Background: Guideline-directed medical therapy (use of beta-blockers, ACE inhibitor/angiotensin receptor blockers, and mineralocorticoid antagonists) provides clear benefits on mortality and morbidity in patients with HFrEF. Dapagliflozin (Farxiga) belongs to a class of sodium-glucose transporter 2 (SGLT2) inhibitors that inhibits reabsorption of sodium and glucose in the kidney and treats type 2 diabetes. This new class of drugs is emerging as an effective tool in the management of HFrEF based on the recent publication of the primary results of the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure). It demonstrated substantial benefits in terms of heart failure symptoms, hospitalizations, and mortality when added to triple therapy for patients with chronic HFrEF regardless of the presence of diabetes.

• Dapagliflozin showed a clinically significant benefit on health status (symptoms, physical function, and quality of life). Improved health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo was sustained for more than 8 months.
• Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of ages studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals.

Bottom line: Follow-up DAPA-HF studies further support the role of SGLT2 inhibitor dapagliflozin in improving mortality, reducing hospitalization, and improving the quality of life in patients with HFrEF and is considered a safe option across all age groups.

Citations: Kosiborod MN et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: Results from the DAPA-HF trial. Circulation. 2020 Jan 14;141(2):90-9. Martinez FA et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age. Insights from DAPA-HF. Circulation. 2020 Jan 14;141:100-11.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: Guideline-directed medical therapy (use of beta-blockers, ACE inhibitor/angiotensin receptor blockers, and mineralocorticoid antagonists) provides clear benefits on mortality and morbidity in patients with HFrEF. Dapagliflozin (Farxiga) belongs to a class of sodium-glucose transporter 2 (SGLT2) inhibitors that inhibits reabsorption of sodium and glucose in the kidney and treats type 2 diabetes. This new class of drugs is emerging as an effective tool in the management of HFrEF based on the recent publication of the primary results of the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure). It demonstrated substantial benefits in terms of heart failure symptoms, hospitalizations, and mortality when added to triple therapy for patients with chronic HFrEF regardless of the presence of diabetes.

• Dapagliflozin showed a clinically significant benefit on health status (symptoms, physical function, and quality of life). Improved health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo was sustained for more than 8 months.
• Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of ages studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals.

Bottom line: Follow-up DAPA-HF studies further support the role of SGLT2 inhibitor dapagliflozin in improving mortality, reducing hospitalization, and improving the quality of life in patients with HFrEF and is considered a safe option across all age groups.

Citations: Kosiborod MN et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: Results from the DAPA-HF trial. Circulation. 2020 Jan 14;141(2):90-9. Martinez FA et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age. Insights from DAPA-HF. Circulation. 2020 Jan 14;141:100-11.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: Guideline-directed medical therapy (use of beta-blockers, ACE inhibitor/angiotensin receptor blockers, and mineralocorticoid antagonists) provides clear benefits on mortality and morbidity in patients with HFrEF. Dapagliflozin (Farxiga) belongs to a class of sodium-glucose transporter 2 (SGLT2) inhibitors that inhibits reabsorption of sodium and glucose in the kidney and treats type 2 diabetes. This new class of drugs is emerging as an effective tool in the management of HFrEF based on the recent publication of the primary results of the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure). It demonstrated substantial benefits in terms of heart failure symptoms, hospitalizations, and mortality when added to triple therapy for patients with chronic HFrEF regardless of the presence of diabetes.

• Dapagliflozin showed a clinically significant benefit on health status (symptoms, physical function, and quality of life). Improved health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo was sustained for more than 8 months.
• Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of ages studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals.

Bottom line: Follow-up DAPA-HF studies further support the role of SGLT2 inhibitor dapagliflozin in improving mortality, reducing hospitalization, and improving the quality of life in patients with HFrEF and is considered a safe option across all age groups.

Citations: Kosiborod MN et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: Results from the DAPA-HF trial. Circulation. 2020 Jan 14;141(2):90-9. Martinez FA et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age. Insights from DAPA-HF. Circulation. 2020 Jan 14;141:100-11.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

A new study shows disturbing evidence that malaria is becoming resistant to artemisinin, a drug critical for treatment in Africa. Although artemisinin resistance has long plagued the Mekong Delta, it is relatively new to Africa.
 

In a study published online April 14 in The Lancet Infectious Diseases, researchers found that the typical 3-day course of treatment did not totally eradicate Plasmodium falciparum, the parasite that causes malaria. A delayed clearance of the parasite was shown and found to be associated with a genetic mutation called Pfkelch13 R561H.

P. falciparum isolates with this mutation were found in 7.5% of infected children in one area of Rwanda. Further genomic studies showed that this mutation was locally acquired and did not emerge from Southeast Asia. This is well illustrated in a genomic tree published in Nature Medicine in August, 2020. That study reported data collected from adults from 2013 to 2015.

The delay in reporting the mutation was due, in part, to the burdensome process of whole-genome sequencing and transfection studies, Pascal Ringwald, MD, PhD, coordinator of the Global Malaria Programme at WHO, and coauthor of the Nature Medicine study, said in an interview. In transfection studies, the mutation is inserted into parasites and the resultant effect is observed.

Aline Uwimana, MD, of Rwanda Biomedical Centre. is the lead author on both studies.

Meera Venkatesan, PhD, chief of the Case Management, Monitoring and Evaluation Branch, President’s Malaria Initiative, USAID, noted that the Lancet Infectious Diseases study was a therapeutic efficacy study (TES) on samples from children from 2018. In an interview, Dr. Venkatesan explained that the study is noteworthy because it demonstrated the clinical significance of this mutation with delayed parasite clearance. She did note that although there was a lag in publication of the initial reports of artemisinin resistance mutations, that information – and its implications – was promptly shared with the global malaria research community, as are other findings of public health importance.

Although most of the children got better, this “partial resistance” emerged while patients were taking artemether–lumefantrine. This is a type of artemisinin-based combination therapy (ACT) with two drugs intended to stall the emergence of resistance.

The delayed clearance will be a problem because it can contribute to the selection and spread of the partially resistant malaria parasite.

To slow the spread of artemisinin resistance, Dr. Ringwald emphasized the need to add a gametocidal drug to block the transmission to humans. “You give a single dose of primaquine, which will help stop the spread,” he said in an interview. “Continuing surveillance and mapping. These are priorities.”

So are following national guidelines and banning the use of artemisinin monotherapy. Dr. Ringwald stressed two additional priorities: the need for accurate diagnosis of malaria, and the need to use “good-quality drugs and to avoid substandard or fake medicines” by not purchasing drugs on the street.

Unscrupulous individuals are also selling artemisia preparations to treat or prevent COVID-19, when it has no such activity. Similarly, artemisia teas are sold as herbal remedies and nutraceuticals.

Philippe Guérin, MD, director of the Worldwide Antimalarial Resistance Network (WWARN), listed the same recommendations, focusing a bit more on accurate detection of malaria and treatment with a multidrug regimen plus primaquine. You need “to have different first-line treatment (different ACTs) to avoid drug pressure” and resistance to the partner drug emerging, he said in an interview.

Such multiple first-line treatments rely on artemisinin in combination with various drugs, but this can cause some logistical challenges. Resistance is so problematic that the MORU (Mahidol Oxford Tropical Medicine Research Unit) Tropical Health Network in Bangkok is studying triple drug combinations, adding amodiaquine or mefloquine to an artemisinin-based combination.

Dr. Guérin emphasized two other problems regarding the monitoring of malaria resistance in Africa (although not specifically Rwanda). One is the inability to do adequate surveillance in active conflict zones and areas of instability. The other is that COVID-19 is causing resources to be taken away from malaria and redirected to the more immediate crisis. By having to focus on the immediate viral pandemic, public-health authorities are missing the chance to address other critically important infectious diseases with large burdens – specifically malaria, TB, and HIV – which might have greater impacts on future generations.

Dr. Guérin noted that although we now have solid evidence of artemisinin resistance in Rwanda, and isolated cases in other African countries, we have little idea of the magnitude of the problem because testing is not widespread throughout parts of the continent.

What would widespread P. falciparum malaria resistance in Africa mean? Children are the most vulnerable to malaria, and account for two-thirds of the deaths. One study suggests there could be 78 million more cases over a 5-year period, along with far more deaths. Hence, there is a heightened urgency to implement the outlined strategies to prevent a looming catastrophe.

The authors have disclosed no relevant financial relationships.

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

A new study shows disturbing evidence that malaria is becoming resistant to artemisinin, a drug critical for treatment in Africa. Although artemisinin resistance has long plagued the Mekong Delta, it is relatively new to Africa.
 

In a study published online April 14 in The Lancet Infectious Diseases, researchers found that the typical 3-day course of treatment did not totally eradicate Plasmodium falciparum, the parasite that causes malaria. A delayed clearance of the parasite was shown and found to be associated with a genetic mutation called Pfkelch13 R561H.

P. falciparum isolates with this mutation were found in 7.5% of infected children in one area of Rwanda. Further genomic studies showed that this mutation was locally acquired and did not emerge from Southeast Asia. This is well illustrated in a genomic tree published in Nature Medicine in August, 2020. That study reported data collected from adults from 2013 to 2015.

The delay in reporting the mutation was due, in part, to the burdensome process of whole-genome sequencing and transfection studies, Pascal Ringwald, MD, PhD, coordinator of the Global Malaria Programme at WHO, and coauthor of the Nature Medicine study, said in an interview. In transfection studies, the mutation is inserted into parasites and the resultant effect is observed.

Aline Uwimana, MD, of Rwanda Biomedical Centre. is the lead author on both studies.

Meera Venkatesan, PhD, chief of the Case Management, Monitoring and Evaluation Branch, President’s Malaria Initiative, USAID, noted that the Lancet Infectious Diseases study was a therapeutic efficacy study (TES) on samples from children from 2018. In an interview, Dr. Venkatesan explained that the study is noteworthy because it demonstrated the clinical significance of this mutation with delayed parasite clearance. She did note that although there was a lag in publication of the initial reports of artemisinin resistance mutations, that information – and its implications – was promptly shared with the global malaria research community, as are other findings of public health importance.

Although most of the children got better, this “partial resistance” emerged while patients were taking artemether–lumefantrine. This is a type of artemisinin-based combination therapy (ACT) with two drugs intended to stall the emergence of resistance.

The delayed clearance will be a problem because it can contribute to the selection and spread of the partially resistant malaria parasite.

To slow the spread of artemisinin resistance, Dr. Ringwald emphasized the need to add a gametocidal drug to block the transmission to humans. “You give a single dose of primaquine, which will help stop the spread,” he said in an interview. “Continuing surveillance and mapping. These are priorities.”

So are following national guidelines and banning the use of artemisinin monotherapy. Dr. Ringwald stressed two additional priorities: the need for accurate diagnosis of malaria, and the need to use “good-quality drugs and to avoid substandard or fake medicines” by not purchasing drugs on the street.

Unscrupulous individuals are also selling artemisia preparations to treat or prevent COVID-19, when it has no such activity. Similarly, artemisia teas are sold as herbal remedies and nutraceuticals.

Philippe Guérin, MD, director of the Worldwide Antimalarial Resistance Network (WWARN), listed the same recommendations, focusing a bit more on accurate detection of malaria and treatment with a multidrug regimen plus primaquine. You need “to have different first-line treatment (different ACTs) to avoid drug pressure” and resistance to the partner drug emerging, he said in an interview.

Such multiple first-line treatments rely on artemisinin in combination with various drugs, but this can cause some logistical challenges. Resistance is so problematic that the MORU (Mahidol Oxford Tropical Medicine Research Unit) Tropical Health Network in Bangkok is studying triple drug combinations, adding amodiaquine or mefloquine to an artemisinin-based combination.

Dr. Guérin emphasized two other problems regarding the monitoring of malaria resistance in Africa (although not specifically Rwanda). One is the inability to do adequate surveillance in active conflict zones and areas of instability. The other is that COVID-19 is causing resources to be taken away from malaria and redirected to the more immediate crisis. By having to focus on the immediate viral pandemic, public-health authorities are missing the chance to address other critically important infectious diseases with large burdens – specifically malaria, TB, and HIV – which might have greater impacts on future generations.

Dr. Guérin noted that although we now have solid evidence of artemisinin resistance in Rwanda, and isolated cases in other African countries, we have little idea of the magnitude of the problem because testing is not widespread throughout parts of the continent.

What would widespread P. falciparum malaria resistance in Africa mean? Children are the most vulnerable to malaria, and account for two-thirds of the deaths. One study suggests there could be 78 million more cases over a 5-year period, along with far more deaths. Hence, there is a heightened urgency to implement the outlined strategies to prevent a looming catastrophe.

The authors have disclosed no relevant financial relationships.

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

A new study shows disturbing evidence that malaria is becoming resistant to artemisinin, a drug critical for treatment in Africa. Although artemisinin resistance has long plagued the Mekong Delta, it is relatively new to Africa.
 

In a study published online April 14 in The Lancet Infectious Diseases, researchers found that the typical 3-day course of treatment did not totally eradicate Plasmodium falciparum, the parasite that causes malaria. A delayed clearance of the parasite was shown and found to be associated with a genetic mutation called Pfkelch13 R561H.

P. falciparum isolates with this mutation were found in 7.5% of infected children in one area of Rwanda. Further genomic studies showed that this mutation was locally acquired and did not emerge from Southeast Asia. This is well illustrated in a genomic tree published in Nature Medicine in August, 2020. That study reported data collected from adults from 2013 to 2015.

The delay in reporting the mutation was due, in part, to the burdensome process of whole-genome sequencing and transfection studies, Pascal Ringwald, MD, PhD, coordinator of the Global Malaria Programme at WHO, and coauthor of the Nature Medicine study, said in an interview. In transfection studies, the mutation is inserted into parasites and the resultant effect is observed.

Aline Uwimana, MD, of Rwanda Biomedical Centre. is the lead author on both studies.

Meera Venkatesan, PhD, chief of the Case Management, Monitoring and Evaluation Branch, President’s Malaria Initiative, USAID, noted that the Lancet Infectious Diseases study was a therapeutic efficacy study (TES) on samples from children from 2018. In an interview, Dr. Venkatesan explained that the study is noteworthy because it demonstrated the clinical significance of this mutation with delayed parasite clearance. She did note that although there was a lag in publication of the initial reports of artemisinin resistance mutations, that information – and its implications – was promptly shared with the global malaria research community, as are other findings of public health importance.

Although most of the children got better, this “partial resistance” emerged while patients were taking artemether–lumefantrine. This is a type of artemisinin-based combination therapy (ACT) with two drugs intended to stall the emergence of resistance.

The delayed clearance will be a problem because it can contribute to the selection and spread of the partially resistant malaria parasite.

To slow the spread of artemisinin resistance, Dr. Ringwald emphasized the need to add a gametocidal drug to block the transmission to humans. “You give a single dose of primaquine, which will help stop the spread,” he said in an interview. “Continuing surveillance and mapping. These are priorities.”

So are following national guidelines and banning the use of artemisinin monotherapy. Dr. Ringwald stressed two additional priorities: the need for accurate diagnosis of malaria, and the need to use “good-quality drugs and to avoid substandard or fake medicines” by not purchasing drugs on the street.

Unscrupulous individuals are also selling artemisia preparations to treat or prevent COVID-19, when it has no such activity. Similarly, artemisia teas are sold as herbal remedies and nutraceuticals.

Philippe Guérin, MD, director of the Worldwide Antimalarial Resistance Network (WWARN), listed the same recommendations, focusing a bit more on accurate detection of malaria and treatment with a multidrug regimen plus primaquine. You need “to have different first-line treatment (different ACTs) to avoid drug pressure” and resistance to the partner drug emerging, he said in an interview.

Such multiple first-line treatments rely on artemisinin in combination with various drugs, but this can cause some logistical challenges. Resistance is so problematic that the MORU (Mahidol Oxford Tropical Medicine Research Unit) Tropical Health Network in Bangkok is studying triple drug combinations, adding amodiaquine or mefloquine to an artemisinin-based combination.

Dr. Guérin emphasized two other problems regarding the monitoring of malaria resistance in Africa (although not specifically Rwanda). One is the inability to do adequate surveillance in active conflict zones and areas of instability. The other is that COVID-19 is causing resources to be taken away from malaria and redirected to the more immediate crisis. By having to focus on the immediate viral pandemic, public-health authorities are missing the chance to address other critically important infectious diseases with large burdens – specifically malaria, TB, and HIV – which might have greater impacts on future generations.

Dr. Guérin noted that although we now have solid evidence of artemisinin resistance in Rwanda, and isolated cases in other African countries, we have little idea of the magnitude of the problem because testing is not widespread throughout parts of the continent.

What would widespread P. falciparum malaria resistance in Africa mean? Children are the most vulnerable to malaria, and account for two-thirds of the deaths. One study suggests there could be 78 million more cases over a 5-year period, along with far more deaths. Hence, there is a heightened urgency to implement the outlined strategies to prevent a looming catastrophe.

The authors have disclosed no relevant financial relationships.

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

Key clinical point: Three countries that implemented an immediate postpartum family planning (IPPFP) intervention that focused on long-acting reversible contraception (LARC) showed a significant increase in the number of girls and women who opted for an IUD or implant within 48 hours of delivery. 

Major finding: The mean percentage of IPP LARC adoption among all deliveries in the countries that implemented the intervention programs was 10.01%, compared to 0.77% in countries providing standard postpartum care without the intervention.

Study details: The data come from a review of immediate postpartum long-acting reversible contraception (IPP LARC) from 2016 to 2019 in three countries that focused on LARC intervention (Democratic Republic of Congo, Somalia, and Pakistan) including training delivery-room providers on counseling and provision of IPPFP; and three countries the did not implement this intervention (Rwanda, Syria, and Yemen).

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Gallagher MC et al. Front Glob Womens Health. 2021 Apr 6. doi: 10.3389/fgwh.2021.613338.

Key clinical point: Three countries that implemented an immediate postpartum family planning (IPPFP) intervention that focused on long-acting reversible contraception (LARC) showed a significant increase in the number of girls and women who opted for an IUD or implant within 48 hours of delivery. 

Major finding: The mean percentage of IPP LARC adoption among all deliveries in the countries that implemented the intervention programs was 10.01%, compared to 0.77% in countries providing standard postpartum care without the intervention.

Study details: The data come from a review of immediate postpartum long-acting reversible contraception (IPP LARC) from 2016 to 2019 in three countries that focused on LARC intervention (Democratic Republic of Congo, Somalia, and Pakistan) including training delivery-room providers on counseling and provision of IPPFP; and three countries the did not implement this intervention (Rwanda, Syria, and Yemen).

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Gallagher MC et al. Front Glob Womens Health. 2021 Apr 6. doi: 10.3389/fgwh.2021.613338.

Key clinical point: Three countries that implemented an immediate postpartum family planning (IPPFP) intervention that focused on long-acting reversible contraception (LARC) showed a significant increase in the number of girls and women who opted for an IUD or implant within 48 hours of delivery. 

Major finding: The mean percentage of IPP LARC adoption among all deliveries in the countries that implemented the intervention programs was 10.01%, compared to 0.77% in countries providing standard postpartum care without the intervention.

Study details: The data come from a review of immediate postpartum long-acting reversible contraception (IPP LARC) from 2016 to 2019 in three countries that focused on LARC intervention (Democratic Republic of Congo, Somalia, and Pakistan) including training delivery-room providers on counseling and provision of IPPFP; and three countries the did not implement this intervention (Rwanda, Syria, and Yemen).

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Gallagher MC et al. Front Glob Womens Health. 2021 Apr 6. doi: 10.3389/fgwh.2021.613338.

Key clinical point: Contraceptive use among adolescents in the United States increased overall from 2006 to 2019, although consistent condom use declined.

Major finding: From 2006-2010 to 2015-2019, adolescents aged 15 to 19 years reported an 86% increased use of any contraception, a 26% increased use of multiple contraception methods, and a 3% increased use of IUDs or implants. 

Study details: The data come from a review of adolescents aged 15 to 19 years from the National Surveys of Family Growth, including 4,662 individuals from 2006-2010, 4,134 from 2011-2015, and 3,182 from 2015-2019.

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Lindberg LD et al. Contraception: X. 2021 Apr 8. doi: 10.1016/j.conx.2021.100064.

Key clinical point: Contraceptive use among adolescents in the United States increased overall from 2006 to 2019, although consistent condom use declined.

Major finding: From 2006-2010 to 2015-2019, adolescents aged 15 to 19 years reported an 86% increased use of any contraception, a 26% increased use of multiple contraception methods, and a 3% increased use of IUDs or implants. 

Study details: The data come from a review of adolescents aged 15 to 19 years from the National Surveys of Family Growth, including 4,662 individuals from 2006-2010, 4,134 from 2011-2015, and 3,182 from 2015-2019.

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Lindberg LD et al. Contraception: X. 2021 Apr 8. doi: 10.1016/j.conx.2021.100064.

Key clinical point: Contraceptive use among adolescents in the United States increased overall from 2006 to 2019, although consistent condom use declined.

Major finding: From 2006-2010 to 2015-2019, adolescents aged 15 to 19 years reported an 86% increased use of any contraception, a 26% increased use of multiple contraception methods, and a 3% increased use of IUDs or implants. 

Study details: The data come from a review of adolescents aged 15 to 19 years from the National Surveys of Family Growth, including 4,662 individuals from 2006-2010, 4,134 from 2011-2015, and 3,182 from 2015-2019.

Disclosures: The study was supported by an anonymous foundation. The researchers had no financial conflicts to disclose.

Source: Lindberg LD et al. Contraception: X. 2021 Apr 8. doi: 10.1016/j.conx.2021.100064.

Key clinical point: The generally positive attitudes towards contraception but low levels of use highlight the need for greater communication about behavior change among health professionals and medical students to increase their roles as change agents in their communities.

Major finding: Although 58% of the respondents were sexually active, only 18% were using a contraceptive at the time of the survey; however, 83% of contraceptive users were satisfied with past use. In addition, approximately half of respondents discussed contraception with their partners and four-fifths said they would encourage others in contraceptive use, although only 18% were involved in providing family planning methods.

Study details: The data come from a cross-sectional survey of 400 health workers and clinical care medical students in Ghana between January 1, 2018, and June 30, 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Agbeno EK et al. Int J Reprod Med. 2021 Mar 22. doi: 10.1155/2021/6631790. 

Key clinical point: The generally positive attitudes towards contraception but low levels of use highlight the need for greater communication about behavior change among health professionals and medical students to increase their roles as change agents in their communities.

Major finding: Although 58% of the respondents were sexually active, only 18% were using a contraceptive at the time of the survey; however, 83% of contraceptive users were satisfied with past use. In addition, approximately half of respondents discussed contraception with their partners and four-fifths said they would encourage others in contraceptive use, although only 18% were involved in providing family planning methods.

Study details: The data come from a cross-sectional survey of 400 health workers and clinical care medical students in Ghana between January 1, 2018, and June 30, 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Agbeno EK et al. Int J Reprod Med. 2021 Mar 22. doi: 10.1155/2021/6631790. 

Key clinical point: The generally positive attitudes towards contraception but low levels of use highlight the need for greater communication about behavior change among health professionals and medical students to increase their roles as change agents in their communities.

Major finding: Although 58% of the respondents were sexually active, only 18% were using a contraceptive at the time of the survey; however, 83% of contraceptive users were satisfied with past use. In addition, approximately half of respondents discussed contraception with their partners and four-fifths said they would encourage others in contraceptive use, although only 18% were involved in providing family planning methods.

Study details: The data come from a cross-sectional survey of 400 health workers and clinical care medical students in Ghana between January 1, 2018, and June 30, 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.

Source: Agbeno EK et al. Int J Reprod Med. 2021 Mar 22. doi: 10.1155/2021/6631790. 

Key clinical point: Levonorgestrel was noninferior to copper IUD for emergency contraception, with similar pregnancy rates and adverse events reported for both methods.

Major finding: Pregnancy rates were 1 in 317 (0.3%) in the levonorgestrel group and 0 in 321 (0%) in the copper IUD group in the modified intent-to-treat analysis.

Study details: The data come from a randomized trial of 317 women who received levonorgestrel IUD and 321 who received copper IUDs and provided 1-month outcome data.

Disclosures: The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the University of Utah, with funding in part from the National Institutes of Health (NIH) National Center for Research Resources and National Center for Advancing Translational Sciences; and grants to the lead author and several coauthors from the NIH Office of Research on Women’s Health and the Eunice Kennedy Shriver NICHD.

Source:  Turok DK et al.  N Engl J Med. 2021 Jan 28. doi: 10.1056/NEJMoa2022141.

Key clinical point: Levonorgestrel was noninferior to copper IUD for emergency contraception, with similar pregnancy rates and adverse events reported for both methods.

Major finding: Pregnancy rates were 1 in 317 (0.3%) in the levonorgestrel group and 0 in 321 (0%) in the copper IUD group in the modified intent-to-treat analysis.

Study details: The data come from a randomized trial of 317 women who received levonorgestrel IUD and 321 who received copper IUDs and provided 1-month outcome data.

Disclosures: The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the University of Utah, with funding in part from the National Institutes of Health (NIH) National Center for Research Resources and National Center for Advancing Translational Sciences; and grants to the lead author and several coauthors from the NIH Office of Research on Women’s Health and the Eunice Kennedy Shriver NICHD.

Source:  Turok DK et al.  N Engl J Med. 2021 Jan 28. doi: 10.1056/NEJMoa2022141.

Key clinical point: Levonorgestrel was noninferior to copper IUD for emergency contraception, with similar pregnancy rates and adverse events reported for both methods.

Major finding: Pregnancy rates were 1 in 317 (0.3%) in the levonorgestrel group and 0 in 321 (0%) in the copper IUD group in the modified intent-to-treat analysis.

Study details: The data come from a randomized trial of 317 women who received levonorgestrel IUD and 321 who received copper IUDs and provided 1-month outcome data.

Disclosures: The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the University of Utah, with funding in part from the National Institutes of Health (NIH) National Center for Research Resources and National Center for Advancing Translational Sciences; and grants to the lead author and several coauthors from the NIH Office of Research on Women’s Health and the Eunice Kennedy Shriver NICHD.

Source:  Turok DK et al.  N Engl J Med. 2021 Jan 28. doi: 10.1056/NEJMoa2022141.

Key clinical point: Use of progestin-only contraception was associated with greater breast hypertrophy and pain in adolescents with macromastia.

Major finding: Compared to controls, macromastia patients who used progestin-only contraceptives were 500% more likely to report breast pain (odds ratio 4.94); macromastia patients who used progestin-only contraception also had significantly more breast tissue resected during mammaplasty and greater musculoskeletal pain. 

Study details: The data come from a retrospective study of 378 macromastia patients aged 12 to 21 years and 378 controls; 5.3% of macromastia patients and 28.0% of controls used progestin-only contraception.

Disclosures: The study was supported in part by the Plastic Surgery Foundation. The researchers had no financial conflicts to disclose.

Source: Nuzzi LC et al. Plast Reconstr Surg Glob Open. 2021 Feb 12. doi: 10.1097/GOX.0000000000003421.

Key clinical point: Use of progestin-only contraception was associated with greater breast hypertrophy and pain in adolescents with macromastia.

Major finding: Compared to controls, macromastia patients who used progestin-only contraceptives were 500% more likely to report breast pain (odds ratio 4.94); macromastia patients who used progestin-only contraception also had significantly more breast tissue resected during mammaplasty and greater musculoskeletal pain. 

Study details: The data come from a retrospective study of 378 macromastia patients aged 12 to 21 years and 378 controls; 5.3% of macromastia patients and 28.0% of controls used progestin-only contraception.

Disclosures: The study was supported in part by the Plastic Surgery Foundation. The researchers had no financial conflicts to disclose.

Source: Nuzzi LC et al. Plast Reconstr Surg Glob Open. 2021 Feb 12. doi: 10.1097/GOX.0000000000003421.

Key clinical point: Use of progestin-only contraception was associated with greater breast hypertrophy and pain in adolescents with macromastia.

Major finding: Compared to controls, macromastia patients who used progestin-only contraceptives were 500% more likely to report breast pain (odds ratio 4.94); macromastia patients who used progestin-only contraception also had significantly more breast tissue resected during mammaplasty and greater musculoskeletal pain. 

Study details: The data come from a retrospective study of 378 macromastia patients aged 12 to 21 years and 378 controls; 5.3% of macromastia patients and 28.0% of controls used progestin-only contraception.

Disclosures: The study was supported in part by the Plastic Surgery Foundation. The researchers had no financial conflicts to disclose.

Source: Nuzzi LC et al. Plast Reconstr Surg Glob Open. 2021 Feb 12. doi: 10.1097/GOX.0000000000003421.

Key clinical point: Among healthy young women taking oral contraceptives, pulse wave velocity was lower in active women compared with inactive women, suggesting that physical activity may mitigate the risk of arterial stiffness associated with OC use.   

Major finding: Pulse wave velocity as an indicator of arterial stiffness was similar in oral contraceptive users and non-users, however, PWV was significantly lower in active women vs. inactive women (5.4 ms ^-1 vs. 6.3 ms ^-1).

Study details: The data come from a cross-sectional study of 49 healthy young women with an average age of 21.9 years, divided into four groups (inactive vs. active, OC use vs. non-OC use).

Disclosures: The study was supported in part by the European Union and the New Aquitaine region through the Habisan program (CPER-FEDER). The researchers had no financial conflicts to disclose.

Source: Enea C et al. Int J Environ Res Public Health. 2021 Mar 25. doi: 10.3390/ijerph18073393.

Key clinical point: Among healthy young women taking oral contraceptives, pulse wave velocity was lower in active women compared with inactive women, suggesting that physical activity may mitigate the risk of arterial stiffness associated with OC use.   

Major finding: Pulse wave velocity as an indicator of arterial stiffness was similar in oral contraceptive users and non-users, however, PWV was significantly lower in active women vs. inactive women (5.4 ms ^-1 vs. 6.3 ms ^-1).

Study details: The data come from a cross-sectional study of 49 healthy young women with an average age of 21.9 years, divided into four groups (inactive vs. active, OC use vs. non-OC use).

Disclosures: The study was supported in part by the European Union and the New Aquitaine region through the Habisan program (CPER-FEDER). The researchers had no financial conflicts to disclose.

Source: Enea C et al. Int J Environ Res Public Health. 2021 Mar 25. doi: 10.3390/ijerph18073393.

Key clinical point: Among healthy young women taking oral contraceptives, pulse wave velocity was lower in active women compared with inactive women, suggesting that physical activity may mitigate the risk of arterial stiffness associated with OC use.   

Major finding: Pulse wave velocity as an indicator of arterial stiffness was similar in oral contraceptive users and non-users, however, PWV was significantly lower in active women vs. inactive women (5.4 ms ^-1 vs. 6.3 ms ^-1).

Study details: The data come from a cross-sectional study of 49 healthy young women with an average age of 21.9 years, divided into four groups (inactive vs. active, OC use vs. non-OC use).

Disclosures: The study was supported in part by the European Union and the New Aquitaine region through the Habisan program (CPER-FEDER). The researchers had no financial conflicts to disclose.

Source: Enea C et al. Int J Environ Res Public Health. 2021 Mar 25. doi: 10.3390/ijerph18073393.

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at [email protected].

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at [email protected].

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at [email protected].

Key clinical point: In a biomechanical ex vivo analysis, metal uterine sounds caused uterine perforation, but the manufacturer’s plastic intrauterine device placement rod did not.

Major finding: The lowest mean maximum force generated for IUD placement was 12.3 Newtons with the levonorgestrel intrauterine system placement instrument, followed by 14.1 Newtons with the copper T380A intrauterine device placement instrument 14.1 Newtons; the highest mean maximum force of 17.9 N occurred with the metal sound (P < 0.01).

Study details: The data come from 16 premenopausal women with benign conditions who provided hysterectomy sections at a single center.

Disclosures: The study was funded indirectly through grants to the University of Utah from Bayer, Bioceptive, Sebela, Medicines 360, Merck, and Cooper Surgical. Lead author Dr. Duncan had no financial conflicts to disclose.

Source: Duncan J et al. BMC Womens Health. 2021 Apr 7. doi: 10.1186/s12905-021-01285-6.

Key clinical point: In a biomechanical ex vivo analysis, metal uterine sounds caused uterine perforation, but the manufacturer’s plastic intrauterine device placement rod did not.

Major finding: The lowest mean maximum force generated for IUD placement was 12.3 Newtons with the levonorgestrel intrauterine system placement instrument, followed by 14.1 Newtons with the copper T380A intrauterine device placement instrument 14.1 Newtons; the highest mean maximum force of 17.9 N occurred with the metal sound (P < 0.01).

Study details: The data come from 16 premenopausal women with benign conditions who provided hysterectomy sections at a single center.

Disclosures: The study was funded indirectly through grants to the University of Utah from Bayer, Bioceptive, Sebela, Medicines 360, Merck, and Cooper Surgical. Lead author Dr. Duncan had no financial conflicts to disclose.

Source: Duncan J et al. BMC Womens Health. 2021 Apr 7. doi: 10.1186/s12905-021-01285-6.

Key clinical point: In a biomechanical ex vivo analysis, metal uterine sounds caused uterine perforation, but the manufacturer’s plastic intrauterine device placement rod did not.

Major finding: The lowest mean maximum force generated for IUD placement was 12.3 Newtons with the levonorgestrel intrauterine system placement instrument, followed by 14.1 Newtons with the copper T380A intrauterine device placement instrument 14.1 Newtons; the highest mean maximum force of 17.9 N occurred with the metal sound (P < 0.01).

Study details: The data come from 16 premenopausal women with benign conditions who provided hysterectomy sections at a single center.

Disclosures: The study was funded indirectly through grants to the University of Utah from Bayer, Bioceptive, Sebela, Medicines 360, Merck, and Cooper Surgical. Lead author Dr. Duncan had no financial conflicts to disclose.

Source: Duncan J et al. BMC Womens Health. 2021 Apr 7. doi: 10.1186/s12905-021-01285-6.