Women's Health

The impact of prediagnosis aspirin use on mortality in women with breast cancer is significantly tied to epigenetic changes in certain breast cancer-related genes, investigators reported.

While studies have shown aspirin reduces the risk of breast cancer development, there is limited and inconsistent data on the effect of aspirin on prognosis and mortality after a diagnosis of breast cancer, Tengteng Wang, PhD, from the department of epidemiology at the University of North Carolina at Chapel Hill and coauthors wrote in Cancer.

To address this, they analyzed data from 1,508 women who had a first diagnosis of primary breast cancer and were involved in the Long Island Breast Cancer Study Project; they then looked at the women’s methylation status, which is a mechanism of epigenetic change.

Around one in five participants reported ever using aspirin, and the analysis showed that ever use of aspirin was associated with an overall 13% decrease in breast cancer–specific mortality.

However researchers saw significant interactions between aspirin use and LINE-1 methylation status – which is a marker of methylation of genetic elements that play key roles in maintaining genomic stability – and breast cancer–specific genes.

They found that aspirin use in women with LINE-1 hypomethylation was associated with a risk of breast cancer–specific mortality that was 45% higher than that of nonusers (P = .05).

Compared with nonusers, aspirin users with methylated tumor BRCA1 promoter had significant 16% higher breast cancer mortality (P = .04) and 67% higher all-cause mortality (P = .02). However the study showed aspirin did not affect mortality in women with unmethylated BRCA1 promoter.

Among women with the PR breast cancer gene, aspirin use by those with methylation of the PR promoter was associated with a 63% higher breast cancer–specific mortality, but methylation showed no statistically significant effect on all-cause mortality, compared with nonusers.

The study found no significant change when they restricted the analysis to receptor-positive or invasive breast cancer, and the associations remained consistent even after adjusting for global methylation.

“Our findings suggest that the association between aspirin use and mortality after breast cancer may depend on methylation profiles and warrant further investigation,” the authors wrote. “These findings, if confirmed, may provide new biological insights into the association between aspirin use and breast cancer prognosis, may affect clinical decision making by identifying a subgroup of patients with breast cancer using epigenetic markers for whom prediagnosis aspirin use affects subsequent mortality, and may help refine risk-reduction strategies to improve survival among women with breast cancer.”

The study was partly supported by the National Institutes of Health. One author declared personal fees from the private sector outside the submitted work.

SOURCE: Wang T et al. Cancer. 2019 Aug 12. doi: 10.1002/cncr.32364.

The impact of prediagnosis aspirin use on mortality in women with breast cancer is significantly tied to epigenetic changes in certain breast cancer-related genes, investigators reported.

While studies have shown aspirin reduces the risk of breast cancer development, there is limited and inconsistent data on the effect of aspirin on prognosis and mortality after a diagnosis of breast cancer, Tengteng Wang, PhD, from the department of epidemiology at the University of North Carolina at Chapel Hill and coauthors wrote in Cancer.

To address this, they analyzed data from 1,508 women who had a first diagnosis of primary breast cancer and were involved in the Long Island Breast Cancer Study Project; they then looked at the women’s methylation status, which is a mechanism of epigenetic change.

Around one in five participants reported ever using aspirin, and the analysis showed that ever use of aspirin was associated with an overall 13% decrease in breast cancer–specific mortality.

However researchers saw significant interactions between aspirin use and LINE-1 methylation status – which is a marker of methylation of genetic elements that play key roles in maintaining genomic stability – and breast cancer–specific genes.

They found that aspirin use in women with LINE-1 hypomethylation was associated with a risk of breast cancer–specific mortality that was 45% higher than that of nonusers (P = .05).

Compared with nonusers, aspirin users with methylated tumor BRCA1 promoter had significant 16% higher breast cancer mortality (P = .04) and 67% higher all-cause mortality (P = .02). However the study showed aspirin did not affect mortality in women with unmethylated BRCA1 promoter.

Among women with the PR breast cancer gene, aspirin use by those with methylation of the PR promoter was associated with a 63% higher breast cancer–specific mortality, but methylation showed no statistically significant effect on all-cause mortality, compared with nonusers.

The study found no significant change when they restricted the analysis to receptor-positive or invasive breast cancer, and the associations remained consistent even after adjusting for global methylation.

“Our findings suggest that the association between aspirin use and mortality after breast cancer may depend on methylation profiles and warrant further investigation,” the authors wrote. “These findings, if confirmed, may provide new biological insights into the association between aspirin use and breast cancer prognosis, may affect clinical decision making by identifying a subgroup of patients with breast cancer using epigenetic markers for whom prediagnosis aspirin use affects subsequent mortality, and may help refine risk-reduction strategies to improve survival among women with breast cancer.”

The study was partly supported by the National Institutes of Health. One author declared personal fees from the private sector outside the submitted work.

SOURCE: Wang T et al. Cancer. 2019 Aug 12. doi: 10.1002/cncr.32364.

The impact of prediagnosis aspirin use on mortality in women with breast cancer is significantly tied to epigenetic changes in certain breast cancer-related genes, investigators reported.

While studies have shown aspirin reduces the risk of breast cancer development, there is limited and inconsistent data on the effect of aspirin on prognosis and mortality after a diagnosis of breast cancer, Tengteng Wang, PhD, from the department of epidemiology at the University of North Carolina at Chapel Hill and coauthors wrote in Cancer.

To address this, they analyzed data from 1,508 women who had a first diagnosis of primary breast cancer and were involved in the Long Island Breast Cancer Study Project; they then looked at the women’s methylation status, which is a mechanism of epigenetic change.

Around one in five participants reported ever using aspirin, and the analysis showed that ever use of aspirin was associated with an overall 13% decrease in breast cancer–specific mortality.

However researchers saw significant interactions between aspirin use and LINE-1 methylation status – which is a marker of methylation of genetic elements that play key roles in maintaining genomic stability – and breast cancer–specific genes.

They found that aspirin use in women with LINE-1 hypomethylation was associated with a risk of breast cancer–specific mortality that was 45% higher than that of nonusers (P = .05).

Compared with nonusers, aspirin users with methylated tumor BRCA1 promoter had significant 16% higher breast cancer mortality (P = .04) and 67% higher all-cause mortality (P = .02). However the study showed aspirin did not affect mortality in women with unmethylated BRCA1 promoter.

Among women with the PR breast cancer gene, aspirin use by those with methylation of the PR promoter was associated with a 63% higher breast cancer–specific mortality, but methylation showed no statistically significant effect on all-cause mortality, compared with nonusers.

The study found no significant change when they restricted the analysis to receptor-positive or invasive breast cancer, and the associations remained consistent even after adjusting for global methylation.

“Our findings suggest that the association between aspirin use and mortality after breast cancer may depend on methylation profiles and warrant further investigation,” the authors wrote. “These findings, if confirmed, may provide new biological insights into the association between aspirin use and breast cancer prognosis, may affect clinical decision making by identifying a subgroup of patients with breast cancer using epigenetic markers for whom prediagnosis aspirin use affects subsequent mortality, and may help refine risk-reduction strategies to improve survival among women with breast cancer.”

The study was partly supported by the National Institutes of Health. One author declared personal fees from the private sector outside the submitted work.

SOURCE: Wang T et al. Cancer. 2019 Aug 12. doi: 10.1002/cncr.32364.

SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.

“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.

Dr. Secor offered these pearls about PCOS:

• Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
• Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
• Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
• Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
• Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
• Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.

Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.

SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.

“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.

Dr. Secor offered these pearls about PCOS:

• Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
• Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
• Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
• Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
• Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
• Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.

Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.

SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.

“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.

Dr. Secor offered these pearls about PCOS:

• Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
• Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
• Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
• Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
• Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
• Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.

Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.

Here are 5 articles from the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Smoking cessation could delay or prevent rheumatoid arthritis

To take the posttest, go to: https://bit.ly/2YguN2r
Expires February 22, 2020

2. No increased pregnancy loss risk for women conceiving soon after stillbirth

To take the posttest, go to: https://bit.ly/2ZnMaLc
Expires March 4, 2020

3. Total plasma tau correlates with dementia onset, Alzheimer’s disease

To take the posttest, go to: https://bit.ly/2YeglYV
Expires March 9, 2020

4. MI, strokes spike during 30 days after cancer diagnosis

To take the posttest, go to: https://bit.ly/2GCKZAv
Expires March 12, 2020

5. Combination model predicts imminent preeclampsia

To take the posttest, go to: https://bit.ly/2LTohrO
Expires February 21, 2020

Here are 5 articles from the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Smoking cessation could delay or prevent rheumatoid arthritis

To take the posttest, go to: https://bit.ly/2YguN2r
Expires February 22, 2020

2. No increased pregnancy loss risk for women conceiving soon after stillbirth

To take the posttest, go to: https://bit.ly/2ZnMaLc
Expires March 4, 2020

3. Total plasma tau correlates with dementia onset, Alzheimer’s disease

To take the posttest, go to: https://bit.ly/2YeglYV
Expires March 9, 2020

4. MI, strokes spike during 30 days after cancer diagnosis

To take the posttest, go to: https://bit.ly/2GCKZAv
Expires March 12, 2020

5. Combination model predicts imminent preeclampsia

To take the posttest, go to: https://bit.ly/2LTohrO
Expires February 21, 2020

Here are 5 articles from the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Smoking cessation could delay or prevent rheumatoid arthritis

To take the posttest, go to: https://bit.ly/2YguN2r
Expires February 22, 2020

2. No increased pregnancy loss risk for women conceiving soon after stillbirth

To take the posttest, go to: https://bit.ly/2ZnMaLc
Expires March 4, 2020

3. Total plasma tau correlates with dementia onset, Alzheimer’s disease

To take the posttest, go to: https://bit.ly/2YeglYV
Expires March 9, 2020

4. MI, strokes spike during 30 days after cancer diagnosis

To take the posttest, go to: https://bit.ly/2GCKZAv
Expires March 12, 2020

5. Combination model predicts imminent preeclampsia

To take the posttest, go to: https://bit.ly/2LTohrO
Expires February 21, 2020

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

 

 

TREATMENT FAILURE

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

 

 

TREATMENT FAILURE

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

 

 

TREATMENT FAILURE

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

EVIDENCE SUMMARY

A 2013 systematic review studied the effect of dispensing a larger amount of pills on pregnancy rate, abortion rate, and overall cost to the health care system.¹ Three of the 4 studies analyzed found lower rates of pregnancy and abortion, as well as lower cost despite increased pill wastage, in the groups that received more medication. The 1 study that didn’t show a significant difference between groups compared only short durations (1 vs 4 months).

The systematic review included a large retrospective cohort study from 2011 that examined public insurance data from more than 84,000 patients to compare pregnancy rates in women who were given a 1-year supply of oral contraceptives (12 or 13 packs) vs those given 1 or 3 packs at a time.² The study found pregnancy rates of 2.9%, 3.3%, and 1.2% for 1, 3, and 12 or 13 months, respectively (P < .05; absolute risk reduction [ARR] = 1.7%; number needed to treat [NNT] = 59; relative risk reduction = 41%).

More pills lead to longer use of contraception

The systematic review also included a 2011 trial of 700 women starting oral contraceptives.³ It randomized them to receive a 7- or 3-month supply at their initial visit, then evaluated use of oral contraception at 6 months. All women were invited back for a 3-month follow-up visit, at which time the 3-month supply group would receive additional medication.

Fifty-one percent of the 7-month group were still using oral contraceptives at 6 months compared with 35% of the 3-month group (P < .001; NNT = 7). The contrast was starker for women younger than 18 years (49% vs 12%; NNT = 3). Notably, of the women who stopped using contraception, more in the 3-month group stopped because they ran out of medication (P = .02). Subjects in the 7-month group were more likely to have given birth and more likely to have 2 or more children.

A 2017 case study examined proposed legislation in California that required health plans to cover a 12-month supply of combined hormonal contraceptives.⁴ The California Health Benefits Review Program surveyed health insurers and reviewed contraception usage patterns. They found that, if the legislation passed, the state could expect a 30% reduction in unintended pregnancy (ARR = 2%; NNT = 50), resulting in 6000 fewer live births and 7000 fewer abortions per year.

RECOMMENDATIONS

The Centers for Disease Control and Prevention (CDC)’s Selected Practice Recommendations for Contraceptive Use recommend prescribing or providing as much as a 1-year supply of combined hormonal contraceptives at the initial visit and each return visit.⁵

The American College of Obstetricians and Gynecologists (ACOG) supports over-the-counter access to oral contraceptives, effectively allowing an unlimited supply.⁶

EDITOR’S TAKEAWAY

Adequate evidence of benefits and strong support from the CDC and ACOG should encourage us to offer 1-year supplies of combined oral contraceptives. Even though the higher-quality studies reviewed also showed a cost savings, up-front patient expense may remain a challenge.

EVIDENCE SUMMARY

A 2013 systematic review studied the effect of dispensing a larger amount of pills on pregnancy rate, abortion rate, and overall cost to the health care system.¹ Three of the 4 studies analyzed found lower rates of pregnancy and abortion, as well as lower cost despite increased pill wastage, in the groups that received more medication. The 1 study that didn’t show a significant difference between groups compared only short durations (1 vs 4 months).

The systematic review included a large retrospective cohort study from 2011 that examined public insurance data from more than 84,000 patients to compare pregnancy rates in women who were given a 1-year supply of oral contraceptives (12 or 13 packs) vs those given 1 or 3 packs at a time.² The study found pregnancy rates of 2.9%, 3.3%, and 1.2% for 1, 3, and 12 or 13 months, respectively (P < .05; absolute risk reduction [ARR] = 1.7%; number needed to treat [NNT] = 59; relative risk reduction = 41%).

More pills lead to longer use of contraception

The systematic review also included a 2011 trial of 700 women starting oral contraceptives.³ It randomized them to receive a 7- or 3-month supply at their initial visit, then evaluated use of oral contraception at 6 months. All women were invited back for a 3-month follow-up visit, at which time the 3-month supply group would receive additional medication.

Fifty-one percent of the 7-month group were still using oral contraceptives at 6 months compared with 35% of the 3-month group (P < .001; NNT = 7). The contrast was starker for women younger than 18 years (49% vs 12%; NNT = 3). Notably, of the women who stopped using contraception, more in the 3-month group stopped because they ran out of medication (P = .02). Subjects in the 7-month group were more likely to have given birth and more likely to have 2 or more children.

A 2017 case study examined proposed legislation in California that required health plans to cover a 12-month supply of combined hormonal contraceptives.⁴ The California Health Benefits Review Program surveyed health insurers and reviewed contraception usage patterns. They found that, if the legislation passed, the state could expect a 30% reduction in unintended pregnancy (ARR = 2%; NNT = 50), resulting in 6000 fewer live births and 7000 fewer abortions per year.

RECOMMENDATIONS

The Centers for Disease Control and Prevention (CDC)’s Selected Practice Recommendations for Contraceptive Use recommend prescribing or providing as much as a 1-year supply of combined hormonal contraceptives at the initial visit and each return visit.⁵

The American College of Obstetricians and Gynecologists (ACOG) supports over-the-counter access to oral contraceptives, effectively allowing an unlimited supply.⁶

EDITOR’S TAKEAWAY

Adequate evidence of benefits and strong support from the CDC and ACOG should encourage us to offer 1-year supplies of combined oral contraceptives. Even though the higher-quality studies reviewed also showed a cost savings, up-front patient expense may remain a challenge.

EVIDENCE SUMMARY

A 2013 systematic review studied the effect of dispensing a larger amount of pills on pregnancy rate, abortion rate, and overall cost to the health care system.¹ Three of the 4 studies analyzed found lower rates of pregnancy and abortion, as well as lower cost despite increased pill wastage, in the groups that received more medication. The 1 study that didn’t show a significant difference between groups compared only short durations (1 vs 4 months).

The systematic review included a large retrospective cohort study from 2011 that examined public insurance data from more than 84,000 patients to compare pregnancy rates in women who were given a 1-year supply of oral contraceptives (12 or 13 packs) vs those given 1 or 3 packs at a time.² The study found pregnancy rates of 2.9%, 3.3%, and 1.2% for 1, 3, and 12 or 13 months, respectively (P < .05; absolute risk reduction [ARR] = 1.7%; number needed to treat [NNT] = 59; relative risk reduction = 41%).

More pills lead to longer use of contraception

The systematic review also included a 2011 trial of 700 women starting oral contraceptives.³ It randomized them to receive a 7- or 3-month supply at their initial visit, then evaluated use of oral contraception at 6 months. All women were invited back for a 3-month follow-up visit, at which time the 3-month supply group would receive additional medication.

Fifty-one percent of the 7-month group were still using oral contraceptives at 6 months compared with 35% of the 3-month group (P < .001; NNT = 7). The contrast was starker for women younger than 18 years (49% vs 12%; NNT = 3). Notably, of the women who stopped using contraception, more in the 3-month group stopped because they ran out of medication (P = .02). Subjects in the 7-month group were more likely to have given birth and more likely to have 2 or more children.

A 2017 case study examined proposed legislation in California that required health plans to cover a 12-month supply of combined hormonal contraceptives.⁴ The California Health Benefits Review Program surveyed health insurers and reviewed contraception usage patterns. They found that, if the legislation passed, the state could expect a 30% reduction in unintended pregnancy (ARR = 2%; NNT = 50), resulting in 6000 fewer live births and 7000 fewer abortions per year.

RECOMMENDATIONS

The Centers for Disease Control and Prevention (CDC)’s Selected Practice Recommendations for Contraceptive Use recommend prescribing or providing as much as a 1-year supply of combined hormonal contraceptives at the initial visit and each return visit.⁵

The American College of Obstetricians and Gynecologists (ACOG) supports over-the-counter access to oral contraceptives, effectively allowing an unlimited supply.⁶

EDITOR’S TAKEAWAY

Adequate evidence of benefits and strong support from the CDC and ACOG should encourage us to offer 1-year supplies of combined oral contraceptives. Even though the higher-quality studies reviewed also showed a cost savings, up-front patient expense may remain a challenge.

The human placenta does not have a microbiome, and bacterial placental infection is not a common cause of adverse pregnancy outcomes such as preeclampsia or spontaneous preterm birth, a study has found.

dimarik/Getty Images

Dr. Marcus C. de Goffau, of Wellcome Sanger Institute, Cambridge, England, and coauthors wrote that placental dysfunction is linked to a number of common adverse pregnancy outcomes, but in many cases the cause of that dysfunction is unknown.

“Several studies have used sequencing-based methods for bacterial detection (metagenomics and 16S rRNA gene amplicon sequencing), and have concluded that the placenta is physiologically colonized by a diverse population of bacteria (the ‘placental microbiome’) and that the nature of this colonization may differ between healthy and complicated pregnancies,” they wrote.

In a paper published in the July 31 edition of Nature (doi: 10.1038/s41586-019-1451-5), researchers reported the outcomes of a study involving two cohorts. The first included 80 babies delivered by prelabor caesarean section, of whom 20 were small for gestational age, 20 were delivered to mothers with preeclampsia, and 40 were matched controls. The second cohort comprised 100 patients with preeclampsia, 100 small-for-gestational-age infants, 100 preterm births, and 198 matched controls, with two controls having been used twice.

The bacterial content of the placentas was analyzed via deep metagenomic sequencing of total DNA and 16S rRNA gene amplicon sequencing in cohort 1, and 16S rRNA gene amplicon from two different kits for cohort 2’s samples. In the first cohort, samples were also spiked with Salmonella bongori as a positive control.

For cohort 1, researchers were able to detect the S. bongori in all samples, but all other bacterial signals showed clear links to different batches, which the authors said showed they were the result of contamination. This was further supported by the discovery that the Escherichia coli signal seen in a number of batches was all from the same bacterial strain.

In the second cohort, researchers found Bradyrhizobium in nearly all samples, and Burkholderia – which has been thought to play a role in preterm birth – in some samples.

However in the case of the Burkholderia, significant variation between different runs of tests was found, and both Bradyrhizobium and Burkholderia were also found in negative controls.

Researchers also saw a high prevalence of four “ecologically unexpected” bacterial groups but were able to show that these were likely contaminants from a reagent used to wash the placental samples.

The study found that vaginal organisms such as lactobacilli and vaginosis-associated bacteria were more abundant in the second cohort, where babies were delivered by a mix of vaginal, intrapartum and prelabor caesarean section, compared with the first cohort, who were all prelabor caesarean section deliveries.

The only organism that met all the criteria for a genuine placenta-associated bacterial signal was Streptococcus agalactiae, but the authors found no association between it and pregnancy outcomes.

However, they did sound a warning that the perinatal transmission of S. agalactiae from the mother’s genital tract to the neonate could be a cause of fatal sepsis in the infant.

“Further studies will be required to determine the association between the presence of the organism in the placenta and fetal or neonatal disease,” they wrote.

The researchers also found significant associations between the delivery-associated vaginal bacteria Lactobacillus iners and preeclampsia, and between Streptococcus anginosus and the Ureaplasma genus – both of which are associated with vaginosis – and preterm birth.

“We conclude that bacterial placental infection is not a major cause of placentally related complications of human pregnancy and that the human placenta does not have a resident microbiome,” the authors wrote. “Although we see no evidence of a placental microbiome, the frequency of detection of vaginal bacteria in the placenta increased after intrapartum [cesarean] section, suggesting ascending or haematogenous spread.”

The Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre supported the study. Five authors declared grants and support from private industry outside the submitted work.

SOURCE: de Goffau M et al. Nature. 2019 Jul 31. doi: 10.1038/s41586-019-1451-5.

The human placenta does not have a microbiome, and bacterial placental infection is not a common cause of adverse pregnancy outcomes such as preeclampsia or spontaneous preterm birth, a study has found.

dimarik/Getty Images

Dr. Marcus C. de Goffau, of Wellcome Sanger Institute, Cambridge, England, and coauthors wrote that placental dysfunction is linked to a number of common adverse pregnancy outcomes, but in many cases the cause of that dysfunction is unknown.

“Several studies have used sequencing-based methods for bacterial detection (metagenomics and 16S rRNA gene amplicon sequencing), and have concluded that the placenta is physiologically colonized by a diverse population of bacteria (the ‘placental microbiome’) and that the nature of this colonization may differ between healthy and complicated pregnancies,” they wrote.

In a paper published in the July 31 edition of Nature (doi: 10.1038/s41586-019-1451-5), researchers reported the outcomes of a study involving two cohorts. The first included 80 babies delivered by prelabor caesarean section, of whom 20 were small for gestational age, 20 were delivered to mothers with preeclampsia, and 40 were matched controls. The second cohort comprised 100 patients with preeclampsia, 100 small-for-gestational-age infants, 100 preterm births, and 198 matched controls, with two controls having been used twice.

The bacterial content of the placentas was analyzed via deep metagenomic sequencing of total DNA and 16S rRNA gene amplicon sequencing in cohort 1, and 16S rRNA gene amplicon from two different kits for cohort 2’s samples. In the first cohort, samples were also spiked with Salmonella bongori as a positive control.

For cohort 1, researchers were able to detect the S. bongori in all samples, but all other bacterial signals showed clear links to different batches, which the authors said showed they were the result of contamination. This was further supported by the discovery that the Escherichia coli signal seen in a number of batches was all from the same bacterial strain.

In the second cohort, researchers found Bradyrhizobium in nearly all samples, and Burkholderia – which has been thought to play a role in preterm birth – in some samples.

However in the case of the Burkholderia, significant variation between different runs of tests was found, and both Bradyrhizobium and Burkholderia were also found in negative controls.

Researchers also saw a high prevalence of four “ecologically unexpected” bacterial groups but were able to show that these were likely contaminants from a reagent used to wash the placental samples.

The study found that vaginal organisms such as lactobacilli and vaginosis-associated bacteria were more abundant in the second cohort, where babies were delivered by a mix of vaginal, intrapartum and prelabor caesarean section, compared with the first cohort, who were all prelabor caesarean section deliveries.

The only organism that met all the criteria for a genuine placenta-associated bacterial signal was Streptococcus agalactiae, but the authors found no association between it and pregnancy outcomes.

However, they did sound a warning that the perinatal transmission of S. agalactiae from the mother’s genital tract to the neonate could be a cause of fatal sepsis in the infant.

“Further studies will be required to determine the association between the presence of the organism in the placenta and fetal or neonatal disease,” they wrote.

The researchers also found significant associations between the delivery-associated vaginal bacteria Lactobacillus iners and preeclampsia, and between Streptococcus anginosus and the Ureaplasma genus – both of which are associated with vaginosis – and preterm birth.

“We conclude that bacterial placental infection is not a major cause of placentally related complications of human pregnancy and that the human placenta does not have a resident microbiome,” the authors wrote. “Although we see no evidence of a placental microbiome, the frequency of detection of vaginal bacteria in the placenta increased after intrapartum [cesarean] section, suggesting ascending or haematogenous spread.”

The Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre supported the study. Five authors declared grants and support from private industry outside the submitted work.

SOURCE: de Goffau M et al. Nature. 2019 Jul 31. doi: 10.1038/s41586-019-1451-5.

The human placenta does not have a microbiome, and bacterial placental infection is not a common cause of adverse pregnancy outcomes such as preeclampsia or spontaneous preterm birth, a study has found.

dimarik/Getty Images

Dr. Marcus C. de Goffau, of Wellcome Sanger Institute, Cambridge, England, and coauthors wrote that placental dysfunction is linked to a number of common adverse pregnancy outcomes, but in many cases the cause of that dysfunction is unknown.

“Several studies have used sequencing-based methods for bacterial detection (metagenomics and 16S rRNA gene amplicon sequencing), and have concluded that the placenta is physiologically colonized by a diverse population of bacteria (the ‘placental microbiome’) and that the nature of this colonization may differ between healthy and complicated pregnancies,” they wrote.

In a paper published in the July 31 edition of Nature (doi: 10.1038/s41586-019-1451-5), researchers reported the outcomes of a study involving two cohorts. The first included 80 babies delivered by prelabor caesarean section, of whom 20 were small for gestational age, 20 were delivered to mothers with preeclampsia, and 40 were matched controls. The second cohort comprised 100 patients with preeclampsia, 100 small-for-gestational-age infants, 100 preterm births, and 198 matched controls, with two controls having been used twice.

The bacterial content of the placentas was analyzed via deep metagenomic sequencing of total DNA and 16S rRNA gene amplicon sequencing in cohort 1, and 16S rRNA gene amplicon from two different kits for cohort 2’s samples. In the first cohort, samples were also spiked with Salmonella bongori as a positive control.

For cohort 1, researchers were able to detect the S. bongori in all samples, but all other bacterial signals showed clear links to different batches, which the authors said showed they were the result of contamination. This was further supported by the discovery that the Escherichia coli signal seen in a number of batches was all from the same bacterial strain.

In the second cohort, researchers found Bradyrhizobium in nearly all samples, and Burkholderia – which has been thought to play a role in preterm birth – in some samples.

However in the case of the Burkholderia, significant variation between different runs of tests was found, and both Bradyrhizobium and Burkholderia were also found in negative controls.

Researchers also saw a high prevalence of four “ecologically unexpected” bacterial groups but were able to show that these were likely contaminants from a reagent used to wash the placental samples.

The study found that vaginal organisms such as lactobacilli and vaginosis-associated bacteria were more abundant in the second cohort, where babies were delivered by a mix of vaginal, intrapartum and prelabor caesarean section, compared with the first cohort, who were all prelabor caesarean section deliveries.

The only organism that met all the criteria for a genuine placenta-associated bacterial signal was Streptococcus agalactiae, but the authors found no association between it and pregnancy outcomes.

However, they did sound a warning that the perinatal transmission of S. agalactiae from the mother’s genital tract to the neonate could be a cause of fatal sepsis in the infant.

“Further studies will be required to determine the association between the presence of the organism in the placenta and fetal or neonatal disease,” they wrote.

The researchers also found significant associations between the delivery-associated vaginal bacteria Lactobacillus iners and preeclampsia, and between Streptococcus anginosus and the Ureaplasma genus – both of which are associated with vaginosis – and preterm birth.

“We conclude that bacterial placental infection is not a major cause of placentally related complications of human pregnancy and that the human placenta does not have a resident microbiome,” the authors wrote. “Although we see no evidence of a placental microbiome, the frequency of detection of vaginal bacteria in the placenta increased after intrapartum [cesarean] section, suggesting ascending or haematogenous spread.”

The Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre supported the study. Five authors declared grants and support from private industry outside the submitted work.

SOURCE: de Goffau M et al. Nature. 2019 Jul 31. doi: 10.1038/s41586-019-1451-5.

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

The general fertility rate in the United States decreased 2% between 2017 and 2018, according to a report from the Centers for Disease Control and Prevention.

©fotolia

Fertility rates, defined as births per 1,000 women aged 15-44 years, declined for all racial/ethnic groups studied.

Teen birth rates, or births among girls aged 15-19 years, declined from 2017 to 2018 as well.

These data come from the National Vital Statistics System’s Natality Data File, which includes information from birth certificates for all births in the United States.

The data show a decline in the general fertility rate from 60.3 per 1,000 women in 2017 to 59.1 per 1,000 women in 2018, a significant decrease (P less than .05).

Fertility rates declined across the three largest racial/ethnic groups studied, decreasing:

• 3% in Hispanic women, from 67.6 to 65.9 per 1,000.
• 2% in non-Hispanic black women, from 63.1 to 62.0 per 1,000.
• 2% in non-Hispanic white women, from 57.2 to 56.3 per 1,000.

Similarly, teen birth rates declined 7% from 2017 to 2018, decreasing from 18.8 to 17.4 births per 1,000 girls aged 15-19 years (P less than .05). Rates decreased:

• 8% in Hispanic teens, from 28.9 to 26.7 per 1,000.
• 4% in non-Hispanic black teens, from 27.5 to 26.3 per 1,000.
• 8% in non-Hispanic white teens, from 13.2 to 12.1 per 1,000.

The data also show an increase in the rate of vaginal births after previous cesarean (VBAC) delivery. The percentage of VBAC deliveries increased from 12.8% in 2017 to 13.3% in 2018 (P less than .05).

VBAC delivery rates increased across all racial/ethnic groups studied, although the increase among non-Hispanic back women was not significant.

Finally, the report shows an increase in preterm and early term births from 2017 to 2018. Preterm deliveries (less than 37 weeks of gestation) increased from 9.93% to 10.02%, and early term deliveries (37-38 weeks) increased from 26.00% to 26.53% (P less than .05).

At the same time, full-term births (39-40 weeks) decreased from 57.49% to 57.24%, and late- and post-term births (41 weeks or more) decreased from 6.58 % to 6.20% (P less than .05). These findings were consistent across the racial/ethnic groups studied.

jensmith@mdedge.com

SOURCE: Martin JA et al. NCHS Data Brief. 2019 July; no 346.

The general fertility rate in the United States decreased 2% between 2017 and 2018, according to a report from the Centers for Disease Control and Prevention.

©fotolia

Fertility rates, defined as births per 1,000 women aged 15-44 years, declined for all racial/ethnic groups studied.

Teen birth rates, or births among girls aged 15-19 years, declined from 2017 to 2018 as well.

These data come from the National Vital Statistics System’s Natality Data File, which includes information from birth certificates for all births in the United States.

The data show a decline in the general fertility rate from 60.3 per 1,000 women in 2017 to 59.1 per 1,000 women in 2018, a significant decrease (P less than .05).

Fertility rates declined across the three largest racial/ethnic groups studied, decreasing:

• 3% in Hispanic women, from 67.6 to 65.9 per 1,000.
• 2% in non-Hispanic black women, from 63.1 to 62.0 per 1,000.
• 2% in non-Hispanic white women, from 57.2 to 56.3 per 1,000.

Similarly, teen birth rates declined 7% from 2017 to 2018, decreasing from 18.8 to 17.4 births per 1,000 girls aged 15-19 years (P less than .05). Rates decreased:

• 8% in Hispanic teens, from 28.9 to 26.7 per 1,000.
• 4% in non-Hispanic black teens, from 27.5 to 26.3 per 1,000.
• 8% in non-Hispanic white teens, from 13.2 to 12.1 per 1,000.

The data also show an increase in the rate of vaginal births after previous cesarean (VBAC) delivery. The percentage of VBAC deliveries increased from 12.8% in 2017 to 13.3% in 2018 (P less than .05).

VBAC delivery rates increased across all racial/ethnic groups studied, although the increase among non-Hispanic back women was not significant.

Finally, the report shows an increase in preterm and early term births from 2017 to 2018. Preterm deliveries (less than 37 weeks of gestation) increased from 9.93% to 10.02%, and early term deliveries (37-38 weeks) increased from 26.00% to 26.53% (P less than .05).

At the same time, full-term births (39-40 weeks) decreased from 57.49% to 57.24%, and late- and post-term births (41 weeks or more) decreased from 6.58 % to 6.20% (P less than .05). These findings were consistent across the racial/ethnic groups studied.

jensmith@mdedge.com

SOURCE: Martin JA et al. NCHS Data Brief. 2019 July; no 346.

The general fertility rate in the United States decreased 2% between 2017 and 2018, according to a report from the Centers for Disease Control and Prevention.

©fotolia

Fertility rates, defined as births per 1,000 women aged 15-44 years, declined for all racial/ethnic groups studied.

Teen birth rates, or births among girls aged 15-19 years, declined from 2017 to 2018 as well.

These data come from the National Vital Statistics System’s Natality Data File, which includes information from birth certificates for all births in the United States.

The data show a decline in the general fertility rate from 60.3 per 1,000 women in 2017 to 59.1 per 1,000 women in 2018, a significant decrease (P less than .05).

Fertility rates declined across the three largest racial/ethnic groups studied, decreasing:

• 3% in Hispanic women, from 67.6 to 65.9 per 1,000.
• 2% in non-Hispanic black women, from 63.1 to 62.0 per 1,000.
• 2% in non-Hispanic white women, from 57.2 to 56.3 per 1,000.

Similarly, teen birth rates declined 7% from 2017 to 2018, decreasing from 18.8 to 17.4 births per 1,000 girls aged 15-19 years (P less than .05). Rates decreased:

• 8% in Hispanic teens, from 28.9 to 26.7 per 1,000.
• 4% in non-Hispanic black teens, from 27.5 to 26.3 per 1,000.
• 8% in non-Hispanic white teens, from 13.2 to 12.1 per 1,000.

The data also show an increase in the rate of vaginal births after previous cesarean (VBAC) delivery. The percentage of VBAC deliveries increased from 12.8% in 2017 to 13.3% in 2018 (P less than .05).

VBAC delivery rates increased across all racial/ethnic groups studied, although the increase among non-Hispanic back women was not significant.

Finally, the report shows an increase in preterm and early term births from 2017 to 2018. Preterm deliveries (less than 37 weeks of gestation) increased from 9.93% to 10.02%, and early term deliveries (37-38 weeks) increased from 26.00% to 26.53% (P less than .05).

At the same time, full-term births (39-40 weeks) decreased from 57.49% to 57.24%, and late- and post-term births (41 weeks or more) decreased from 6.58 % to 6.20% (P less than .05). These findings were consistent across the racial/ethnic groups studied.

jensmith@mdedge.com

SOURCE: Martin JA et al. NCHS Data Brief. 2019 July; no 346.

Timely postpartum care for Medicaid enrollees varies considerably, ranging from 17% to 74% among the states, according to the Centers for Medicare & Medicaid Services.

A national median of 60% of women saw a health care provider within 21-56 days of their delivery, CMS reported in its Medicaid and Children’s Health Insurance Program Scorecard.

“Medicaid is the largest payer for maternity care in the United States. The program has an important role to play in improving maternal and perinatal health outcomes,” the CMS noted.

New Hampshire’s rate of 74% was the highest of any state, just edging out Maryland and Rhode Island, each at 73%. The only other states over 70% were Connecticut and New York, which both reported rates of 71%, scorecard data show.

In Wyoming, the state with the lowest rate, 17% of Medicaid enrollees received timely postpartum care. The other four states with rates below 40% were Oklahoma (22%), Colorado (35%), Iowa (37%), and Missouri (38%), the CMS said after a recent refresh of data in the scorecard.


“The included populations … can vary by state. For example, some states report data on certain populations such as those covered under managed care but not those covered under fee for service. This variation in data and calculation methods can affect measure performance and comparisons between states,” the CMS said.

The scorecard is based on Mathematica analysis of Medicaid and CHIP Program System reports for the 2017 Adult Core Set, and the measurement period was Nov. 6, 2015, to Nov. 5, 2016. Twelve states did not report data on postpartum care to the CMS.

“More and more states are voluntarily reporting their health outcomes in the scorecard, and the new data is leading us into an era of increased transparency and accountability, so that together we can improve the quality of care we give to the vulnerable Americans that depend on this vital program,” CMS Administrator Seema Verma said in a written statement.

rfranki@mdedge.com

Timely postpartum care for Medicaid enrollees varies considerably, ranging from 17% to 74% among the states, according to the Centers for Medicare & Medicaid Services.

A national median of 60% of women saw a health care provider within 21-56 days of their delivery, CMS reported in its Medicaid and Children’s Health Insurance Program Scorecard.

“Medicaid is the largest payer for maternity care in the United States. The program has an important role to play in improving maternal and perinatal health outcomes,” the CMS noted.

New Hampshire’s rate of 74% was the highest of any state, just edging out Maryland and Rhode Island, each at 73%. The only other states over 70% were Connecticut and New York, which both reported rates of 71%, scorecard data show.

In Wyoming, the state with the lowest rate, 17% of Medicaid enrollees received timely postpartum care. The other four states with rates below 40% were Oklahoma (22%), Colorado (35%), Iowa (37%), and Missouri (38%), the CMS said after a recent refresh of data in the scorecard.


“The included populations … can vary by state. For example, some states report data on certain populations such as those covered under managed care but not those covered under fee for service. This variation in data and calculation methods can affect measure performance and comparisons between states,” the CMS said.

The scorecard is based on Mathematica analysis of Medicaid and CHIP Program System reports for the 2017 Adult Core Set, and the measurement period was Nov. 6, 2015, to Nov. 5, 2016. Twelve states did not report data on postpartum care to the CMS.

“More and more states are voluntarily reporting their health outcomes in the scorecard, and the new data is leading us into an era of increased transparency and accountability, so that together we can improve the quality of care we give to the vulnerable Americans that depend on this vital program,” CMS Administrator Seema Verma said in a written statement.

rfranki@mdedge.com

Timely postpartum care for Medicaid enrollees varies considerably, ranging from 17% to 74% among the states, according to the Centers for Medicare & Medicaid Services.

A national median of 60% of women saw a health care provider within 21-56 days of their delivery, CMS reported in its Medicaid and Children’s Health Insurance Program Scorecard.

“Medicaid is the largest payer for maternity care in the United States. The program has an important role to play in improving maternal and perinatal health outcomes,” the CMS noted.

New Hampshire’s rate of 74% was the highest of any state, just edging out Maryland and Rhode Island, each at 73%. The only other states over 70% were Connecticut and New York, which both reported rates of 71%, scorecard data show.

In Wyoming, the state with the lowest rate, 17% of Medicaid enrollees received timely postpartum care. The other four states with rates below 40% were Oklahoma (22%), Colorado (35%), Iowa (37%), and Missouri (38%), the CMS said after a recent refresh of data in the scorecard.


“The included populations … can vary by state. For example, some states report data on certain populations such as those covered under managed care but not those covered under fee for service. This variation in data and calculation methods can affect measure performance and comparisons between states,” the CMS said.

The scorecard is based on Mathematica analysis of Medicaid and CHIP Program System reports for the 2017 Adult Core Set, and the measurement period was Nov. 6, 2015, to Nov. 5, 2016. Twelve states did not report data on postpartum care to the CMS.

“More and more states are voluntarily reporting their health outcomes in the scorecard, and the new data is leading us into an era of increased transparency and accountability, so that together we can improve the quality of care we give to the vulnerable Americans that depend on this vital program,” CMS Administrator Seema Verma said in a written statement.

rfranki@mdedge.com

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.