Clinical Review

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

VIDEO 1A Liberal use of your nonscanning hand on dynamic scanning shows “wiggling” of debris classic of a hemorrhagic corpus luteum

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VIDEO 1B Liberal use of your nonscanning hand helps identify a small postmenopausal ovary

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VIDEO 2A Dynamic scanning can give the correct diagnosis even though clips were used! This clip appears to show a relatively normal uterus

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VIDEO 2B Dynamic scanning can give the correct diagnosis even though clips were used! Same patient as in Video 2A showing what appears to be a solid adnexal mass

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VIDEO 2C Dynamic scan clearly shows the “mass” to be a pedunculated fibroid

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VIDEO 3A Video clip of a classic endometrioma

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VIDEO 3B Classic endometrioma showing no Doppler flow internally

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VIDEO 4A Video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

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VIDEO 4B Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

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VIDEO 4C Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

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VIDEO 5A Sliding organ sign with normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5B  Sliding sign showing adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5C Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5D Left ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5E Right ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5F Normal mobility even with a classic endometrioma (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 5G Adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

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VIDEO 6A Dynamic scanning shows the ovary to be “stuck” in the cul-de-sac in a patient with endometriosis

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VIDEO 6B Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

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VIDEO 6C Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

--

VIDEO 7 Cystocele or urethral lengthening are key elements for the diagnosis of incontinence with or without pelvic relaxation

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VIDEO 8 Urethral lengthening is a key element for the diagnosis of incontinence with or without pelvic relaxation

VIDEO 1A Liberal use of your nonscanning hand on dynamic scanning shows “wiggling” of debris classic of a hemorrhagic corpus luteum

--

VIDEO 1B Liberal use of your nonscanning hand helps identify a small postmenopausal ovary

--

VIDEO 2A Dynamic scanning can give the correct diagnosis even though clips were used! This clip appears to show a relatively normal uterus

--

VIDEO 2B Dynamic scanning can give the correct diagnosis even though clips were used! Same patient as in Video 2A showing what appears to be a solid adnexal mass

--

VIDEO 2C Dynamic scan clearly shows the “mass” to be a pedunculated fibroid

--

VIDEO 3A Video clip of a classic endometrioma

--

VIDEO 3B Classic endometrioma showing no Doppler flow internally

--

VIDEO 4A Video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 4B Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 4C Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 5A Sliding organ sign with normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5B  Sliding sign showing adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5C Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5D Left ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5E Right ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5F Normal mobility even with a classic endometrioma (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5G Adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 6A Dynamic scanning shows the ovary to be “stuck” in the cul-de-sac in a patient with endometriosis

--

VIDEO 6B Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

--

VIDEO 6C Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

--

VIDEO 7 Cystocele or urethral lengthening are key elements for the diagnosis of incontinence with or without pelvic relaxation

--

VIDEO 8 Urethral lengthening is a key element for the diagnosis of incontinence with or without pelvic relaxation

VIDEO 1A Liberal use of your nonscanning hand on dynamic scanning shows “wiggling” of debris classic of a hemorrhagic corpus luteum

--

VIDEO 1B Liberal use of your nonscanning hand helps identify a small postmenopausal ovary

--

VIDEO 2A Dynamic scanning can give the correct diagnosis even though clips were used! This clip appears to show a relatively normal uterus

--

VIDEO 2B Dynamic scanning can give the correct diagnosis even though clips were used! Same patient as in Video 2A showing what appears to be a solid adnexal mass

--

VIDEO 2C Dynamic scan clearly shows the “mass” to be a pedunculated fibroid

--

VIDEO 3A Video clip of a classic endometrioma

--

VIDEO 3B Classic endometrioma showing no Doppler flow internally

--

VIDEO 4A Video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 4B Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 4C Another example of video of dynamic assessment in a patient with pain symptoms with a hydrosalpinx

--

VIDEO 5A Sliding organ sign with normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5B  Sliding sign showing adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5C Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5D Left ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5E Right ovary: Normal mobility (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5F Normal mobility even with a classic endometrioma (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 5G Adherent ovary (Courtesy of Dr. Ilan Timor-Tritsch)

--

VIDEO 6A Dynamic scanning shows the ovary to be “stuck” in the cul-de-sac in a patient with endometriosis

--

VIDEO 6B Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

--

VIDEO 6C Dynamic scanning in another patient with endometriosis showing markedly retroverted uterus with adherent bowel posteriorly

--

VIDEO 7 Cystocele or urethral lengthening are key elements for the diagnosis of incontinence with or without pelvic relaxation

--

VIDEO 8 Urethral lengthening is a key element for the diagnosis of incontinence with or without pelvic relaxation

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Female genital cutting (FGC), also known as female circumcision or female genital mutilation, is defined by the World Health Organization (WHO) as “the partial or total removal of the external female genitalia, or other injury to the female genital organs for non-medical reasons.”¹ It is a culturally determined practice that is mainly concentrated in certain parts of Africa, the Middle East, and Asia and now is observed worldwide among migrants from those areas.¹ Approximately 200 million women and girls alive today have undergone FGC in 31 countries, although encouragingly the practice’s prevalence seems to be declining, especially among younger women.²

Too often, FGC goes unrecognized in women who present for medical care, even in cases where a genitourinary exam is performed and documented.^3,4 As a result, patients face delays in diagnosis and management of associated complications and symptoms. Female genital cutting is usually excluded from medical school or residency training curricula,⁵ and physicians often lack familiarity with the necessary clinical or surgical management of patients who have had the procedure.⁶ It is crucial, however, that ObGyns feel comfortable recognizing FGC and clinically caring for pregnant and nonpregnant patients who have undergone the procedure. The obstetric-gynecologic setting should be the clinical space in which FGC is correctly diagnosed and from where patients with complications can be referred for appropriate care.

FGC: Through the lens of inequity

Providing culturally competent and sensitive care to women who have undergone FGC is paramount to reducing health care inequities for these patients. Beyond the medical recommendations we review below, we suggest the following considerations when approaching care for these patients.

Acknowledge our biases. It is paramount for us, as providers, to acknowledge our own biases and how these might affect our relationship with the patient and how our care is received. This starts with our language and terminology: The term female genital mutilation can be judgmental or offensive to our patients, many of whom do not consider themselves to have been mutilated. This is why we prefer to use the term female genital cutting, or whichever word the patient uses, so as not to alienate a patient who might already face many other barriers and microaggressions in seeking health care.

Control our responses. Another way we must check our bias is by controlling our reactions during history taking or examining patients who have undergone FGC. Understandably, providers might be shocked to hear patients recount their childhood experiences of FGC or by examining an infibulated scar, but patients report noticing and experiencing hurt, distress, and shame when providers display judgment, horror, or disgust.⁷ Patients have reported that they are acutely aware that they might be viewed as “backward” and “primitive” in US health care settings.⁸ These kinds of feelings and experiences can further exacerbate patients’ distrust and avoidance of the health care system altogether. Therefore, providers should acknowledge their own biases regarding the issue as well as those of their staff and work to mitigate them.

Avoid stigmatization. While FGC can have long-term effects (discussed below), it is important to remember that many women who have undergone FGC do not experience symptoms that are bothersome or feel that FGC is central to their lives or lived experiences. While we must be thorough in our history taking to explore possible urinary, gynecologic, and sexual symptoms of concern and bother to the patient, we must avoid stigmatizing our patients by assuming that all who have undergone FGC are “sexually disabled,” which may lead a provider to recommend medically unindicated intervention, such as clitoral reconstruction.⁹

Continue to: Classifying FGC types...

Classifying FGC types

The WHO has classified FGC into 4 different types¹:

• type 1, partial or total removal of the clitoris or prepuce
• type 2, partial or total removal of part of the clitoris and labia minora
• type 3 (also known as infibulation), the narrowing of the vaginal orifice by cutting, removing, and/or repositioning the labia, and
• type 4, all other procedures to the female genitalia for nonmedical reasons.

Long-term complications

Female genital cutting, especially types 2 and 3, can lead to long-term obstetric and gynecologic complications that the ObGyn should be able to diagnose and manage (TABLE).

The most common long-term complications of FGC are dysmenorrhea, dyspareunia, recurrent vaginal and urinary tract infections, and sexual dysfunction/dissatisfaction.¹⁰ One recent cross-sectional study that used validated questionnaires on pelvic floor and psychosexual symptoms found that women with FGC had higher distress scores than women who had not undergone FGC, indicating various pelvic floor symptoms responsible for impact on their daily lives.¹¹

Infertility can result from a combination of physical barriers (vaginal stenosis and an infibulated scar) and psychologic barriers secondary to dyspareunia, for example.¹² Labor and delivery also presents a challenge to both patients and providers, especially in cases of infibulation. Studies show that patients who have undergone FGC are at increased risk of adverse obstetric outcomes, including postpartum hemorrhage, episiotomy, cesarean delivery, and extended hospital stay.¹³ Neonatal complications, including infant resuscitation and perinatal death, are more commonly reported in studies outside the United States.¹³

Clinical management recommendations

It is important to be aware of the WHO FCG classifications and be able to recognize evidence of the procedure on examination. The ObGyn should perform a detailed physical exam of the external genitalia as well as a pelvic floor exam of every patient. If the patient does not disclose a history of FGC but it is suspected based on the examination, the clinician should inquire sensitively if the patient is aware of having undergone any genital procedures.

Especially when a history of FGC has been confirmed, clinicians should ask patients sensitively about their urinary and sexual function and satisfaction. Validated tools, such as the Female Sexual Function Index, the Female Sexual Distress Scale, and the Pelvic Floor Disability Index, may be helpful in gathering an objective and detailed assessment of the patient’s symptoms and level of distress.¹⁴ Clinicians also should ask about the patient’s detailed obstetric history, particularly regarding the second stage, delivery, and postpartum complications. The clinician also should specifically inquire about a history of defibulation or additional genital procedures.

Patients with urethral strictures or stenosis may require an exam under anesthesia, cystoscopy, urethral dilation, or urethroplasty.¹² Those with chronic urinary tract or vaginal infections may require chronic oral suppressive therapy or defibulation (described below). Defibulation also may be considered for relief of severe dysmenorrhea and menorrhagia that may be resulting from hematocolpos. The ObGyn also should make certain to evaluate for other common causes of these symptoms that may be unrelated to FGC, such as endometriosis.

Many women who have undergone FGC do not report dyspareunia or sexual dissatisfaction; however, infibulation especially has been associated with higher rates of these sequelae.¹² In addition to defibulation, pelvic floor physical therapy with an experienced therapist may be helpful for patients with pelvic floor dysfunction, vaginismus, and/or dyspareunia.

The defibulation procedure

Defibulation (or deinfibulation) is a surgical reconstructive procedure that opens the infibulated scar of patients who have undergone type 3 FGC (infibulation), thus exposing the urethra and introitus, and in almost half of cases an intact clitoris.¹⁵ Defibulation may be specifically requested by a patient or it may be recommended by the ObGyn either for reducing complications of pregnancy or to address the patient’s gynecologic, sexual, or urogynecologic symptoms by allowing penetrative intercourse, urinary flow, physiologic delivery, and menstruation.¹⁶

Defibulation should be performed under regional or general anesthesia and can be performed during pregnancy (or even in labor). An anterior incision is made on the infibulated scar, creating a new labia major, and the edges are sutured separately. Postoperatively, patients should be instructed to perform sitz baths and to expect a change in their urinary voiding stream.¹² The few studies that have evaluated defibulation have shown high rates of success in addressing preoperative symptoms; the complication rates of defibulation are low and the satisfaction rates are high.¹⁶

The ethical conundrum of reinfibulation

Reinfibulation is defined as the restitching or reapproximation of scar tissue or the labia after delivery or a gynecologic procedure, and it is often performed routinely after every delivery in patients’ countries of origin.¹⁷

Postpartum reinfibulation on patient request raises legal and ethical issues for the ObGyn. In the United Kingdom, reinfibulation is illegal, and some international organizations, including the International Federation of Gynecology and Obstetrics and the WHO, have recommended against the practice. In the United States, reinfibulation of an adult is legal, as it falls under the umbrella of elective female genital cosmetic surgery.^18,19

The procedure could create or exacerbate long-term complications and should generally be discouraged. However, if despite extensive counseling (preferably in the prenatal period) a patient insists on having the procedure, the ObGyn may need to elevate the principle of patient autonomy and either comply or find a practitioner who is comfortable performing it. One retrospective review in Switzerland suggested that specific care and informative counseling prenatally with the inclusion of a patient’s partner in the discussion can improve the acceptability of defibulation without reinfibulation.²⁰

Conclusion

It is important for ObGyns to be familiar with the practice of FGC and to be trained in its recognition on examination and care for the long-term complications that can result from the practice. At the same time, ObGyns should be especially conscious of their biases in order to provide culturally competent care and reduce health care stigmatization and inequities for these patients.

Female genital cutting (FGC), also known as female circumcision or female genital mutilation, is defined by the World Health Organization (WHO) as “the partial or total removal of the external female genitalia, or other injury to the female genital organs for non-medical reasons.”¹ It is a culturally determined practice that is mainly concentrated in certain parts of Africa, the Middle East, and Asia and now is observed worldwide among migrants from those areas.¹ Approximately 200 million women and girls alive today have undergone FGC in 31 countries, although encouragingly the practice’s prevalence seems to be declining, especially among younger women.²

Too often, FGC goes unrecognized in women who present for medical care, even in cases where a genitourinary exam is performed and documented.^3,4 As a result, patients face delays in diagnosis and management of associated complications and symptoms. Female genital cutting is usually excluded from medical school or residency training curricula,⁵ and physicians often lack familiarity with the necessary clinical or surgical management of patients who have had the procedure.⁶ It is crucial, however, that ObGyns feel comfortable recognizing FGC and clinically caring for pregnant and nonpregnant patients who have undergone the procedure. The obstetric-gynecologic setting should be the clinical space in which FGC is correctly diagnosed and from where patients with complications can be referred for appropriate care.

FGC: Through the lens of inequity

Providing culturally competent and sensitive care to women who have undergone FGC is paramount to reducing health care inequities for these patients. Beyond the medical recommendations we review below, we suggest the following considerations when approaching care for these patients.

Acknowledge our biases. It is paramount for us, as providers, to acknowledge our own biases and how these might affect our relationship with the patient and how our care is received. This starts with our language and terminology: The term female genital mutilation can be judgmental or offensive to our patients, many of whom do not consider themselves to have been mutilated. This is why we prefer to use the term female genital cutting, or whichever word the patient uses, so as not to alienate a patient who might already face many other barriers and microaggressions in seeking health care.

Control our responses. Another way we must check our bias is by controlling our reactions during history taking or examining patients who have undergone FGC. Understandably, providers might be shocked to hear patients recount their childhood experiences of FGC or by examining an infibulated scar, but patients report noticing and experiencing hurt, distress, and shame when providers display judgment, horror, or disgust.⁷ Patients have reported that they are acutely aware that they might be viewed as “backward” and “primitive” in US health care settings.⁸ These kinds of feelings and experiences can further exacerbate patients’ distrust and avoidance of the health care system altogether. Therefore, providers should acknowledge their own biases regarding the issue as well as those of their staff and work to mitigate them.

Avoid stigmatization. While FGC can have long-term effects (discussed below), it is important to remember that many women who have undergone FGC do not experience symptoms that are bothersome or feel that FGC is central to their lives or lived experiences. While we must be thorough in our history taking to explore possible urinary, gynecologic, and sexual symptoms of concern and bother to the patient, we must avoid stigmatizing our patients by assuming that all who have undergone FGC are “sexually disabled,” which may lead a provider to recommend medically unindicated intervention, such as clitoral reconstruction.⁹

Continue to: Classifying FGC types...

Classifying FGC types

The WHO has classified FGC into 4 different types¹:

• type 1, partial or total removal of the clitoris or prepuce
• type 2, partial or total removal of part of the clitoris and labia minora
• type 3 (also known as infibulation), the narrowing of the vaginal orifice by cutting, removing, and/or repositioning the labia, and
• type 4, all other procedures to the female genitalia for nonmedical reasons.

Long-term complications

Female genital cutting, especially types 2 and 3, can lead to long-term obstetric and gynecologic complications that the ObGyn should be able to diagnose and manage (TABLE).

The most common long-term complications of FGC are dysmenorrhea, dyspareunia, recurrent vaginal and urinary tract infections, and sexual dysfunction/dissatisfaction.¹⁰ One recent cross-sectional study that used validated questionnaires on pelvic floor and psychosexual symptoms found that women with FGC had higher distress scores than women who had not undergone FGC, indicating various pelvic floor symptoms responsible for impact on their daily lives.¹¹

Infertility can result from a combination of physical barriers (vaginal stenosis and an infibulated scar) and psychologic barriers secondary to dyspareunia, for example.¹² Labor and delivery also presents a challenge to both patients and providers, especially in cases of infibulation. Studies show that patients who have undergone FGC are at increased risk of adverse obstetric outcomes, including postpartum hemorrhage, episiotomy, cesarean delivery, and extended hospital stay.¹³ Neonatal complications, including infant resuscitation and perinatal death, are more commonly reported in studies outside the United States.¹³

Clinical management recommendations

It is important to be aware of the WHO FCG classifications and be able to recognize evidence of the procedure on examination. The ObGyn should perform a detailed physical exam of the external genitalia as well as a pelvic floor exam of every patient. If the patient does not disclose a history of FGC but it is suspected based on the examination, the clinician should inquire sensitively if the patient is aware of having undergone any genital procedures.

Especially when a history of FGC has been confirmed, clinicians should ask patients sensitively about their urinary and sexual function and satisfaction. Validated tools, such as the Female Sexual Function Index, the Female Sexual Distress Scale, and the Pelvic Floor Disability Index, may be helpful in gathering an objective and detailed assessment of the patient’s symptoms and level of distress.¹⁴ Clinicians also should ask about the patient’s detailed obstetric history, particularly regarding the second stage, delivery, and postpartum complications. The clinician also should specifically inquire about a history of defibulation or additional genital procedures.

Patients with urethral strictures or stenosis may require an exam under anesthesia, cystoscopy, urethral dilation, or urethroplasty.¹² Those with chronic urinary tract or vaginal infections may require chronic oral suppressive therapy or defibulation (described below). Defibulation also may be considered for relief of severe dysmenorrhea and menorrhagia that may be resulting from hematocolpos. The ObGyn also should make certain to evaluate for other common causes of these symptoms that may be unrelated to FGC, such as endometriosis.

Many women who have undergone FGC do not report dyspareunia or sexual dissatisfaction; however, infibulation especially has been associated with higher rates of these sequelae.¹² In addition to defibulation, pelvic floor physical therapy with an experienced therapist may be helpful for patients with pelvic floor dysfunction, vaginismus, and/or dyspareunia.

The defibulation procedure

Defibulation (or deinfibulation) is a surgical reconstructive procedure that opens the infibulated scar of patients who have undergone type 3 FGC (infibulation), thus exposing the urethra and introitus, and in almost half of cases an intact clitoris.¹⁵ Defibulation may be specifically requested by a patient or it may be recommended by the ObGyn either for reducing complications of pregnancy or to address the patient’s gynecologic, sexual, or urogynecologic symptoms by allowing penetrative intercourse, urinary flow, physiologic delivery, and menstruation.¹⁶

Defibulation should be performed under regional or general anesthesia and can be performed during pregnancy (or even in labor). An anterior incision is made on the infibulated scar, creating a new labia major, and the edges are sutured separately. Postoperatively, patients should be instructed to perform sitz baths and to expect a change in their urinary voiding stream.¹² The few studies that have evaluated defibulation have shown high rates of success in addressing preoperative symptoms; the complication rates of defibulation are low and the satisfaction rates are high.¹⁶

The ethical conundrum of reinfibulation

Reinfibulation is defined as the restitching or reapproximation of scar tissue or the labia after delivery or a gynecologic procedure, and it is often performed routinely after every delivery in patients’ countries of origin.¹⁷

Postpartum reinfibulation on patient request raises legal and ethical issues for the ObGyn. In the United Kingdom, reinfibulation is illegal, and some international organizations, including the International Federation of Gynecology and Obstetrics and the WHO, have recommended against the practice. In the United States, reinfibulation of an adult is legal, as it falls under the umbrella of elective female genital cosmetic surgery.^18,19

The procedure could create or exacerbate long-term complications and should generally be discouraged. However, if despite extensive counseling (preferably in the prenatal period) a patient insists on having the procedure, the ObGyn may need to elevate the principle of patient autonomy and either comply or find a practitioner who is comfortable performing it. One retrospective review in Switzerland suggested that specific care and informative counseling prenatally with the inclusion of a patient’s partner in the discussion can improve the acceptability of defibulation without reinfibulation.²⁰

Conclusion

It is important for ObGyns to be familiar with the practice of FGC and to be trained in its recognition on examination and care for the long-term complications that can result from the practice. At the same time, ObGyns should be especially conscious of their biases in order to provide culturally competent care and reduce health care stigmatization and inequities for these patients.

Female genital cutting (FGC), also known as female circumcision or female genital mutilation, is defined by the World Health Organization (WHO) as “the partial or total removal of the external female genitalia, or other injury to the female genital organs for non-medical reasons.”¹ It is a culturally determined practice that is mainly concentrated in certain parts of Africa, the Middle East, and Asia and now is observed worldwide among migrants from those areas.¹ Approximately 200 million women and girls alive today have undergone FGC in 31 countries, although encouragingly the practice’s prevalence seems to be declining, especially among younger women.²

Too often, FGC goes unrecognized in women who present for medical care, even in cases where a genitourinary exam is performed and documented.^3,4 As a result, patients face delays in diagnosis and management of associated complications and symptoms. Female genital cutting is usually excluded from medical school or residency training curricula,⁵ and physicians often lack familiarity with the necessary clinical or surgical management of patients who have had the procedure.⁶ It is crucial, however, that ObGyns feel comfortable recognizing FGC and clinically caring for pregnant and nonpregnant patients who have undergone the procedure. The obstetric-gynecologic setting should be the clinical space in which FGC is correctly diagnosed and from where patients with complications can be referred for appropriate care.

FGC: Through the lens of inequity

Providing culturally competent and sensitive care to women who have undergone FGC is paramount to reducing health care inequities for these patients. Beyond the medical recommendations we review below, we suggest the following considerations when approaching care for these patients.

Acknowledge our biases. It is paramount for us, as providers, to acknowledge our own biases and how these might affect our relationship with the patient and how our care is received. This starts with our language and terminology: The term female genital mutilation can be judgmental or offensive to our patients, many of whom do not consider themselves to have been mutilated. This is why we prefer to use the term female genital cutting, or whichever word the patient uses, so as not to alienate a patient who might already face many other barriers and microaggressions in seeking health care.

Control our responses. Another way we must check our bias is by controlling our reactions during history taking or examining patients who have undergone FGC. Understandably, providers might be shocked to hear patients recount their childhood experiences of FGC or by examining an infibulated scar, but patients report noticing and experiencing hurt, distress, and shame when providers display judgment, horror, or disgust.⁷ Patients have reported that they are acutely aware that they might be viewed as “backward” and “primitive” in US health care settings.⁸ These kinds of feelings and experiences can further exacerbate patients’ distrust and avoidance of the health care system altogether. Therefore, providers should acknowledge their own biases regarding the issue as well as those of their staff and work to mitigate them.

Avoid stigmatization. While FGC can have long-term effects (discussed below), it is important to remember that many women who have undergone FGC do not experience symptoms that are bothersome or feel that FGC is central to their lives or lived experiences. While we must be thorough in our history taking to explore possible urinary, gynecologic, and sexual symptoms of concern and bother to the patient, we must avoid stigmatizing our patients by assuming that all who have undergone FGC are “sexually disabled,” which may lead a provider to recommend medically unindicated intervention, such as clitoral reconstruction.⁹

Continue to: Classifying FGC types...

Classifying FGC types

The WHO has classified FGC into 4 different types¹:

• type 1, partial or total removal of the clitoris or prepuce
• type 2, partial or total removal of part of the clitoris and labia minora
• type 3 (also known as infibulation), the narrowing of the vaginal orifice by cutting, removing, and/or repositioning the labia, and
• type 4, all other procedures to the female genitalia for nonmedical reasons.

Long-term complications

Female genital cutting, especially types 2 and 3, can lead to long-term obstetric and gynecologic complications that the ObGyn should be able to diagnose and manage (TABLE).

The most common long-term complications of FGC are dysmenorrhea, dyspareunia, recurrent vaginal and urinary tract infections, and sexual dysfunction/dissatisfaction.¹⁰ One recent cross-sectional study that used validated questionnaires on pelvic floor and psychosexual symptoms found that women with FGC had higher distress scores than women who had not undergone FGC, indicating various pelvic floor symptoms responsible for impact on their daily lives.¹¹

Infertility can result from a combination of physical barriers (vaginal stenosis and an infibulated scar) and psychologic barriers secondary to dyspareunia, for example.¹² Labor and delivery also presents a challenge to both patients and providers, especially in cases of infibulation. Studies show that patients who have undergone FGC are at increased risk of adverse obstetric outcomes, including postpartum hemorrhage, episiotomy, cesarean delivery, and extended hospital stay.¹³ Neonatal complications, including infant resuscitation and perinatal death, are more commonly reported in studies outside the United States.¹³

Clinical management recommendations

It is important to be aware of the WHO FCG classifications and be able to recognize evidence of the procedure on examination. The ObGyn should perform a detailed physical exam of the external genitalia as well as a pelvic floor exam of every patient. If the patient does not disclose a history of FGC but it is suspected based on the examination, the clinician should inquire sensitively if the patient is aware of having undergone any genital procedures.

Especially when a history of FGC has been confirmed, clinicians should ask patients sensitively about their urinary and sexual function and satisfaction. Validated tools, such as the Female Sexual Function Index, the Female Sexual Distress Scale, and the Pelvic Floor Disability Index, may be helpful in gathering an objective and detailed assessment of the patient’s symptoms and level of distress.¹⁴ Clinicians also should ask about the patient’s detailed obstetric history, particularly regarding the second stage, delivery, and postpartum complications. The clinician also should specifically inquire about a history of defibulation or additional genital procedures.

Patients with urethral strictures or stenosis may require an exam under anesthesia, cystoscopy, urethral dilation, or urethroplasty.¹² Those with chronic urinary tract or vaginal infections may require chronic oral suppressive therapy or defibulation (described below). Defibulation also may be considered for relief of severe dysmenorrhea and menorrhagia that may be resulting from hematocolpos. The ObGyn also should make certain to evaluate for other common causes of these symptoms that may be unrelated to FGC, such as endometriosis.

Many women who have undergone FGC do not report dyspareunia or sexual dissatisfaction; however, infibulation especially has been associated with higher rates of these sequelae.¹² In addition to defibulation, pelvic floor physical therapy with an experienced therapist may be helpful for patients with pelvic floor dysfunction, vaginismus, and/or dyspareunia.

The defibulation procedure

Defibulation (or deinfibulation) is a surgical reconstructive procedure that opens the infibulated scar of patients who have undergone type 3 FGC (infibulation), thus exposing the urethra and introitus, and in almost half of cases an intact clitoris.¹⁵ Defibulation may be specifically requested by a patient or it may be recommended by the ObGyn either for reducing complications of pregnancy or to address the patient’s gynecologic, sexual, or urogynecologic symptoms by allowing penetrative intercourse, urinary flow, physiologic delivery, and menstruation.¹⁶

Defibulation should be performed under regional or general anesthesia and can be performed during pregnancy (or even in labor). An anterior incision is made on the infibulated scar, creating a new labia major, and the edges are sutured separately. Postoperatively, patients should be instructed to perform sitz baths and to expect a change in their urinary voiding stream.¹² The few studies that have evaluated defibulation have shown high rates of success in addressing preoperative symptoms; the complication rates of defibulation are low and the satisfaction rates are high.¹⁶

The ethical conundrum of reinfibulation

Reinfibulation is defined as the restitching or reapproximation of scar tissue or the labia after delivery or a gynecologic procedure, and it is often performed routinely after every delivery in patients’ countries of origin.¹⁷

Postpartum reinfibulation on patient request raises legal and ethical issues for the ObGyn. In the United Kingdom, reinfibulation is illegal, and some international organizations, including the International Federation of Gynecology and Obstetrics and the WHO, have recommended against the practice. In the United States, reinfibulation of an adult is legal, as it falls under the umbrella of elective female genital cosmetic surgery.^18,19

The procedure could create or exacerbate long-term complications and should generally be discouraged. However, if despite extensive counseling (preferably in the prenatal period) a patient insists on having the procedure, the ObGyn may need to elevate the principle of patient autonomy and either comply or find a practitioner who is comfortable performing it. One retrospective review in Switzerland suggested that specific care and informative counseling prenatally with the inclusion of a patient’s partner in the discussion can improve the acceptability of defibulation without reinfibulation.²⁰

Conclusion

It is important for ObGyns to be familiar with the practice of FGC and to be trained in its recognition on examination and care for the long-term complications that can result from the practice. At the same time, ObGyns should be especially conscious of their biases in order to provide culturally competent care and reduce health care stigmatization and inequities for these patients.

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●

Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.

In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.

What is the yield of a RASopathy gene panel with specific prenatal findings?

Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.

RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.¹

RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.

Cohort of pregnancies that received a RASopathy panel

Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.

Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.

Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.

Study outcomes

Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.

Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.

Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.

Continue to: Study strengths and limitations...

Study strengths and limitations

This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.

The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.

Sequencing provides insights into twin pregnancies

Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.

You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.

Study eligibility criteria and treatment protocol

The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.

Study outcomes

The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).

An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.

The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.

By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.

Continue to: Study strengths and limitations...

Study strengths and limitations

The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.

The genetic landscape of the placenta

Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.

Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.

Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.

A cohort study of placentas

The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.

In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.

Placental biopsies revealed “bottlenecks” of genetic differentiation

Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.

The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.

Early insights into human placental cells

This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.

As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●