 2020), Biftu Mengesha, MD, MAS; Kavita Shah Arora, MD, MBE, MS; and Barbara Levy, MD, stated that, “The COVID-19 pandemic…has highlighted the continued poor outcomes our health and health care systems create for Black, Indigenous, and Latinx communities.” They implored readers to “advocate as physicians and leaders in our settings for every policy, practice, and procedure to be scrutinized using an antiracist lens” and set out action items for doing so. OBG Management followed up with a poll for readers: “Should institutions implement implicit bias training and policies for inclusion and diversity to address health care inequities?”

In their column, “Physician leadership: Racial disparities and racism. Where do we go from here?” (August 2020), Biftu Mengesha, MD, MAS; Kavita Shah Arora, MD, MBE, MS; and Barbara Levy, MD, stated that, “The COVID-19 pandemic…has highlighted the continued poor outcomes our health and health care systems create for Black, Indigenous, and Latinx communities.” They implored readers to “advocate as physicians and leaders in our settings for every policy, practice, and procedure to be scrutinized using an antiracist lens” and set out action items for doing so. OBG Management followed up with a poll for readers: “Should institutions implement implicit bias training and policies for inclusion and diversity to address health care inequities?”

In their column, “Physician leadership: Racial disparities and racism. Where do we go from here?” (August 2020), Biftu Mengesha, MD, MAS; Kavita Shah Arora, MD, MBE, MS; and Barbara Levy, MD, stated that, “The COVID-19 pandemic…has highlighted the continued poor outcomes our health and health care systems create for Black, Indigenous, and Latinx communities.” They implored readers to “advocate as physicians and leaders in our settings for every policy, practice, and procedure to be scrutinized using an antiracist lens” and set out action items for doing so. OBG Management followed up with a poll for readers: “Should institutions implement implicit bias training and policies for inclusion and diversity to address health care inequities?”

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

In Part 1 of this article in the December 2020 issue of OBG Management, I discussed the reasons that pessaries are an effective treatment option for many women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI) and provided details on the types of pessaries available.

In this article, I highlight the steps in fitting a pessary, pessary aftercare, and potential complications associated with pessary use. In addition, I discuss the effectiveness of pessary treatment for POP and SUI as well as for preterm labor prevention and defecatory disorders.

The pessary fitting process

For a given patient, the best size pessary is the smallest one that will not fall out. The only “rule” for fitting a pessary is that a woman’s internal vaginal caliber should be wider than her introitus.

When fitting a pessary, goals include that the selected pessary:

• should be comfortable for the patient to wear
• is not easily expelled
• does not interfere with urination or defecation
• does not cause vaginal irritation.

The presence or absence of a cervix or uterus does not affect pessary choice.

Most experts agree that the process for fitting the right size pessary is one of trial and error. As with fitting a contraceptive diaphragm, the clinician should perform a manual examination to estimate the integrity and width of the perineum and the depth of the vagina to roughly approximate the pessary size that might best fit. Using a set of “fitting pessaries,” a pessary of the estimated size should be placed into the vagina and the fit evaluated as to whether the device is too big, too small, or appropriate. If the pessary is easily expelled, larger sizes should be tried until the pessary remains in place or the patient is uncomfortable. Once the pessary is in place, the clinician should be able to run his or her finger around the entire pessary; if this is not possible, the pessary is too tight. In addition, the pessary should remain more than one finger breadth above the introitus when the patient is standing or bearing down.

Since many patients who require a pessary are elderly, their perineal skin and vaginal mucosa may be atrophic and fragile. Inserting a pessary can be uncomfortable and can cause abrasions or tears. Successfully fitting a pessary may require extra care under these circumstances. The following steps may help alleviate these difficulties:

• Explain the fitting process to the patient in detail.
• Employ lubrication liberally.
• Enlarge the introitus by applying gentle digital pressure on the posterior fourchette.
• Apply 2% lidocaine ointment several minutes prior to pessary fitting to help decrease patient discomfort.
• Treat the patient for several weeks with vaginal estrogen cream before attempting to fit a pessary if severe vulvovaginal atrophy is present.

Once the type and size of the pessary are selected and a pessary is inserted, evaluate the patient with the pessary in place. Assess for the following:

Discomfort. Ask the patient if she feels discomfort with the pessary in position. A patient with a properly fitting pessary should not feel that it is in place. If she does feel discomfort initially, the discomfort will only increase with time and the issue should be addressed at that time.

Expulsion. Test to make certain that the pessary is not easily expelled from the vagina. Have the patient walk, cough, squat, and even jump if possible.

Urination. Have the patient urinate with the pessary in place. This tests for her ability to void while wearing the pessary and shows whether the contraction of pelvic muscles during voiding results in expulsion of the pessary. (Experience shows that it is best to do this with a plastic “hat” over the toilet so that if the pessary is expelled, it does not drop into the bowl.)

Re-examination. After these provocative tests, examine the patient again to ensure that the pessary has not slid out of place.

Depending on whether or not your office stocks pessaries, at this point the patient is either given the correct type and size of pessary or it is ordered for her. If the former, the patient should try placing it herself; if she is unable to, the clinician should place it for her. In either event, its position should be checked. If the pessary has to be ordered, the patient must schedule an appointment to return for pessary insertion.

Whether the pessary is supplied by the office or ordered, instruct the patient on how to insert and remove the pessary, how frequently to remove it for cleansing (see below), and signs to watch for, such as vaginal bleeding, inability to void or defecate, or pelvic pain.

It is advisable to schedule a subsequent visit for 2 to 3 weeks after initial pessary placement to assess how the patient is doing and to address any issues that have developed.

Continue to: Special circumstances...

It is safe for a patient with a pessary in place to undergo magnetic resonance imaging.¹ Patients should be informed, however, that full body scans, such as at airports, will detect pessaries. Patients may need to obtain a physician’s note to document that the pessary is a medical device.

Finally, several factors may prevent successful pessary fitting. These include prior pelvic surgery, obesity, short vaginal length (less than 6–7 cm), and a vaginal introitus width of greater than 4 finger breadths.

Necessary pessary aftercare

Once a pessary is in place and the patient is comfortable with it, the only maintenance necessary is the pessary’s intermittent removal for cleansing and for evaluation of the vaginal mucosa for erosion and ulcerations. How frequently this should be done varies based on the type of pessary, the amount of discharge that a woman produces, whether or not an odor develops after prolonged wearing of the pessary, and whether or not the patient’s vaginal mucosa has been abraded.

The question of timing for pessary cleaning

Although there are many opinions about how often pessaries should be removed and cleaned, no data in the literature support any specific interval. Pessaries that are easily removed by women themselves can be cleaned as frequently as desired, often on a weekly basis. The patient simply removes the pessary, washes it with soap and water, and reinserts it. For pessaries that are difficult to remove (such as the Gellhorn, cube, or donut) or for women who are physically unable to remove their own ring pessary, the clinician should remove and clean the pessary in the office every 3 to 6 months. It has been shown that there is no difference in complications from pessary use with either of these intervals.²

Prior to any vaginal surgical procedure, patients must be instructed to remove their pessary 10 to 14 days beforehand so that the surgeon can see the full extent of prolapse when making decisions about reconstruction and so that any vaginal mucosal erosions or abrasions have time to heal.

Office visits for follow-up care

The pessary “cleaning visit” has several goals, including to:

• see if the pessary is meeting the patient’s needs in terms of resolving symptoms of prolapse and/or restoring urinary continence
• discuss with the patient any problems she may be having, such as pelvic discomfort or pressure, difficulty voiding or defecating, excessive vaginal discharge, or vaginal odor
• check for vaginal mucosal erosion or ulceration; such vaginal lesions often can be prevented by the prophylactic use of either estrogen vaginal cream twice weekly or the continuous use of an estradiol vaginal ring in addition to the pessary
• evaluate the condition of the pessary itself and clean it with soap and water.

Continue to: Potential complications of pessary use...

The most common complications experienced by pessary users are:

Odor or excessive discharge. Bacterial vaginosis (BV) occurs more frequently in women who use pessaries. The symptoms of BV can be minimized—but unfortunately not totally eliminated—by the prophylactic use of antiseptic vaginal creams or gels, such as metronidazole, clindamycin, Trimo-San (oxyquinoline sulfate and sodium lauryl sulfate), and others. Inserting the gel vaginally once a week can significantly reduce discharge and odor.³

Vaginal mucosal erosion and ulceration. These are treated by removing the pessary for 2 weeks during which time estrogen cream is applied daily or an estradiol vaginal ring is put in place. If no resolution occurs after 2 weeks, the nonhealing vaginal mucosa should be biopsied.

Pressure on the rectum or bladder. If the pessary causes significant discomfort or interferes with voiding function, then either a different size or a different type pessary should be tried

Patients may discontinue pessary use for a variety of reasons. Among these are:

• discomfort
• inadequate improvement of POP or incontinence symptoms
• expulsion of the pessary during daily activities
• the patient’s desire for surgery instead
• worsening of urine leakage
• difficulty inserting or removing the pessary
• damage to the vaginal mucosa
• pain during removal of the pessary in the office.

Pessary effectiveness for POP and SUI symptoms

As might be expected with a device that is available in so many forms and is used to treat varied types of POP and SUI, the data concerning the success rates of pessary use vary considerably. These rates depend on the definition of success, that is, complete or partial control of prolapse and/or incontinence; which devices are being evaluated; and the nature and severity of the POP and/or SUI being treated.

That being said, a review of the literature reveals that the rates of prolapse symptom relief vary from 48% to 92% (TABLE 1).^4-13

As for success in relieving symptoms of incontinence, studies show improvements in from 40% to 77% of patients (TABLE 2).^6,8,14-17

In addition, some studies show a 50% improvement in bowel symptoms (urgency, obstruction, and anal incontinence) with the use of a pessary.^9,18

How pessaries compare with surgery

While surgery has the advantage of being a one-time fix with a very high rate of initial success in correcting both POP and incontinence, surgery also has potential drawbacks:

• It is an invasive procedure with the discomfort and risk of complications any surgery entails.
• There is a relatively high rate of prolapse recurrence.
• It exposes the patient to the possibility of mesh erosion if mesh is employed either for POP support or incontinence treatment.

Pessaries, on the other hand, are inexpensive, nonsurgical, removable, and allow for immediate correction of symptoms. Moreover, if the pessary is tried and is found to be unsatisfactory, surgery always can be performed subsequently.

Drawbacks of pessary treatment compared with surgery include the:

• ongoing need to wear an artificial internal device
• need for intermittent pessary removal and cleansing
• inability to have sexual intercourse with certain kinds of pessaries in place
• possible accumulation of vaginal discharge and odor.

Sexual activity and pessaries

Studies by Fernando, Meriwether, and Kuhn concur that for a substantial number of pessary users who are sexually active, both frequency and satisfaction with sexual intercourse are increased.^8,19,20 Kuhn further showed that desire, orgasm, and lubrication improved with the use of pessaries.²⁰ While some types of pessaries do require removal for intercourse, Clemons reported that issues involving sexual activity are not associated with pessary discontinuation.²¹

Using a pessary to predict a surgical outcome

Because a pessary elevates the pelvic organs, supports the vaginal walls, and lifts the bladder and urethra into a position that simulates the results of surgical repair, trial placement of a pessary can be used as a fairly accurate predictive tool to model what pelvic support and continence status will be after a proposed surgical procedure.^22,23 This is especially important because a significant number of patients with POP will have their occult stress incontinence unmasked following a reparative procedure.²⁴ A brief pessary trial prior to surgery, therefore, can be a useful tool for both patient and surgeon.

Continue to: Pessaries for prevention of preterm labor...

Pessaries for prevention of preterm labor

Almost 1 in 10 births in the United States occurs before 37 completed weeks of gestation.²⁵ Obstetricians have long thought that in women at risk for preterm delivery, the use of a pessary might help reduce the pressure of the growing uterus on the cervix and thus help prevent premature cervical dilation. It also has been thought that use of a pessary would be a safer and less invasive alternative to cervical cerclage. Many studies have evaluated the use of pessaries for the prevention of preterm labor with a mixture of positive (TABLE 3)^26-29 and negative results (TABLE 4).^30-33

From these data, it is reasonable to conclude that:

• The final answer concerning the effectiveness or lack thereof of pessary use in preventing preterm delivery is not yet in.
• Any advantage there might be to using pessaries to prevent preterm delivery cannot be too significant if multiple studies show as many negative outcomes as positive ones.

Pessary effectiveness in defecatory disorders

Vaginal birth has the potential to create multiple anatomic injuries in the anus, lower pelvis, and perineum that can affect defecation and bowel control. Tears of the anal sphincter, whether obvious or occult, may heal incompletely or be repaired inadequately.³⁴ Nerve innervation of the perianal and perineal areas can be interrupted or damaged by stretching, tearing, or prolonged compression. Of healthy parous adult women, 7% to 16% admit incontinence of gas or feces.^35,36

In addition, when a rectocele is present, stool in the lower rectum may cause bulging of the anterior rectal wall into the vagina, preventing stool from passing out of the anus. This sometimes requires women to digitally press their posterior vaginal walls during defecation to evacuate stool successfully. The question thus arises as to whether or not pessary placement and subsequent relief of rectoceles might facilitate bowel movements and decrease or eliminate defecatory dysfunction.

As with the issue of pessary use for prevention of preterm delivery, the answer is mixed. For instance, while Brazell¹⁸ showed that there was an overall improvement in bowel symptoms in pessary users, a study by Komesu¹⁰ did not demonstrate improvement.

There is, however, a relatively new device specifically designed to control defecatory problems: the vaginal bowel control system (Eclipse; Pelvalon). The silicon device is placed intravaginally as one does a pessary. After insertion, it is inflated via a valve and syringe. It works by putting pressure on and reversibly closing the lower rectum, thus blocking the uncontrolled passage of stool and gas. It can be worn continuously or intermittently, but it does need to be deflated for normal bowel movements. One trial of this device demonstrated a 50% reduction in incontinence episodes with a patient satisfaction rate of 84% at 3 months.³⁷ This device may well prove to be a valuable nonsurgical approach to the treatment of fecal incontinence. Unfortunately, the device is relatively expensive and usually is not covered by insurance as third-party payers do not consider it to be a pessary (which generally is covered).

Practice management particulars

Useful information on Current Procedural Terminology codes for pessaries, diagnostic codes, and the cost of various pessaries is provided in TABLE 5,³⁸TABLE 6,³⁹ and TABLE 7.^40-42

A contemporary device used since antiquity

Pessaries, considered “old-fashioned” by many gynecologists, are actually a very cost-effective and useful tool for the correction of POP and SUI. It behooves all who provide medical care to women to be familiar with them, to know when they might be useful, and to know how to fit and prescribe them. ●

CASE Unidentified ectopic pregnancy leads to rupture*

A 33-year-old woman (G1 P0010) with 2 positive home pregnancy tests presents to the emergency department (ED) reporting intermittent vaginal bleeding for 3 days. Her last menstrual period was 10 weeks ago, but she reports that her menses are always irregular. She has a history of asymptomatic chlamydia, as well as spontaneous abortion 2 years prior. At present, she denies abdominal pain or vaginal discharge.

Upon examination her vital signs are: temperature, 98.3 °F; pulse, 112 bpm, with a resting rate of 16 bpm; blood pressure (BP), 142/91 mm Hg; pulse O2, 99%; height, 4’ 3”; weight, 115 lb. Her labs are: hemoglobin, 12.1 g/dL; hematocrit, 38%; serum human chorionic gonadotropin (hCG) 236 mIU/mL. Upon pelvic examination, no active bleeding is noted. She agrees to be followed up by her gynecologist and is given a prescription for serum hCG in 2 days. She is instructed to return to the ED should she have pain or increased vaginal bleeding.

Three days later, the patient follows up with her gynecologist reporting mild cramping. She notes having had an episode of heavy vaginal bleeding and a “weakly positive” home pregnancy test. Transvaginal ultrasonography notes endometrial thickness 0.59 mm and unremarkable adnexa. A urine pregnancy test performed in the office is positive; urinalysis is positive for nitrites. With the bleeding slowed, the gynecologist’s overall impression is that the patient has undergone complete spontaneous abortion. She prescribes Macrobid for the urinary tract infection. She does not obtain the ED-prescribed serum HCG levels, as she feels, since complete spontaneous abortion has occurred there is no need to obtain a follow-up serum HCG.

Five days later, the patient returns to the ED reporting abdominal pain after eating. Fever and productive cough of 2 days are noted. The patient states that she had a recent miscarriage. The overall impression of the patient’s condition is bronchitis, and it is noted on the patient’s record, “unlikely ectopic pregnancy and pregnancy test may be false positive,” hence a pregnancy test is not ordered. Examination reveals mild suprapubic tenderness with no rebound; no pelvic exam is performed. The patient is instructed to follow up with a health care clinic within a week, and to return to the ED with severe abdominal pain, higher fever, or any new concerning symptoms. A Zithromax Z-pak is prescribed.

Four days later, the patient is brought by ambulance to the ED of the local major medical center with severe abdominal pain involving the right lower quadrant. She states that she had a miscarriage 3 weeks prior and was recently treated for bronchitis. She has dizziness when standing. Her vital signs are: temperature, 97.8 °F; heart rate, 95 bpm; BP, 72/48 mm Hg; pulse O2, 100%. She reports her abdominal pain to be 6/10.

The patient is given a Lactated Ringer’s bolus of 1,000 mL for a hypotensive episode. Computed tomography is obtained and notes, “low attenuation in the left adnexa with a dilated fallopian tube.” A large heterogeneous collection of fluid in the pelvis is noted with active extravasation, consistent with an “acute bleed.”

The patient is brought to the operating room with a diagnosis of probable ruptured ectopic pregnancy. Intraoperatively she is noted to have a right ruptured ectopic and left tubo-ovarian abscess. The surgeon proceeds with right salpingectomy and left salpingo-oophorectomy. Three liters of hemoperitoneum is found.

She is followed postoperatively with serum hCG until levels are negative. Her postoperative course is uneventful. Her only future option for pregnancy is through assisted reproductive technology (ART) with in vitro fertilization (IVF). The patient sues the gynecologist and second ED physician for presumed inappropriate assessment for ectopic pregnancy.

*The “facts” of this case are a composite, drawn from several cases to illustrate medical and legal issues. The statement of facts should be considered hypothetical.

Continue to: WHAT’S THE VERDICT?...

WHAT’S THE VERDICT?

A defense verdict is returned.

Medical considerations

The incidence of ectopic pregnancy is 2% of all pregnancies, with a higher incidence (about 4%) among infertility patients.¹ Up to 10% of ectopic pregnancies have no symptoms.²

Clinical presentations. Classic signs of ectopic pregnancy include:

• abdominal pain
• vaginal bleeding
• late menses (often noted).

A recent case of ectopic pregnancy presenting with chest pain was reported.³ Clinicians must never lose site of the fact that ectopic pregnancy is the most common cause of maternal mortality in the first trimester, with an incidence of 1% to 10% of all first-trimester deaths.⁴

Risk factors include pelvic inflammatory disease, as demonstrated in the opening case. “The silent epidemic of chlamydia” comes to mind, and tobacco smoking can adversely affect tubal cilia, as can pelvic adhesions and/or prior tubal surgery. All of these factors can predispose a patient to ectopic pregnancy; in addition, intrauterine devices, endometriosis, tubal ligation (or ligation reversal), all can set the stage for an ectopic pregnancy.⁵ Appropriate serum hCG monitoring during early pregnancy can assist in sorting out pregnancies of unknown location (PUL; FIGURE). First trimester ultrasonography, at 5 weeks gestation, usually identifies early intrauterine gestation.

Heterotopic pregnancy includes an intrauterine gestation and an ectopic pregnancy. This presentation includes the presence of a “pseudosac” in the endometrial cavity plus an extrauterine gestation. Heterotopic pregnancies have become somewhat more common as ART/IVF has unfolded, especially prior to the predominance of single embryo transfer.

Managing ectopic pregnancy

For cases of early pregnancy complicated by intermittent bleeding and/or pain, monitoring with serum hCG levels at 48-hour intervals to distinguish a viable IUP from an abnormal IUP or an ectopic is appropriate. The “discriminatory zone” collates serum hCG levels with findings on ultrasonography. Specific lower limits of serum hCG levels are not clear cut, with recommendations of 3,500 mIU/mL to provide sonographic evidence of an intrauterine gestation “to avoid misdiagnosis and possible interruption of intrauterine pregnancy,” as conveyed in the American College of Obstetricians and Gynecologists 2018 practice bulletin.⁸ Serum progesterone levels also have been suggested to complement hCG levels; a progesterone level of <20 nmol/L is consistent with an abnormal pregnancy, whereas levels >25 nmol/L are suggestive of a viable pregnancy.² Inhibin A levels also have been suggested to be helpful, but they are not an ideal monitoring tool.

While most ectopic pregnancies are located in the fallopian tube, other locations also can be abdominal or ovarian. In addition, cesarean scar ectopic pregnancy can occur and often is associated with delay in diagnosis and greater morbidity due to such delay.⁹ With regard to ovarian ectopic, Spiegelberg criteria are established for diagnosis (TABLE 1).¹⁰

Appropriate management of an ectopic pregnancy is dependent upon the gestational age, serum hCG levels, and imaging findings, as well as the patient’s symptoms and exam findings. Treatment is established in large part on a case-by-case basis and includes, for early pregnancy, expectant management and use of methotrexate (TABLE 2).¹¹ Dilation and curettage may be used to identify the pregnancy’s location when the serum hCG level is below 2,000 mIU/mL and there is no evidence of an IUP on ultrasound. Surgical treatment can include minimally invasive salpingostomy or salpingectomy and, depending on circumstance, laparotomy may be indicated.

Continue to: Legal perspective...

Legal perspective

Lawsuits related to ectopic pregnancy are not a new phenomenon. In fact, in 1897, a physician in Ohio who misdiagnosed an “extrauterine pregnancy” as appendicitis was the center of a malpractice lawsuit.¹³ Unrecognized or mishandled ectopic pregnancy can result in serious injuries—in the range of 1% to 10% (see above) of maternal deaths are related to ectopic pregnancy.¹⁴ Ectopic pregnancy cases, therefore, have been the subject of substantial litigation over the years. An informal, noncomprehensive review of malpractice lawsuits brought from 2000 to 2019, found more than 300 ectopic pregnancy cases. Given the large number of malpractice claims against ObGyns,¹⁵ ectopic pregnancy cases are only a small portion of all ObGyn malpractice cases.¹⁶

A common claim: negligent diagnosis or treatment

The most common basis for lawsuits in cases of ectopic pregnancy is the clinician’s negligent failure to properly diagnose the ectopic nature of the pregnancy. There are also a number of cases claiming negligent treatment of an identified ectopic pregnancy. Not every missed diagnosis, or unsuccessful treatment, leads to liability, of course. It is only when a diagnosis or treatment fails to meet the standard of care within the profession that there should be liability. That standard of care is generally defined by what a reasonably prudent physician would do under the circumstances. Expert witnesses, who are familiar with the standard of practice within the specialty, are usually necessary to establish what that practice is. Both the plaintiff and the defense obtain experts, the former to prove what the standard of care is and that the standard was not met in the case at hand. The defense experts are usually arguing that the standard of care was met.¹⁷ Inadequate diagnosis of ectopic pregnancy or other condition may arise from a failure to take a sufficient history, conduct an appropriately thorough physical examination, recognize any of the symptoms that would suggest it is present, use and conduct ultrasound correctly, or follow-up appropriately with additional testing.¹⁸

A malpractice claim of negligent treatment can involve any the following circumstances¹⁹:

• failure to establish an appropriate treatment plan
• prescribing inappropriate medications for the patient (eg, methotrexate, when it is contraindicated)
• delivering the wrong medication or the wrong amount of the right medication
• performing a procedure badly
• undertaking a new treatment without adequate instruction and preparation.

Given the nature and risks of ectopic pregnancy, ongoing, frequent contact with the patient is essential from the point at which the condition is suspected. The greater the risk of harm (probability or consequence), the more careful any professional ought to be. Because ectopic pregnancy is not an uncommon occurrence, and because it can have devastating effects, including death, a reasonably prudent practitioner would be especially aware of the clinical presentations discussed above.²⁰ In the opening case, the treatment plan was not well documented.

Negligence must lead to patient harm. In addition to negligence (proving that the physician did not act in accordance with the standard of care), to prevail in a malpractice case, the plaintiff-patient must prove that the negligence caused the injury, or worsened it. If the failure to make a diagnosis would not have made any difference in a harm the patient suffered, there are no damages and no liability. Suppose, for example, that a physician negligently failed to diagnose ectopic pregnancy, but performed surgery expecting to find the misdiagnosed condition. In the course of the surgery, however, the surgeon discovered and appropriately treated the ectopic pregnancy. (A version of this happened in the old 19th century case mentioned above.) The negligence of the physician did not cause harm, so there are no damages and no liability.

Continue to: Informed consent is vital...

Informed consent is vital

A part of malpractice is informed consent (or the absence of it)—issues that can arise in any medical care.²¹ It is wise to pay particular attention in cases where the nature of the illness is unknown, and where there are significant uncertainties and the nature of testing and treatment may change substantially over a period of a few days or few weeks. As always, informed consent should include a discussion of what process or procedure is proposed, its risks and benefits, alternative approaches that might be available, and the risk of doing nothing. Frequently, the uncertainty of ectopic pregnancy complicates the informed consent process.²²

Because communication with the patient is an essential function of informed consent, the consent process should productively be used in PUL and similar cases to inform the patient about the uncertainty, and the testing and (nonsurgical) treatment that will occur. This is an opportunity to reinforce the message that the patient must maintain ongoing communication with the physician’s office about changes in her condition, and appear for each appointment scheduled. If more invasive procedures—notably surgery—become required, a separate consent process should be completed, because the risks and considerations are now meaningfully different than when treatment began. As a general matter, any possible treatment that may result in infertility or reduced reproductive capacity should specifically be included in the consent process.

In the hypothetical case, the gynecologist failed to obtain a follow-up serum hCG level. In addition, the record did not reflect ectopic pregnancy in the differential diagnosis. As noted above, the patient had predisposing factors for an ectopic pregnancy. The physician should have acknowledged the history of sexually transmitted disease predisposing her to an ectopic pregnancy. Monitoring of serum hCG levels until they are negative is appropriate with ectopic, or presumed ectopic, pregnancy management. Appropriate monitoring did not occur in this case. Each of these errors (following up on serum hCG levels and the inadequacy of notations about the possibility of ectopic pregnancy) seem inconsistent with the usual standard of care. Furthermore, as a result of the outcome, the only future option for the patient to pursue pregnancy was IVF.

Other legal issues

There are a number of other legal issues that are associated with the topic of ectopic pregnancy. There is evidence, for example, that Catholic and non-Catholic hospitals treat ectopic pregnancies differently,²³ which may reflect different views on taking a life or the use of methotrexate and its association with abortion.²⁴ In addition, the possibility of an increase in future ectopic pregnancies is one of the “risks” of abortion that pro-life organizations have pushed to see included in abortion informed consent.²⁵ This has led some commentators to conclude that some Catholic hospitals violate federal law in managing ectopic pregnancy. There is also evidence of “overwhelming rates of medical misinformation on pregnancy center websites, including a link between abortion and ectopic pregnancy.”²⁶

The fact that cesarean deliveries are related to an increased risk for ectopic pregnancy (because of the risk of cesarean scar ectopic pregnancy) also has been cited as information that should play a role in the consent process for cesarean delivery.²⁷ In terms of liability, failed tubal ligation leads to a 33% risk of ectopic pregnancy.²⁸ The risk of ectopic pregnancy is also commonly included in surrogacy contracts.²⁹

Why the outcome was for the defense

The opening hypothetical case illustrates some of the uncertainties of medical malpractice cases. As noted, there appeared a deviation from the usual standard of care, particularly the failure to follow up on the serum hCG level. The weakness in the medical record, failing to note the possibility of ectopic pregnancy, also was probably an error but, apparently, the court felt that this did not result in any harm to the patient.

The question arises of how there would be a defense verdict in light of the failure to track consecutive serum hCG levels. A speculative explanation is that there are many uncertainties in most lawsuits. Procedural problems may result in a case being limited, expert witnesses are essential to both the plaintiff and defense, with the quality of their review and testimony possibly uneven. Judges and juries may rely on one expert witness rather than another, juries vary, and the quality of advocacy differs. Any of these situations can contribute to the unpredictability of the outcome of a case. In the case above, the liability was somewhat uncertain, and the various other factors tipped in favor of a defense verdict. ●

CASE Unidentified ectopic pregnancy leads to rupture*

A 33-year-old woman (G1 P0010) with 2 positive home pregnancy tests presents to the emergency department (ED) reporting intermittent vaginal bleeding for 3 days. Her last menstrual period was 10 weeks ago, but she reports that her menses are always irregular. She has a history of asymptomatic chlamydia, as well as spontaneous abortion 2 years prior. At present, she denies abdominal pain or vaginal discharge.

Upon examination her vital signs are: temperature, 98.3 °F; pulse, 112 bpm, with a resting rate of 16 bpm; blood pressure (BP), 142/91 mm Hg; pulse O2, 99%; height, 4’ 3”; weight, 115 lb. Her labs are: hemoglobin, 12.1 g/dL; hematocrit, 38%; serum human chorionic gonadotropin (hCG) 236 mIU/mL. Upon pelvic examination, no active bleeding is noted. She agrees to be followed up by her gynecologist and is given a prescription for serum hCG in 2 days. She is instructed to return to the ED should she have pain or increased vaginal bleeding.

Three days later, the patient follows up with her gynecologist reporting mild cramping. She notes having had an episode of heavy vaginal bleeding and a “weakly positive” home pregnancy test. Transvaginal ultrasonography notes endometrial thickness 0.59 mm and unremarkable adnexa. A urine pregnancy test performed in the office is positive; urinalysis is positive for nitrites. With the bleeding slowed, the gynecologist’s overall impression is that the patient has undergone complete spontaneous abortion. She prescribes Macrobid for the urinary tract infection. She does not obtain the ED-prescribed serum HCG levels, as she feels, since complete spontaneous abortion has occurred there is no need to obtain a follow-up serum HCG.

Five days later, the patient returns to the ED reporting abdominal pain after eating. Fever and productive cough of 2 days are noted. The patient states that she had a recent miscarriage. The overall impression of the patient’s condition is bronchitis, and it is noted on the patient’s record, “unlikely ectopic pregnancy and pregnancy test may be false positive,” hence a pregnancy test is not ordered. Examination reveals mild suprapubic tenderness with no rebound; no pelvic exam is performed. The patient is instructed to follow up with a health care clinic within a week, and to return to the ED with severe abdominal pain, higher fever, or any new concerning symptoms. A Zithromax Z-pak is prescribed.

Four days later, the patient is brought by ambulance to the ED of the local major medical center with severe abdominal pain involving the right lower quadrant. She states that she had a miscarriage 3 weeks prior and was recently treated for bronchitis. She has dizziness when standing. Her vital signs are: temperature, 97.8 °F; heart rate, 95 bpm; BP, 72/48 mm Hg; pulse O2, 100%. She reports her abdominal pain to be 6/10.

The patient is given a Lactated Ringer’s bolus of 1,000 mL for a hypotensive episode. Computed tomography is obtained and notes, “low attenuation in the left adnexa with a dilated fallopian tube.” A large heterogeneous collection of fluid in the pelvis is noted with active extravasation, consistent with an “acute bleed.”

The patient is brought to the operating room with a diagnosis of probable ruptured ectopic pregnancy. Intraoperatively she is noted to have a right ruptured ectopic and left tubo-ovarian abscess. The surgeon proceeds with right salpingectomy and left salpingo-oophorectomy. Three liters of hemoperitoneum is found.

She is followed postoperatively with serum hCG until levels are negative. Her postoperative course is uneventful. Her only future option for pregnancy is through assisted reproductive technology (ART) with in vitro fertilization (IVF). The patient sues the gynecologist and second ED physician for presumed inappropriate assessment for ectopic pregnancy.

*The “facts” of this case are a composite, drawn from several cases to illustrate medical and legal issues. The statement of facts should be considered hypothetical.

Continue to: WHAT’S THE VERDICT?...

WHAT’S THE VERDICT?

A defense verdict is returned.

Medical considerations

The incidence of ectopic pregnancy is 2% of all pregnancies, with a higher incidence (about 4%) among infertility patients.¹ Up to 10% of ectopic pregnancies have no symptoms.²

Clinical presentations. Classic signs of ectopic pregnancy include:

• abdominal pain
• vaginal bleeding
• late menses (often noted).

A recent case of ectopic pregnancy presenting with chest pain was reported.³ Clinicians must never lose site of the fact that ectopic pregnancy is the most common cause of maternal mortality in the first trimester, with an incidence of 1% to 10% of all first-trimester deaths.⁴

Risk factors include pelvic inflammatory disease, as demonstrated in the opening case. “The silent epidemic of chlamydia” comes to mind, and tobacco smoking can adversely affect tubal cilia, as can pelvic adhesions and/or prior tubal surgery. All of these factors can predispose a patient to ectopic pregnancy; in addition, intrauterine devices, endometriosis, tubal ligation (or ligation reversal), all can set the stage for an ectopic pregnancy.⁵ Appropriate serum hCG monitoring during early pregnancy can assist in sorting out pregnancies of unknown location (PUL; FIGURE). First trimester ultrasonography, at 5 weeks gestation, usually identifies early intrauterine gestation.

Heterotopic pregnancy includes an intrauterine gestation and an ectopic pregnancy. This presentation includes the presence of a “pseudosac” in the endometrial cavity plus an extrauterine gestation. Heterotopic pregnancies have become somewhat more common as ART/IVF has unfolded, especially prior to the predominance of single embryo transfer.

Managing ectopic pregnancy

For cases of early pregnancy complicated by intermittent bleeding and/or pain, monitoring with serum hCG levels at 48-hour intervals to distinguish a viable IUP from an abnormal IUP or an ectopic is appropriate. The “discriminatory zone” collates serum hCG levels with findings on ultrasonography. Specific lower limits of serum hCG levels are not clear cut, with recommendations of 3,500 mIU/mL to provide sonographic evidence of an intrauterine gestation “to avoid misdiagnosis and possible interruption of intrauterine pregnancy,” as conveyed in the American College of Obstetricians and Gynecologists 2018 practice bulletin.⁸ Serum progesterone levels also have been suggested to complement hCG levels; a progesterone level of <20 nmol/L is consistent with an abnormal pregnancy, whereas levels >25 nmol/L are suggestive of a viable pregnancy.² Inhibin A levels also have been suggested to be helpful, but they are not an ideal monitoring tool.

While most ectopic pregnancies are located in the fallopian tube, other locations also can be abdominal or ovarian. In addition, cesarean scar ectopic pregnancy can occur and often is associated with delay in diagnosis and greater morbidity due to such delay.⁹ With regard to ovarian ectopic, Spiegelberg criteria are established for diagnosis (TABLE 1).¹⁰

Appropriate management of an ectopic pregnancy is dependent upon the gestational age, serum hCG levels, and imaging findings, as well as the patient’s symptoms and exam findings. Treatment is established in large part on a case-by-case basis and includes, for early pregnancy, expectant management and use of methotrexate (TABLE 2).¹¹ Dilation and curettage may be used to identify the pregnancy’s location when the serum hCG level is below 2,000 mIU/mL and there is no evidence of an IUP on ultrasound. Surgical treatment can include minimally invasive salpingostomy or salpingectomy and, depending on circumstance, laparotomy may be indicated.

Continue to: Legal perspective...

Legal perspective

Lawsuits related to ectopic pregnancy are not a new phenomenon. In fact, in 1897, a physician in Ohio who misdiagnosed an “extrauterine pregnancy” as appendicitis was the center of a malpractice lawsuit.¹³ Unrecognized or mishandled ectopic pregnancy can result in serious injuries—in the range of 1% to 10% (see above) of maternal deaths are related to ectopic pregnancy.¹⁴ Ectopic pregnancy cases, therefore, have been the subject of substantial litigation over the years. An informal, noncomprehensive review of malpractice lawsuits brought from 2000 to 2019, found more than 300 ectopic pregnancy cases. Given the large number of malpractice claims against ObGyns,¹⁵ ectopic pregnancy cases are only a small portion of all ObGyn malpractice cases.¹⁶

A common claim: negligent diagnosis or treatment

The most common basis for lawsuits in cases of ectopic pregnancy is the clinician’s negligent failure to properly diagnose the ectopic nature of the pregnancy. There are also a number of cases claiming negligent treatment of an identified ectopic pregnancy. Not every missed diagnosis, or unsuccessful treatment, leads to liability, of course. It is only when a diagnosis or treatment fails to meet the standard of care within the profession that there should be liability. That standard of care is generally defined by what a reasonably prudent physician would do under the circumstances. Expert witnesses, who are familiar with the standard of practice within the specialty, are usually necessary to establish what that practice is. Both the plaintiff and the defense obtain experts, the former to prove what the standard of care is and that the standard was not met in the case at hand. The defense experts are usually arguing that the standard of care was met.¹⁷ Inadequate diagnosis of ectopic pregnancy or other condition may arise from a failure to take a sufficient history, conduct an appropriately thorough physical examination, recognize any of the symptoms that would suggest it is present, use and conduct ultrasound correctly, or follow-up appropriately with additional testing.¹⁸

A malpractice claim of negligent treatment can involve any the following circumstances¹⁹:

• failure to establish an appropriate treatment plan
• prescribing inappropriate medications for the patient (eg, methotrexate, when it is contraindicated)
• delivering the wrong medication or the wrong amount of the right medication
• performing a procedure badly
• undertaking a new treatment without adequate instruction and preparation.

Given the nature and risks of ectopic pregnancy, ongoing, frequent contact with the patient is essential from the point at which the condition is suspected. The greater the risk of harm (probability or consequence), the more careful any professional ought to be. Because ectopic pregnancy is not an uncommon occurrence, and because it can have devastating effects, including death, a reasonably prudent practitioner would be especially aware of the clinical presentations discussed above.²⁰ In the opening case, the treatment plan was not well documented.