Caleb Rans, PharmD

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

Between 2014 and 2020, the frequency of adverse pregnancy outcomes in the United States increased among women with gestational diabetes, with persisting differences in adverse outcomes by race and ethnicity, according to a report in JAMA

“[Previous] population-based studies on racial and ethnic disparities in gestational diabetes have focused on differences in the rate of diagnosis, rather than adverse pregnancy outcomes,” lead author Kartik K. Venkatesh, MD, PhD, of Ohio State University, Columbus, and colleagues explained.

The researchers conducted a cross-sectional, descriptive study to evaluate whether the frequency of adverse pregnancy outcomes with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.

The data were obtained from the Centers for Disease Control and Prevention’s National Center for Health Statistics Natality Files. Exposures of interest were year of delivery, as well as race and ethnicity.
 

Results

The study cohort included 1,560,822 pregnant women with gestational diabetes aged 15-44 years. Among the study participants the mean age was 31 years (standard deviation, 5.5 years) and the majority were White (48%), followed by Hispanic/Latina (27%), Asian/Pacific Islander (13%), and Black (12%).

There was a significant increase in the overall frequency of transfusion (8.0%; 95% confidence interval, 3.8%-12.4%), preeclampsia or gestational hypertension (4.2%; 95% CI, 3.3%-5.2%), NICU admission (1.0%; 95% CI, 0.3%-1.7%), and preterm birth at less than 37 weeks (0.9%; 95% CI, 0.3%-1.5%) from 2014 to 2020 for these women and their infants.

In addition, there was a significant decrease in the following outcomes: macrosomia (–4.7%; 95% CI, –5.3% to –4.0%), cesarean delivery (–1.4%; 95% CI, –1.7% to –1.1%), primary cesarean delivery (–1.2%; 95% CI, –1.5% to –0.9%), and large for gestational age (–2.3%; 95% CI, –2.8% to –1.8%), but there was no significant differences in maternal ICU admission and small-for-gestational-age infants.

From 2014 through 2020, differences in adverse outcomes by race and ethnicity persisted; in comparison with Whites, Black participants were at significantly higher risk of all evaluated outcomes, except for macrosomia and large for gestational age.

Hispanic/Latina and Asian/Pacific Islander individuals were also at significantly higher risk of preterm birth, NICU admission, maternal ICU admission, and small for gestational age. Furthermore, American Indian participants were at significantly higher risk of all evaluated outcomes, except for cesarean delivery and small for gestational age.
 

Results in context

Health policy researcher Felicia Hill-Briggs, PhD, at the Feinstein Institutes for Medical Research in Manhasset, N.Y. commented: “Two alarming trends highlighted by this study: 1) Racial and ethnic inequities in adverse gestational diabetes outcomes; and 2) the rising rates of gestational diabetes overall – both must and can be halted.”

“Optimizing medical management of gestational diabetes, whether through improved access to diabetes care in pregnancy, behavioral interventions, and pharmacotherapy can decrease the risk of adverse pregnancy outcomes,” Dr. Venkatesh commented. “It is possible that the equitable delivery of these interventions to address glycemic control could decrease racial and ethnic disparities in adverse pregnancy outcomes among individuals with gestational diabetes.”

Dr. Venkatesh and his colleagues acknowledged that a key limitation of the study was the use of administrative data; thus, inferences on maternal care improvements could not be determined.

“Further research could focus on greater understanding of racial and ethnic differences in the management of gestational diabetes,” the researchers concluded.

This study was supported by the Care Innovation and Community Improvement Program at Ohio State University. One author reported receiving grants from the National Institutes of Health outside of this study. The other authors reported no relevant disclosures. Dr. Hill-Briggs had no relevant disclosures.

A cross-sectional study in the United Kingdom has revealed an association between social media use and lower life satisfaction among children and adolescents aged 10-21 years.

“[Our] study provides evidence for age- and sex-specific windows of sensitivity to social media use in adolescence,” lead author Amy Orben, PhD, of the University of Cambridge (England), and colleagues wrote. The findings were published in Nature Communications.

The researchers analyzed cross-sectional and longitudinal data from the Understanding Society dataset and the Millennium Cohort Study. The cross-sectional data was used to investigate the existence of developmental windows of sensitivity to social media, while the longitudinal data was used to evaluate whether sex-specific windows of sensitivity to social media were present during the adolescence period.

These two datasets comprised 84,011 participants aged 10-80 years old. After applying the modeling framework, 17,409 participants aged 10-21 years were included in the analysis.

Longitudinal analyses revealed different developmental windows of sensitivity to social media during adolescence, with higher estimated social media use predicting lower life satisfaction scores 1 year later (regression coefficient [beta], −0.02; 95% confidence interval, −0.03 to −0.01; P = .004).

Among females, the researchers observed a window of sensitivity to social media between the ages of 11 and 13, with higher estimated social media use predicting lower life satisfaction ratings 1 year later (age 11: beta, −0.11; 95% CI, −0.21 to −0.02; P = .020; age 12: beta, −0.14; 95% CI, −0.22 to −0.07; P < .001; age 13: beta, −0.08; 95% CI, −0.15 to −0.01; P = .019).

Among males, a similar window was observed between the ages of 14 and 15 (age 14: beta, −0.10; 95% CI, −0.17 to −0.03; P = .005; age 15: beta, –0.18; 95% CI, −0.29 to −0.08; P = .001).

Furthermore, they showed that a later increase in sensitivity to social media, which was present at age 19 for both females and males, suggested a different underlying process was present in late adolescence (females: beta, −0.16; 95% CI, −0.25 to −0.07; P < .001; males: beta, −0.16; 95% CI, −0.26 to −0.07; P = .001).

“Speculatively, this might be related to changes in the social environment such as a move away from home and subsequent disruptions in social networks,” the researchers wrote.

Importantly, Dr. Orben and colleagues noted that these results should be interpreted with caution. Owing to the cross-sectional nature of the data, causality cannot be inferred from these findings.

“The findings reported here may enable investigation of potential mechanisms of interest, for example, in datasets with pubertal or additional social measurements,” they wrote. “One could also carry out more targeted investigations, for example, by examining the mental health measures only completed by select age ranges in the datasets.”
 

Digital literacy is important, expert says

“Digital literacy and education about social media use is warranted for all ages, starting young,” Yalda T. Uhls, MBA, PhD, of the department of psychology at the University of California, Los Angeles, said in an interview. “Attending to underlying issues for vulnerable ages, such as anxiety, as well as parental support is critical.”

“I would urge social media platforms to pay attention to what kinds of content they are making available to ensure the highest possible quality, and to embed things like suggestions for pauses and other ways to check in on someone who may be experiencing distress when on socials,” Dr. Uhls said. “We also need to increase access to mental health resources for young people and social media could help provide information for those experiencing issues.”

This study was supported by the University of Cambridge and the UK Medical Research Council. The authors reported no relevant disclosures. Dr. Uhls had no relevant disclosures.

A cross-sectional study in the United Kingdom has revealed an association between social media use and lower life satisfaction among children and adolescents aged 10-21 years.

“[Our] study provides evidence for age- and sex-specific windows of sensitivity to social media use in adolescence,” lead author Amy Orben, PhD, of the University of Cambridge (England), and colleagues wrote. The findings were published in Nature Communications.

The researchers analyzed cross-sectional and longitudinal data from the Understanding Society dataset and the Millennium Cohort Study. The cross-sectional data was used to investigate the existence of developmental windows of sensitivity to social media, while the longitudinal data was used to evaluate whether sex-specific windows of sensitivity to social media were present during the adolescence period.

These two datasets comprised 84,011 participants aged 10-80 years old. After applying the modeling framework, 17,409 participants aged 10-21 years were included in the analysis.

Longitudinal analyses revealed different developmental windows of sensitivity to social media during adolescence, with higher estimated social media use predicting lower life satisfaction scores 1 year later (regression coefficient [beta], −0.02; 95% confidence interval, −0.03 to −0.01; P = .004).

Among females, the researchers observed a window of sensitivity to social media between the ages of 11 and 13, with higher estimated social media use predicting lower life satisfaction ratings 1 year later (age 11: beta, −0.11; 95% CI, −0.21 to −0.02; P = .020; age 12: beta, −0.14; 95% CI, −0.22 to −0.07; P < .001; age 13: beta, −0.08; 95% CI, −0.15 to −0.01; P = .019).

Among males, a similar window was observed between the ages of 14 and 15 (age 14: beta, −0.10; 95% CI, −0.17 to −0.03; P = .005; age 15: beta, –0.18; 95% CI, −0.29 to −0.08; P = .001).

Furthermore, they showed that a later increase in sensitivity to social media, which was present at age 19 for both females and males, suggested a different underlying process was present in late adolescence (females: beta, −0.16; 95% CI, −0.25 to −0.07; P < .001; males: beta, −0.16; 95% CI, −0.26 to −0.07; P = .001).

“Speculatively, this might be related to changes in the social environment such as a move away from home and subsequent disruptions in social networks,” the researchers wrote.

Importantly, Dr. Orben and colleagues noted that these results should be interpreted with caution. Owing to the cross-sectional nature of the data, causality cannot be inferred from these findings.

“The findings reported here may enable investigation of potential mechanisms of interest, for example, in datasets with pubertal or additional social measurements,” they wrote. “One could also carry out more targeted investigations, for example, by examining the mental health measures only completed by select age ranges in the datasets.”
 

Digital literacy is important, expert says

“Digital literacy and education about social media use is warranted for all ages, starting young,” Yalda T. Uhls, MBA, PhD, of the department of psychology at the University of California, Los Angeles, said in an interview. “Attending to underlying issues for vulnerable ages, such as anxiety, as well as parental support is critical.”

“I would urge social media platforms to pay attention to what kinds of content they are making available to ensure the highest possible quality, and to embed things like suggestions for pauses and other ways to check in on someone who may be experiencing distress when on socials,” Dr. Uhls said. “We also need to increase access to mental health resources for young people and social media could help provide information for those experiencing issues.”

This study was supported by the University of Cambridge and the UK Medical Research Council. The authors reported no relevant disclosures. Dr. Uhls had no relevant disclosures.

A cross-sectional study in the United Kingdom has revealed an association between social media use and lower life satisfaction among children and adolescents aged 10-21 years.

“[Our] study provides evidence for age- and sex-specific windows of sensitivity to social media use in adolescence,” lead author Amy Orben, PhD, of the University of Cambridge (England), and colleagues wrote. The findings were published in Nature Communications.

The researchers analyzed cross-sectional and longitudinal data from the Understanding Society dataset and the Millennium Cohort Study. The cross-sectional data was used to investigate the existence of developmental windows of sensitivity to social media, while the longitudinal data was used to evaluate whether sex-specific windows of sensitivity to social media were present during the adolescence period.

These two datasets comprised 84,011 participants aged 10-80 years old. After applying the modeling framework, 17,409 participants aged 10-21 years were included in the analysis.

Longitudinal analyses revealed different developmental windows of sensitivity to social media during adolescence, with higher estimated social media use predicting lower life satisfaction scores 1 year later (regression coefficient [beta], −0.02; 95% confidence interval, −0.03 to −0.01; P = .004).

Among females, the researchers observed a window of sensitivity to social media between the ages of 11 and 13, with higher estimated social media use predicting lower life satisfaction ratings 1 year later (age 11: beta, −0.11; 95% CI, −0.21 to −0.02; P = .020; age 12: beta, −0.14; 95% CI, −0.22 to −0.07; P < .001; age 13: beta, −0.08; 95% CI, −0.15 to −0.01; P = .019).

Among males, a similar window was observed between the ages of 14 and 15 (age 14: beta, −0.10; 95% CI, −0.17 to −0.03; P = .005; age 15: beta, –0.18; 95% CI, −0.29 to −0.08; P = .001).

Furthermore, they showed that a later increase in sensitivity to social media, which was present at age 19 for both females and males, suggested a different underlying process was present in late adolescence (females: beta, −0.16; 95% CI, −0.25 to −0.07; P < .001; males: beta, −0.16; 95% CI, −0.26 to −0.07; P = .001).

“Speculatively, this might be related to changes in the social environment such as a move away from home and subsequent disruptions in social networks,” the researchers wrote.

Importantly, Dr. Orben and colleagues noted that these results should be interpreted with caution. Owing to the cross-sectional nature of the data, causality cannot be inferred from these findings.

“The findings reported here may enable investigation of potential mechanisms of interest, for example, in datasets with pubertal or additional social measurements,” they wrote. “One could also carry out more targeted investigations, for example, by examining the mental health measures only completed by select age ranges in the datasets.”
 

Digital literacy is important, expert says

“Digital literacy and education about social media use is warranted for all ages, starting young,” Yalda T. Uhls, MBA, PhD, of the department of psychology at the University of California, Los Angeles, said in an interview. “Attending to underlying issues for vulnerable ages, such as anxiety, as well as parental support is critical.”

“I would urge social media platforms to pay attention to what kinds of content they are making available to ensure the highest possible quality, and to embed things like suggestions for pauses and other ways to check in on someone who may be experiencing distress when on socials,” Dr. Uhls said. “We also need to increase access to mental health resources for young people and social media could help provide information for those experiencing issues.”

This study was supported by the University of Cambridge and the UK Medical Research Council. The authors reported no relevant disclosures. Dr. Uhls had no relevant disclosures.

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

Among Black and White children, higher socioeconomic status (SES) was associated with lower pediatric postoperative mortality, according to a cohort study published in JAMA Network Open. However, this association was not equitable when comparing Black and White children.

The results showed that postoperative mortality rates were significantly higher in Black children in the highest income category, compared with White children in the same category.

“[We] assessed whether increasing family SES is associated with lower pediatric postoperative mortality and, if so, whether this association is equitable among Black and White children,” Brittany L. Willer, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and colleagues wrote.

The researchers retrospectively analyzed data from 51 pediatric tertiary care hospitals apart of the Children’s Hospital Association Pediatric Health Information System. The cohort included children younger than 18 years who underwent inpatient surgical procedures between January 2004 and December 2020.

The exposures of interest were race and parental income quartile; the primary endpoint was risk-adjusted in-hospital mortality rates by race and parental income quartile.
 

Results

The study cohort included 1,378,111 participants, including 248,464 (18.0%) Black and 1,129,647 (82.0%) White children, respectively.

The overall mortality rate was 1.2%, and rates decreased as income quartile increased (1.4% in quartile 1 [lowest income]; 1.3% in quartile 2; 1.0% in quartile 3; and 0.9% in quartile 4 [highest income]; P < .001).

Among participants in the three lowest income quartiles, Black children had 33% greater odds of postoperative death versus White children (adjusted odds ratio, 1.33; 95% confidence interval, 1.27-1.39; P < .001). This difference persisted in children in the highest income quartile (aOR, 1.39; 95% CI, 1.25-1.54; P < .001).

In addition, postoperative mortality rates in Black children in the highest income quartile (1.30%; 95% CI, 1.19%-1.42%) were similar to those of White children in the lowest income quartile (1.20%; 95% CI, 1.16%-1.25%).

“These findings suggest that increasing family SES did not provide equitable advantage to Black, compared with White children, and interventions that target socioeconomic inequities alone may not fully address persistent racial disparities in pediatric postoperative mortality,” wrote Dr. Willer and colleagues. “A multifaceted approach that includes dismantling of socioeconomic barriers, equitable availability of comprehensive pediatric surgical care, and personalized care for children of all races is needed.”

The researchers acknowledged that a potential limitation of the study was the use of zip code–level median household income as a proxy for family SES.
 

A perspective

In an interview, Timothy Joos, MD, a Seattle internist and pediatrician in private practice, said “there is a fair dose of racism and classism inside all of us – recognizing and coming to terms with it are steps toward improving equity issues.

“As providers, we have to remind ourselves to give our most prompt and thorough care to the patients with the most acute and severe illnesses,” Dr. Joos said. “As organizations, we have to pursue feedback from all our clients, but with special outreach to those that are used to not having their voices heard.”

No funding sources were reported. The authors reported no relevant disclosures. Dr. Joos is a member of the Pediatric News editorial advisory board but had no other disclosures.

Among Black and White children, higher socioeconomic status (SES) was associated with lower pediatric postoperative mortality, according to a cohort study published in JAMA Network Open. However, this association was not equitable when comparing Black and White children.

The results showed that postoperative mortality rates were significantly higher in Black children in the highest income category, compared with White children in the same category.

“[We] assessed whether increasing family SES is associated with lower pediatric postoperative mortality and, if so, whether this association is equitable among Black and White children,” Brittany L. Willer, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and colleagues wrote.

The researchers retrospectively analyzed data from 51 pediatric tertiary care hospitals apart of the Children’s Hospital Association Pediatric Health Information System. The cohort included children younger than 18 years who underwent inpatient surgical procedures between January 2004 and December 2020.

The exposures of interest were race and parental income quartile; the primary endpoint was risk-adjusted in-hospital mortality rates by race and parental income quartile.
 

Results

The study cohort included 1,378,111 participants, including 248,464 (18.0%) Black and 1,129,647 (82.0%) White children, respectively.

The overall mortality rate was 1.2%, and rates decreased as income quartile increased (1.4% in quartile 1 [lowest income]; 1.3% in quartile 2; 1.0% in quartile 3; and 0.9% in quartile 4 [highest income]; P < .001).

Among participants in the three lowest income quartiles, Black children had 33% greater odds of postoperative death versus White children (adjusted odds ratio, 1.33; 95% confidence interval, 1.27-1.39; P < .001). This difference persisted in children in the highest income quartile (aOR, 1.39; 95% CI, 1.25-1.54; P < .001).

In addition, postoperative mortality rates in Black children in the highest income quartile (1.30%; 95% CI, 1.19%-1.42%) were similar to those of White children in the lowest income quartile (1.20%; 95% CI, 1.16%-1.25%).

“These findings suggest that increasing family SES did not provide equitable advantage to Black, compared with White children, and interventions that target socioeconomic inequities alone may not fully address persistent racial disparities in pediatric postoperative mortality,” wrote Dr. Willer and colleagues. “A multifaceted approach that includes dismantling of socioeconomic barriers, equitable availability of comprehensive pediatric surgical care, and personalized care for children of all races is needed.”

The researchers acknowledged that a potential limitation of the study was the use of zip code–level median household income as a proxy for family SES.
 

A perspective

In an interview, Timothy Joos, MD, a Seattle internist and pediatrician in private practice, said “there is a fair dose of racism and classism inside all of us – recognizing and coming to terms with it are steps toward improving equity issues.

“As providers, we have to remind ourselves to give our most prompt and thorough care to the patients with the most acute and severe illnesses,” Dr. Joos said. “As organizations, we have to pursue feedback from all our clients, but with special outreach to those that are used to not having their voices heard.”

No funding sources were reported. The authors reported no relevant disclosures. Dr. Joos is a member of the Pediatric News editorial advisory board but had no other disclosures.

Among Black and White children, higher socioeconomic status (SES) was associated with lower pediatric postoperative mortality, according to a cohort study published in JAMA Network Open. However, this association was not equitable when comparing Black and White children.

The results showed that postoperative mortality rates were significantly higher in Black children in the highest income category, compared with White children in the same category.

“[We] assessed whether increasing family SES is associated with lower pediatric postoperative mortality and, if so, whether this association is equitable among Black and White children,” Brittany L. Willer, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and colleagues wrote.

The researchers retrospectively analyzed data from 51 pediatric tertiary care hospitals apart of the Children’s Hospital Association Pediatric Health Information System. The cohort included children younger than 18 years who underwent inpatient surgical procedures between January 2004 and December 2020.

The exposures of interest were race and parental income quartile; the primary endpoint was risk-adjusted in-hospital mortality rates by race and parental income quartile.
 

Results

The study cohort included 1,378,111 participants, including 248,464 (18.0%) Black and 1,129,647 (82.0%) White children, respectively.

The overall mortality rate was 1.2%, and rates decreased as income quartile increased (1.4% in quartile 1 [lowest income]; 1.3% in quartile 2; 1.0% in quartile 3; and 0.9% in quartile 4 [highest income]; P < .001).

Among participants in the three lowest income quartiles, Black children had 33% greater odds of postoperative death versus White children (adjusted odds ratio, 1.33; 95% confidence interval, 1.27-1.39; P < .001). This difference persisted in children in the highest income quartile (aOR, 1.39; 95% CI, 1.25-1.54; P < .001).

In addition, postoperative mortality rates in Black children in the highest income quartile (1.30%; 95% CI, 1.19%-1.42%) were similar to those of White children in the lowest income quartile (1.20%; 95% CI, 1.16%-1.25%).

“These findings suggest that increasing family SES did not provide equitable advantage to Black, compared with White children, and interventions that target socioeconomic inequities alone may not fully address persistent racial disparities in pediatric postoperative mortality,” wrote Dr. Willer and colleagues. “A multifaceted approach that includes dismantling of socioeconomic barriers, equitable availability of comprehensive pediatric surgical care, and personalized care for children of all races is needed.”

The researchers acknowledged that a potential limitation of the study was the use of zip code–level median household income as a proxy for family SES.
 

A perspective

In an interview, Timothy Joos, MD, a Seattle internist and pediatrician in private practice, said “there is a fair dose of racism and classism inside all of us – recognizing and coming to terms with it are steps toward improving equity issues.

“As providers, we have to remind ourselves to give our most prompt and thorough care to the patients with the most acute and severe illnesses,” Dr. Joos said. “As organizations, we have to pursue feedback from all our clients, but with special outreach to those that are used to not having their voices heard.”

No funding sources were reported. The authors reported no relevant disclosures. Dr. Joos is a member of the Pediatric News editorial advisory board but had no other disclosures.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

A genomic study has revealed new insights into the function of anti-Müllerian hormone (AMH) in the context of reproductive biology and fertility.

Insights into the physiological, and potentially therapeutic, function were identified based on data from single-cell RNA sequencing, derived from transcriptomic analysis and immunolabeling of antral follicles.

“The specific contribution of elevated AMH to the molecular pathology of polycystic ovary syndrome (PCOS) and its defining clinical features is unclear, as no study, to date, has examined the effect of chronically elevated AMH in an experimentally controlled in vivo model,” study author Limor Man, MD, of Weill Cornell Medicine, New York, and colleagues wrote. The group’s findings were published in Science Advances.

The researchers used ovarian cortical xenografts with cotransplantation of engineered endothelial cells to examine the effect of chronic paracrine AMH stimulus on human folliculogenesis.

They cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and subsequent analysis. Overall, 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals, defined as intervals greater than 10 weeks.

The researchers found that long-term xenografts showed an accelerated growth rate in the setting of chronically elevated AMH and exhibited a molecular signature indicative of more advanced stages of follicle maturation, including that of luteinization.

In mice, exogenous AMH follicles showed a decreased ratio of primordial to growing follicles and antral follicles of increased diameter.

In addition, transcriptomic and immunolabeling analyses revealed that chronic high AMH had a marked influence on the growth and transcriptomic signature of antral-stage follicles, with a universal increase in factors related to the synthesis and/or metabolism of cholesterol and sex steroid hormones, as well as early expression of factors often seen at later stages of folliculogenesis.

“These data decouple elevated AMH from the metabolic and hyperandrogenic conditions that define PCOS and suggest that chronically elevated AMH induces a molecular cascade that contributes, at least in part, to the anovulatory phenotype in these patients,” the researchers wrote.

Furthermore, they found evidence to suggest that chronic high AMH can induce expression of the luteinizing hormone receptor at earlier stages of folliculogenesis, thereby worsening the disruptive effect of elevated luteinizing hormone from the pituitary.

“[These] findings underscore the broad influence of AMH on transcriptional activity and maturation state of follicles and support an independent role for dysregulation of AMH signaling in driving anovulation in women with PCOS,” they wrote.

While these findings are intriguing, the researchers cautioned against drawing conclusions from the study since elevated AMH is almost always seen in combination with one or more symptomatic hallmarks in PCOS.

“Despite [some] limitations, [our] analysis provides a deep and high-resolution examination of AMH action on human folliculogenesis and suggests a prominent effect on antral follicle maturation,” they explained.
 

Expert perspective

“From age 25, AMH levels begin their decline until reaching undetectable levels at menopause,” Mark P. Trolice, MD, director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview. “Women with PCOS experience a chronic and frustrating pathophysiologic problem whose origins and mechanism have evaded researchers for decades.

“As AMH elevations in utero may contribute to fetal susceptibility to PCOS, this study provides another potential link by suggesting that chronically elevated AMH induces anovulation,” he added. “We await, with great anticipation, future clinical studies to potentially further illustrate the apparent and intriguing role of AMH in the development of PCOS.”

This study was supported by the Queenie Victorina Neri Scholarship and a Research Grant from the American Society for Reproductive Medicine. One author reported financial relationships with Oviva Therapeutics; no other conflicts of interest were reported.

Among children and adolescents aged 5-18 years, concussion was associated with a higher risk of mental health problems, compared with age- and sex-matched children and adolescents with an orthopedic injury, according to a cohort study published in JAMA Network Open.

While concussions are one of the most common head injuries in the pediatric population, the extent to which they increase the risk of new onset psychiatric disorders or subsequent psychopathology is unclear, lead author Andrée-Anne Ledoux, PhD, of the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, and colleagues explained.

The researchers conducted a population-based retrospective cohort study to evaluate associations between concussion and risk of subsequent mental health issues, psychiatric hospitalizations, self-harm, or suicides in children and adolescents, with follow-up ranging from 1 month to 10 years.

The data were obtained from province-wide health administrative databases. Participants with concussion were included in an exposed group, while those with an orthopedic injury were included in a 1:2 age- and sex-matched comparison group.
 

Results

The study cohort comprised 448,803 participants, including 152,321 and 296,482 children and adolescents with concussion and orthopedic injury, respectively.

The incidence rates of any mental health problem were 11,141 per 100,000 person-years in the exposed group and 7,960 per 100,000 person-years in the unexposed group (difference, 3,181; 95% confidence interval, 3,073-3,291 per 100,000 person-years).

After concussion, the exposed group had a greater risk of developing a mental health issue (adjusted hazard ratio, 1.39; 95% CI, 1.37-1.40), psychiatric hospitalization (aHR, 1.47; 95% CI, 1.41-1.53), and self-harm (aHR, 1.49; 95% CI, 1.42-1.56). In addition, there was no significant difference in death by suicide between the exposed and unexposed groups (HR, 1.54; 95% CI, 0.90-2.61).

“Our results suggest that clinicians should assess for preexisting and new mental health symptoms throughout concussion recovery and treat mental health conditions or symptoms or refer the patient to a specialist in pediatric mental health,” wrote Dr. Ledoux and colleagues. “[Clinicians should also] assess suicidal ideation and self-harm behaviors during evaluation and follow-up visits for concussion.”

The researchers acknowledged that a key limitation of the study was the retrospective observational design. In addition, the identification of exposures using diagnostic billing codes could have introduced exposure or outcome misclassification.
 

Expert-recommended resources

“For more information, I’d recommend ‘Pedsconcussion,’ which are evidence-based living guidelines for pediatric concussion care,” Dr. Ledoux said in an interview. “Within domain 8, there are specific guidelines related to the management of mental health issues post concussion.”

Neuropsychology expert Talin Babikian, PhD, of the University of California, Los Angeles, commented: “Studies have shown that even a single psychoeducational session early after a concussion can minimize prolonged recoveries. Ensuring all stakeholders (family, clinicians, school, coach, peers) are on the same page and providing the same information is important to build trust and a sense of safety and agency.

“We want to provide psychoeducation early in the process to avoid unnecessary fear and avoidance. We also want to curtail misattribution of everyday symptoms or symptoms related to an unrelated condition to a brain injury, which are easier to do when caught early,” Dr. Babikian added.

This study was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-term Care. One author reported financial relationships with the University of Ottawa, the National Football League, Parachute Canada, and 360 Concussion Care, an interdisciplinary concussion clinic; no other conflicts of interest were reported.

Among children and adolescents aged 5-18 years, concussion was associated with a higher risk of mental health problems, compared with age- and sex-matched children and adolescents with an orthopedic injury, according to a cohort study published in JAMA Network Open.

While concussions are one of the most common head injuries in the pediatric population, the extent to which they increase the risk of new onset psychiatric disorders or subsequent psychopathology is unclear, lead author Andrée-Anne Ledoux, PhD, of the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, and colleagues explained.

The researchers conducted a population-based retrospective cohort study to evaluate associations between concussion and risk of subsequent mental health issues, psychiatric hospitalizations, self-harm, or suicides in children and adolescents, with follow-up ranging from 1 month to 10 years.

The data were obtained from province-wide health administrative databases. Participants with concussion were included in an exposed group, while those with an orthopedic injury were included in a 1:2 age- and sex-matched comparison group.
 

Results

The study cohort comprised 448,803 participants, including 152,321 and 296,482 children and adolescents with concussion and orthopedic injury, respectively.

The incidence rates of any mental health problem were 11,141 per 100,000 person-years in the exposed group and 7,960 per 100,000 person-years in the unexposed group (difference, 3,181; 95% confidence interval, 3,073-3,291 per 100,000 person-years).

After concussion, the exposed group had a greater risk of developing a mental health issue (adjusted hazard ratio, 1.39; 95% CI, 1.37-1.40), psychiatric hospitalization (aHR, 1.47; 95% CI, 1.41-1.53), and self-harm (aHR, 1.49; 95% CI, 1.42-1.56). In addition, there was no significant difference in death by suicide between the exposed and unexposed groups (HR, 1.54; 95% CI, 0.90-2.61).

“Our results suggest that clinicians should assess for preexisting and new mental health symptoms throughout concussion recovery and treat mental health conditions or symptoms or refer the patient to a specialist in pediatric mental health,” wrote Dr. Ledoux and colleagues. “[Clinicians should also] assess suicidal ideation and self-harm behaviors during evaluation and follow-up visits for concussion.”

The researchers acknowledged that a key limitation of the study was the retrospective observational design. In addition, the identification of exposures using diagnostic billing codes could have introduced exposure or outcome misclassification.
 

Expert-recommended resources

“For more information, I’d recommend ‘Pedsconcussion,’ which are evidence-based living guidelines for pediatric concussion care,” Dr. Ledoux said in an interview. “Within domain 8, there are specific guidelines related to the management of mental health issues post concussion.”

Neuropsychology expert Talin Babikian, PhD, of the University of California, Los Angeles, commented: “Studies have shown that even a single psychoeducational session early after a concussion can minimize prolonged recoveries. Ensuring all stakeholders (family, clinicians, school, coach, peers) are on the same page and providing the same information is important to build trust and a sense of safety and agency.

“We want to provide psychoeducation early in the process to avoid unnecessary fear and avoidance. We also want to curtail misattribution of everyday symptoms or symptoms related to an unrelated condition to a brain injury, which are easier to do when caught early,” Dr. Babikian added.

This study was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-term Care. One author reported financial relationships with the University of Ottawa, the National Football League, Parachute Canada, and 360 Concussion Care, an interdisciplinary concussion clinic; no other conflicts of interest were reported.

Among children and adolescents aged 5-18 years, concussion was associated with a higher risk of mental health problems, compared with age- and sex-matched children and adolescents with an orthopedic injury, according to a cohort study published in JAMA Network Open.

While concussions are one of the most common head injuries in the pediatric population, the extent to which they increase the risk of new onset psychiatric disorders or subsequent psychopathology is unclear, lead author Andrée-Anne Ledoux, PhD, of the Children’s Hospital of Eastern Ontario Research Institute, Ottawa, and colleagues explained.

The researchers conducted a population-based retrospective cohort study to evaluate associations between concussion and risk of subsequent mental health issues, psychiatric hospitalizations, self-harm, or suicides in children and adolescents, with follow-up ranging from 1 month to 10 years.

The data were obtained from province-wide health administrative databases. Participants with concussion were included in an exposed group, while those with an orthopedic injury were included in a 1:2 age- and sex-matched comparison group.
 

Results

The study cohort comprised 448,803 participants, including 152,321 and 296,482 children and adolescents with concussion and orthopedic injury, respectively.

The incidence rates of any mental health problem were 11,141 per 100,000 person-years in the exposed group and 7,960 per 100,000 person-years in the unexposed group (difference, 3,181; 95% confidence interval, 3,073-3,291 per 100,000 person-years).

After concussion, the exposed group had a greater risk of developing a mental health issue (adjusted hazard ratio, 1.39; 95% CI, 1.37-1.40), psychiatric hospitalization (aHR, 1.47; 95% CI, 1.41-1.53), and self-harm (aHR, 1.49; 95% CI, 1.42-1.56). In addition, there was no significant difference in death by suicide between the exposed and unexposed groups (HR, 1.54; 95% CI, 0.90-2.61).

“Our results suggest that clinicians should assess for preexisting and new mental health symptoms throughout concussion recovery and treat mental health conditions or symptoms or refer the patient to a specialist in pediatric mental health,” wrote Dr. Ledoux and colleagues. “[Clinicians should also] assess suicidal ideation and self-harm behaviors during evaluation and follow-up visits for concussion.”

The researchers acknowledged that a key limitation of the study was the retrospective observational design. In addition, the identification of exposures using diagnostic billing codes could have introduced exposure or outcome misclassification.
 

Expert-recommended resources

“For more information, I’d recommend ‘Pedsconcussion,’ which are evidence-based living guidelines for pediatric concussion care,” Dr. Ledoux said in an interview. “Within domain 8, there are specific guidelines related to the management of mental health issues post concussion.”

Neuropsychology expert Talin Babikian, PhD, of the University of California, Los Angeles, commented: “Studies have shown that even a single psychoeducational session early after a concussion can minimize prolonged recoveries. Ensuring all stakeholders (family, clinicians, school, coach, peers) are on the same page and providing the same information is important to build trust and a sense of safety and agency.

“We want to provide psychoeducation early in the process to avoid unnecessary fear and avoidance. We also want to curtail misattribution of everyday symptoms or symptoms related to an unrelated condition to a brain injury, which are easier to do when caught early,” Dr. Babikian added.

This study was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-term Care. One author reported financial relationships with the University of Ottawa, the National Football League, Parachute Canada, and 360 Concussion Care, an interdisciplinary concussion clinic; no other conflicts of interest were reported.

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

Circulating antiphospholipid autoantibodies may contribute to endothelial cell activation and dysfunction in severe COVID-19, researchers report.

In 2020, the same researchers reported results from a preclinical study demonstrating that autoantibodies from patients with active COVID-19 caused clotting in mice.

The new study, published in Arthritis and Rheumatology, found higher-than-expected levels of antiphospholipid autoantibodies in the blood samples of 244 patients hospitalized with COVID-19.

“While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain for the most part cryptic,” write Hui Shi, MD, PhD, and coauthors from the University of Michigan, Ann Arbor, and the National Heart, Lung, and Blood Institute.

When asked for comment on the study, Eline T. Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the Hospital of the University of Pennsylvania in Philadelphia, said, “The autopsy cases for COVID-19 strongly point to thromboembolic complications in many individuals who succumbed to sequelae of the infection.

“Importantly, however, many factors can contribute to this pathology, including the inflammatory milieu, monocyte activation, neutrophil extracellular traps, immune complexes, complement, as well as effects on endothelial cells,” explained Dr. Luning Prak, who was not involved in the study.

“The findings in this paper nicely complement another study by Schmaier et al. that came out recently in JCI Insight that also suggests that endothelial cells can be activated by antibodies, she said.
 

‘Even stronger connection between autoantibody formation and clotting in COVID-19’

Dr. Shi and her team cultured human endothelial cells in serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID sepsis. Using in-cell enzyme-linked immunosorbent assay, they measured levels of key cell adhesion molecules.

After analysis, the researchers found that serum from COVID-19 patients activated cultured endothelial cells to express surface adhesion molecules essential to inflammation and thrombosis, particularly E-selectin, ICAM-1, and VCAM-1.

“The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium,” they explain.

Further analyses revealed that, for a subset of serum samples from patients with severe infection, this activation could be mitigated by depleting total immunoglobulin G.

In addition, supplementation of control serum with patient IgG was adequate to trigger endothelial activation.

On the basis of these results, the researchers hypothesize that antiphospholipid autoantibodies may characterize antibody profiles in severe COVID-19 that activate the endothelium and transition the usually quiescent blood-vessel wall interface toward inflammation and coagulation.

“[These findings] provide an even stronger connection between autoantibody formation and clotting in COVID-19,” Dr. Shi said in an accompanying press release.

Clinical implications

From a clinical perspective, Dr. Shi and her team question whether patients with severe COVID-19 should be tested for antiphospholipid antibodies to assess their risk of thrombosis and progression to respiratory failure.

Moreover, they question whether patients with high antiphospholipid antibody titers might benefit from therapies used in conventional cases of severe antiphospholipid syndrome, such as plasmapheresis, anticoagulation therapy, and complement inhibition, Dr. Shi added.

The researchers hope to answer these and other remaining questions in future studies. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19.

“As we await definitive solutions to the pandemic, these findings add important context to the complex interplay between SARS-CoV-2 infection, the human immune system, and vascular immunobiology,” she concluded.

The study was supported by grants from the Rheumatology Research Foundation, the Michigan Medicine Frankel Cardiovascular Center, and the A. Alfred Taubman Medical Research Institute. One author is an inventor on an unrelated pending patent to the University of Michigan. The other authors and Dr. Luning Prak have disclosed no relevant financial relationships.

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

The Centers for Disease Control and Prevention and the American Academy of Pediatrics recently issued revised milestone guidelines for their developmental surveillance campaign, Learn the Signs, Act Early (LTSAE).

The new guidelines, published in Pediatrics, were drafted in “easy-to-understand” language and identify the behaviors that 75% or more of children should exhibit at certain ages based on developmental resources, existing data, and clinician experience. The previous milestone checklists, developed in 2004, used 50th percentile or average-age milestones.

The CDC, in collaboration with the AAP, convened a group of eight subject matter experts in various fields of child development, including a developmental pediatrician and researcher from Kennedy Krieger Institute, to develop new and clearer guidelines.

“The goals of the group were to identify evidence-informed milestones to include in CDC checklists, clarify when most children can be expected to reach a milestone (to discourage a wait-and-see approach), and support clinical judgment regarding screening between recommended ages,” wrote lead author Jennifer M. Zubler, MD, of the National Center on Birth Defects and Developmental Disabilities in Atlanta, and colleagues.
 

Key changes

The experts established 11 criteria for CDC surveillance milestones and tools, including milestones most children (75% or more) would be expected to reach by defined health supervision visit ages and those that are easily recognized in natural settings.

Criteria for developmental milestones and surveillance tools:

• Milestones are included at the age most (≥75%) children would be expected to demonstrate the milestone.
• Eliminate “warning signs.”
• Are easy for families of different social, cultural, and ethnic backgrounds to observe and use.
• Are able to be answered with yes, not yet, or not sure.
• Use plain language, avoiding vague terms like may, can, and begins.
• Are organized in developmental domains.
• Show progression of skills with age, when possible.
• Milestones are not repeated across checklists.
• Include open-ended questions.
• Include information for developmental promotion.
• Include information on how to act early if there are concerns.

The previous guidelines were critiqued by some clinicians as being “not helpful to individual families who had concerns about their child’s development,” and in some cases, led to delays in diagnoses as decision-makers opted for a “wait-and-see approach.”

“The earlier a child is identified with a developmental delay the better, as treatment as well as learning interventions can begin,” Paul Lipkin, MD, an associate professor of pediatrics at the Johns Hopkins University, Baltimore, said in an accompanying press release. “Revising the guidelines with expertise and data from clinicians in the field accomplishes these goals.”

Additional changes included new checklists for children between the ages of 15 and 30 months, additional social and emotional milestones, as well as the removal of complex language and duplicate milestones. The experts also developed new, open-ended questions to aid discussions with families.

“Review of a child’s development with these milestones opens up a continuous dialogue between a parent and the health care provider about their child’s present and future development,” said Dr. Lipkin.

Originally pioneered in 2005, the LTSAE awareness campaign provides free resources to clinicians and families to support early detection of children with developmental delays and disabilities. After the new guidelines were drafted, they were presented to parents of various racial groups, income levels, and educational backgrounds to confirm ease of use and understandability.

“These criteria and revised checklists can be used to support developmental surveillance, clinical judgment regarding additional developmental screening, and research in developmental surveillance processes,” wrote Dr. Zubler.
 

Expert perspective

“These new guidelines will allow us to catch more children with developmental delays as they raise the threshold to 75% of children achieving those milestones at that particular age,” Karalyn Kinsella, MD, a pediatrician in Cheshire, Conn., said in an interview.

Dr. Kinsella added that the new guidelines simplify the milestones and reduce redundancy across different developmental domains. “Most importantly, it gave me the opportunity to see just how great the CDC milestone tracker app is – I think parents would really like it.”

This project was supported by the CDC and Prevention of the Department of Health & Human Services. One author is a developer of the Ages & Stages Questionnaires and receives royalties from Brookes Publishing, the company that publishes this tool; the other authors have indicated they have no relevant conflicts of interest to disclose.

The Centers for Disease Control and Prevention and the American Academy of Pediatrics recently issued revised milestone guidelines for their developmental surveillance campaign, Learn the Signs, Act Early (LTSAE).

The new guidelines, published in Pediatrics, were drafted in “easy-to-understand” language and identify the behaviors that 75% or more of children should exhibit at certain ages based on developmental resources, existing data, and clinician experience. The previous milestone checklists, developed in 2004, used 50th percentile or average-age milestones.

The CDC, in collaboration with the AAP, convened a group of eight subject matter experts in various fields of child development, including a developmental pediatrician and researcher from Kennedy Krieger Institute, to develop new and clearer guidelines.

“The goals of the group were to identify evidence-informed milestones to include in CDC checklists, clarify when most children can be expected to reach a milestone (to discourage a wait-and-see approach), and support clinical judgment regarding screening between recommended ages,” wrote lead author Jennifer M. Zubler, MD, of the National Center on Birth Defects and Developmental Disabilities in Atlanta, and colleagues.
 

Key changes

The experts established 11 criteria for CDC surveillance milestones and tools, including milestones most children (75% or more) would be expected to reach by defined health supervision visit ages and those that are easily recognized in natural settings.

Criteria for developmental milestones and surveillance tools:

• Milestones are included at the age most (≥75%) children would be expected to demonstrate the milestone.
• Eliminate “warning signs.”
• Are easy for families of different social, cultural, and ethnic backgrounds to observe and use.
• Are able to be answered with yes, not yet, or not sure.
• Use plain language, avoiding vague terms like may, can, and begins.
• Are organized in developmental domains.
• Show progression of skills with age, when possible.
• Milestones are not repeated across checklists.
• Include open-ended questions.
• Include information for developmental promotion.
• Include information on how to act early if there are concerns.

The previous guidelines were critiqued by some clinicians as being “not helpful to individual families who had concerns about their child’s development,” and in some cases, led to delays in diagnoses as decision-makers opted for a “wait-and-see approach.”

“The earlier a child is identified with a developmental delay the better, as treatment as well as learning interventions can begin,” Paul Lipkin, MD, an associate professor of pediatrics at the Johns Hopkins University, Baltimore, said in an accompanying press release. “Revising the guidelines with expertise and data from clinicians in the field accomplishes these goals.”

Additional changes included new checklists for children between the ages of 15 and 30 months, additional social and emotional milestones, as well as the removal of complex language and duplicate milestones. The experts also developed new, open-ended questions to aid discussions with families.

“Review of a child’s development with these milestones opens up a continuous dialogue between a parent and the health care provider about their child’s present and future development,” said Dr. Lipkin.

Originally pioneered in 2005, the LTSAE awareness campaign provides free resources to clinicians and families to support early detection of children with developmental delays and disabilities. After the new guidelines were drafted, they were presented to parents of various racial groups, income levels, and educational backgrounds to confirm ease of use and understandability.

“These criteria and revised checklists can be used to support developmental surveillance, clinical judgment regarding additional developmental screening, and research in developmental surveillance processes,” wrote Dr. Zubler.
 

Expert perspective

“These new guidelines will allow us to catch more children with developmental delays as they raise the threshold to 75% of children achieving those milestones at that particular age,” Karalyn Kinsella, MD, a pediatrician in Cheshire, Conn., said in an interview.

Dr. Kinsella added that the new guidelines simplify the milestones and reduce redundancy across different developmental domains. “Most importantly, it gave me the opportunity to see just how great the CDC milestone tracker app is – I think parents would really like it.”

This project was supported by the CDC and Prevention of the Department of Health & Human Services. One author is a developer of the Ages & Stages Questionnaires and receives royalties from Brookes Publishing, the company that publishes this tool; the other authors have indicated they have no relevant conflicts of interest to disclose.

The Centers for Disease Control and Prevention and the American Academy of Pediatrics recently issued revised milestone guidelines for their developmental surveillance campaign, Learn the Signs, Act Early (LTSAE).

The new guidelines, published in Pediatrics, were drafted in “easy-to-understand” language and identify the behaviors that 75% or more of children should exhibit at certain ages based on developmental resources, existing data, and clinician experience. The previous milestone checklists, developed in 2004, used 50th percentile or average-age milestones.

The CDC, in collaboration with the AAP, convened a group of eight subject matter experts in various fields of child development, including a developmental pediatrician and researcher from Kennedy Krieger Institute, to develop new and clearer guidelines.

“The goals of the group were to identify evidence-informed milestones to include in CDC checklists, clarify when most children can be expected to reach a milestone (to discourage a wait-and-see approach), and support clinical judgment regarding screening between recommended ages,” wrote lead author Jennifer M. Zubler, MD, of the National Center on Birth Defects and Developmental Disabilities in Atlanta, and colleagues.
 

Key changes

The experts established 11 criteria for CDC surveillance milestones and tools, including milestones most children (75% or more) would be expected to reach by defined health supervision visit ages and those that are easily recognized in natural settings.

Criteria for developmental milestones and surveillance tools:

• Milestones are included at the age most (≥75%) children would be expected to demonstrate the milestone.
• Eliminate “warning signs.”
• Are easy for families of different social, cultural, and ethnic backgrounds to observe and use.
• Are able to be answered with yes, not yet, or not sure.
• Use plain language, avoiding vague terms like may, can, and begins.
• Are organized in developmental domains.
• Show progression of skills with age, when possible.
• Milestones are not repeated across checklists.
• Include open-ended questions.
• Include information for developmental promotion.
• Include information on how to act early if there are concerns.

The previous guidelines were critiqued by some clinicians as being “not helpful to individual families who had concerns about their child’s development,” and in some cases, led to delays in diagnoses as decision-makers opted for a “wait-and-see approach.”

“The earlier a child is identified with a developmental delay the better, as treatment as well as learning interventions can begin,” Paul Lipkin, MD, an associate professor of pediatrics at the Johns Hopkins University, Baltimore, said in an accompanying press release. “Revising the guidelines with expertise and data from clinicians in the field accomplishes these goals.”

Additional changes included new checklists for children between the ages of 15 and 30 months, additional social and emotional milestones, as well as the removal of complex language and duplicate milestones. The experts also developed new, open-ended questions to aid discussions with families.

“Review of a child’s development with these milestones opens up a continuous dialogue between a parent and the health care provider about their child’s present and future development,” said Dr. Lipkin.

Originally pioneered in 2005, the LTSAE awareness campaign provides free resources to clinicians and families to support early detection of children with developmental delays and disabilities. After the new guidelines were drafted, they were presented to parents of various racial groups, income levels, and educational backgrounds to confirm ease of use and understandability.

“These criteria and revised checklists can be used to support developmental surveillance, clinical judgment regarding additional developmental screening, and research in developmental surveillance processes,” wrote Dr. Zubler.
 

Expert perspective

“These new guidelines will allow us to catch more children with developmental delays as they raise the threshold to 75% of children achieving those milestones at that particular age,” Karalyn Kinsella, MD, a pediatrician in Cheshire, Conn., said in an interview.

Dr. Kinsella added that the new guidelines simplify the milestones and reduce redundancy across different developmental domains. “Most importantly, it gave me the opportunity to see just how great the CDC milestone tracker app is – I think parents would really like it.”

This project was supported by the CDC and Prevention of the Department of Health & Human Services. One author is a developer of the Ages & Stages Questionnaires and receives royalties from Brookes Publishing, the company that publishes this tool; the other authors have indicated they have no relevant conflicts of interest to disclose.

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.

Exposure to opioid analgesics during the first trimester of pregnancy appears to increase the risk of congenital anomalies diagnosed in the first year of life, researchers report.

While the absolute risk of congenital anomalies was low, these findings add to an increasing body of evidence suggesting that prenatal exposure to opioids may confer harm to infants post partum.

“We undertook a population-based cohort study to estimate associations between opioid analgesic exposure during the first trimester and congenital anomalies using health administrative data capturing all narcotic prescriptions during pregnancy,” lead author Alexa C. Bowie, MPH, of Queen’s University in Kingston, Ont., and colleagues reported in CMAJ.

The researchers retrospectively reviewed administrative health data in a single-payer health care system from 2013 to 2018. They identified parent-infant pair records for all live births and stillbirths that occurred at more than 20 weeks’ gestation.

The exposure of interest was a prescription for any opioid analgesic with a fill date between the estimated date of conception and less than 14 weeks’ gestation. The referent group included any infant not exposed to an opioid analgesic during the index pregnancy period.
 

Results

The study cohort included a total of 599,579 gestational parent-infant pairs. Of these, 11,903 (2.0%) were exposed to opioid analgesics, and most were exposed during the first trimester only (75.8%).

Overall, 2.0% of these infants developed a congenital anomaly during the first year of life; the prevalence of congenital anomalies was 2.0% in unexposed infants and 2.8% in exposed infants.

Relative to unexposed infants, the researchers observed greater risks among infants who were exposed for some anomaly groups, including many specific anomalies, such as ankyloglossia (any opioid: adjusted risk ratio, 1.88; 95% confidence interval, 1.30-2.72; codeine: aRR, 2.14; 95% CI, 1.35-3.40), as well as gastrointestinal anomalies (any opioid: aRR, 1.46; 95% CI, 1.15-1.85; codeine: aRR, 1.53; 95% CI, 1.12-2.09; tramadol: aRR, 2.69; 95% CI 1.34-5.38).

After sensitivity analyses, which included exposure 4 weeks before conception or excluded individuals with exposure to opioid analgesics before pregnancy, the findings remained unchanged.

“Although the overall risk was low, we observed an increased risk of any congenital anomaly with tramadol, and a previously unreported risk with morphine,” the researchers wrote.

“Previous studies reported elevated risks of heart anomalies with first-trimester exposure to any opioid analgesic, codeine, and tramadol, but others reported no association with any opioid analgesic or codeine,” they explained.
 

Interpreting the results

Study author Susan Brogly, PhD, of Queen’s University said “Our population-based study confirms evidence of a small increased risk of birth defects from opioid analgesic exposure in the first trimester that was observed in a recent study of private insurance and Medicaid beneficiaries in the U.S. We further show that this small increased risk is not due to other risk factors for fetal harm in women who may take these medications.”

“An opioid prescription dispensed in the first trimester would imply that there was an acute injury or chronic condition also present in the first trimester, which may also be associated with congenital abnormalities,” commented Elisabeth Poorman, MD, MPH, a clinical instructor and primary care physician at the University of Washington in Seattle.

“Opioid use disorder is often diagnosed incorrectly; since the researchers used diagnostic billing codes to exclude individuals with opioid use disorder, some women may have been missed,” Dr. Poorman explained.

Ms. Bowie and colleagues acknowledged that a key limitation of the study was the identification of cases using diagnostic billing codes. As a result, exposure-dependent recording bias could be present and limit the applicability of the findings.

“The diagnosis and documentation of minor anomalies and those with subtle medical significance could be vulnerable to exposure-dependent recording bias,” Ms. Bowie wrote.

Dr. Poorman recommended that these results should be interpreted with caution given these and other limitations. “Overall, results from this study may imply that there is limited evidence to suspect opioids are related to congenital abnormalities due to a very small difference observed in relatively unequal groups,” she concluded.

This study received funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development and was also supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health. One author reported receiving honoraria from the National Institutes of Health and a grant from the Canadian Institute of Health Research, outside the submitted work. No other competing interests were declared.