This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

This year’s Menopause Update focuses on 2 menopause-related issues relevant to ObGyns and our menopausal patients:

• choosing the safest regimens, particularly with respect to risk of breast cancer, when prescribing hormone therapy (HT) to menopausal women
• reviewing the risks and benefits of premenopausal bilateral salpingo-oophorectomy and the pros and cons of replacement HT in surgically menopausal patients.

We hope that you find this updated information useful as you care for menopausal women.

Revisiting menopausal HT  and the risk of breast cancer:  What we know now

Abenhaim HA, Suissa S,  Azoulay L, et al. Menopausal hormone therapy formulation and breast cancer risk. Obstet Gynecol. 2022;139:1103-1110. doi: 10.1097/AOG.0000000000004723.

Reevaluation of the Women’s Health Initiative randomized controlled trials (WHI RCTs), long-term (median follow-up more than 20 years) cumulative  follow-up data, and results from additional studies have suggested that estrogen therapy (ET) alone in menopausal women with prior hysterectomy does not increase the risk of breast cancer. By contrast, estrogen with progestin (synthetic progestogens that include medroxyprogesterone acetate [MPA] and norethindrone acetate) slightly increases the risk of breast cancer. In the past 10 years, several publications have shed light on whether the type of progestogen affects the risk of breast cancer and can help provide evidence-based information to guide clinicians.

Breast cancer risk with combined HT and synthetic progestin

In the first part of the WHI RCT, women were randomly assigned to receive either conjugated equine estrogen (CEE) plus synthetic progestin (MPA) or a placebo. Combined estrogen-progestin therapy (EPT) was associated with a modestly elevated risk of breast cancer.¹ In the second part of the WHI trial, CEE only (estrogen alone, ET) was compared with placebo among women with prior  hysterectomy, with no effect found on breast cancer incidence.²

Most older observational studies published in 2003 to 2005 found that neither CEE nor estradiol appeared to increase the risk of breast cancer when used alone.^3-5 However, estrogen use in combination with synthetic progestins (MPA, norethindrone, levonorgestrel, and norgestrel) has been associated with an increased risk of breast cancer,^4,6 while the elevated risk of breast cancer with micronized progesterone has been less substantial.^7,8

Continue to: Newer data suggest the type of progestogen used affects risk...

In a report published in the June 2022 issue of Obstetrics and Gynecology, Abenhaim and colleagues used a nested population-based case-control study of administrative data available in the UK Clinical Practice Research Datalink and provider prescriptions to evaluate the additive effect on the risk of breast cancer of the type of progestogen (micronized progesterone or synthetic progestins) when combined with estradiol for the treatment of menopausal symptoms.⁹ A cohort of 561,379 women was included in the case-control study (10:1 ratio), 43,183 in the case group (patients diagnosed with invasive breast cancer), and 431,830 in the matched control group.

Overall, in the stratified analysis, a small but significant increase in the risk of breast cancer was found in ever users of menopausal HT (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.09–1.15). Neither estradiol (OR, 1.04; 95% CI, 1.00–1.09) nor CEE (OR, 1.01; 95% CI, 0.96–1.06) was associated with an elevated risk of being diagnosed with invasive breast cancer. Of note, no elevated risk of breast cancer was associated with combination estrogen-progesterone therapy. However, the risk of breast cancer for women who had used synthetic progestins, mostly MPA, was significantly elevated (OR, 1.28; 95% CI, 1.22-1.35). Notably, this modestly elevated odds ratio with the use of estrogen-progestin HT is almost identical to that observed with CEE/ MPA in the WHI.¹ Similar findings were found in women aged 50 to 60 years.

The adjusted analyses from the large WHI RCTs provide additional support: the synthetic progestin MPA combined with CEE showed a higher risk of breast cancer than CEE alone in women with prior hysterectomy.¹⁰

In the long-term follow-up of the WHI RCTs, after a median of 20.3 years postrandomization, prior randomization to CEE alone for postmenopausal women with prior hysterectomy was associated with a significantly lowered risk of breast cancer incidence and mortality.¹¹ By contrast, prior randomization to CEE plus MPA (EPT) for women with an intact uterus was associated with a small but significantly increased incidence of breast cancer but no significant difference in breast cancer mortality.

In the French E3N EPIC population-based prospective cohort study, Fournier and colleagues^4,5 found that women who received estrogen combined with synthetic progestins (mostly MPA) had a higher risk of breast cancer, with an age-adjusted relative risk of 1.4 (95% CI, 1.2–1.7), a finding not seen in women who received estrogen combined with micronized progesterone, similar to findings by Cordina-Duverger and colleagues and Simin and colleagues.^12,13 In the E3N study, only 948 women were identified with breast cancer; 268 of these had used synthetic progestins.^4,5

Both the Abenhaim cohort⁹ and the longterm outcomes of WHI RCT trial data¹¹ found a significant contributing effect of MPA (synthetic progestin) in the risk of breast cancer. Progestogens are not thought to exert a class effect. Although it is clear that progestogens (progesterone or progestins) prevent estrogeninduced endometrial neoplasia when dosed adequately, different types of progestogens have a differential risk of breast epithelium proliferation and carcinogenic potential.¹⁴ A systematic review by Stute and colleagues found that micronized progesterone did not appear to alter mammographic breast density assessments or breast biopsy results.¹⁵

Race considerations

The study by Abenhaim and colleagues was unable to address the issues of race or ethnicity.⁹ However, in the racially diverse WHI trial of women with prior hysterectomy, estrogen-alone use significantly reduced breast cancer incidence in all participants.^10,16 Post hoc analysis of the 1,616 Black women with prior hysterectomy in the WHI RCT showed a significantly decreased breast cancer incidence with use of estrogen alone (hazard ratio [HR], 0.47; 95% CI, 0.26–0.82).¹ When race was evaluated in the long-term cumulative follow-up of the WHI trial, estrogen-alone use significantly reduced breast cancer incidence in Black women, with no adverse effect on coronary heart disease, global index, or all-cause mortality, and with fewer cases of venous thromboembolism.¹⁷ The global index findings were favorable for Black women in their 50s and those with vasomotor symptoms.

Continue to: Impact of HT in women with an elevated risk of breast cancer...

Impact of HT in women with an elevated risk of breast cancer

Abenhaim and colleagues could not evaluate the effect of HT in women with a baseline elevated risk of breast cancer.⁹ For these women, HT may be recommended after premature surgical menopause due to increased risks for coronary heart disease, osteoporosis, genitourinary syndrome of menopause, and cognitive changes when estrogen is not taken postsurgery through to at least the average age of menopause, considered age 51.^18,19

Marchetti and colleagues reviewed 3 clinical trials that assessed breast cancer events in 1,100 BRCA gene mutation carriers with intact breasts who underwent risk-reducing salpingo-oophorectomy (RRSO) who used or did not use HT.²⁰ For BRCA1 and BRCA2 mutation carriers who received HT after RRSO, no elevated risk of breast cancer risk was seen (HR, 0.98; 95% CI, 0.63–1.52). There was a nonsignificant reduction in breast cancer risk for the estrogen-alone users compared with EPT HT (OR, 0.53; 95% CI, 0.25–1.15). Thus, short-term use of HT, estrogen alone or EPT, does not appear to elevate the risk of breast cancer after RRSO in these high-risk women.

Individualizing HT  for menopausal symptoms

The data presented provide reassuring evidence that longer-term use of ET does not appear to increase breast cancer risk, regardless of the type of estrogen (CEE or estradiol).^4,5,9,11 For women with a uterus, micronized progesterone has less (if any) effect on breast cancer risk. By contrast, the use of synthetic progestins (such as MPA), when combined with estrogen, has been associated with a small but real increased breast cancer risk.

The most evident benefit of HT is in treating vasomotor symptoms and preventing bone loss for those at elevated risk in healthy women without contraindications who initiate systemic HT when younger than age 60 or within 10 years of menopause onset. Benefit and risk ratio depends on age and time from menopause onset when HT is initiated. Hormone therapy safety varies depending on type, dose, duration, route of administration, timing of initiation, and whether, and type, of progestogen is used. Transdermal estradiol, particularly when dosed at 0.05 mg or less, has been shown to have less thrombotic and stroke risk than oral estrogen.²¹

Individualizing treatment includes using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of benefits and risks of continuing or discontinuing HT or changing to lower doses. ObGyns who follow best practices in prescribing systemic HT can now help menopausal patients with bothersome symptoms take advantage of systemic HT’s benefits while providing reassurance regarding menopausal HT’s safety.¹⁸ Transdermal therapy is a safer option for women at elevated baseline risk of venous thrombosis (for example, obese women) and older patients. Likewise, given its safety with respect to risk of breast cancer, the use of micronized progesterone over synthetic progestins should be considered when prescribing EPT to women with an intact uterus.

Continue to: Benefits of avoiding BSO in women at average risk of ovarian cancer...

Benefits of avoiding BSO in women at average risk of ovarian cancer

Erickson Z, Rocca WA, Smith CY, et al. Time trends in unilateral and bilateral oophorectomy in a geographically defined American population. Obstet Gynecol. 2022;139:724-734. doi: 10.1097/ AOG.0000000000004728.

In 2005, gynecologist William Parker, MD, and colleagues used modeling methodology to assess the long-term risks and benefits of performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women at average risk for ovarian cancer.²³ They concluded that practicing ovarian conservation until age 65 increased women’s long-term survival. Among their findings were that women with BSO before age 55 had an 8.6% excess overall mortality by age 80, while those with oophorectomy before age 59 had 3.9% excess mortality. They noted a sustained, but decreasing, mortality benefit until the age of 75 and stated that at no age did their model suggest higher mortality in women who chose ovarian conservation. Parker and colleagues concluded that ovarian conservation until at least age 65 benefited long-term survival for women at average risk for ovarian cancer when undergoing hysterectomy for benign disease.²³

Certain risks decreased, others increased

A second report in 2009 by Parker and colleagues from the large prospective Nurses’ Health Study found that, while BSO at the time of hysterectomy for benign disease was associated with a decreased risk of breast and ovarian cancer, BSO was associated with an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer.²⁴ Similar to the findings of the 2005 report, the authors noted that in no analysis or age group was BSO associated with increased survival. They also noted that compared with those who underwent BSO before age 50 and used ET, women with no history of ET use had an approximately 2-fold elevated risk of new onset coronary heart disease (HR, 1.98; 95% CI, 1.18–3.32).²⁴

In 2007, Walter Rocca, MD, a Mayo Clinic neurologist with a particular interest in the epidemiology of dementia, and colleagues at the Mayo Clinic published results of a study that assessed a cohort of women who had undergone unilateral oophorectomy or BSO prior to the onset of menopause.²⁵ The risk of cognitive impairment or dementia was higher in these women compared with women who had intact ovaries (HR, 1.46; 95% CI, 1.13-1.90). Of note, this elevated risk was confined to those who underwent oophorectomy before 49 years of age and were not prescribed estrogen until age 50 or older.²⁵

In a subsequent publication, Rocca and colleagues pointed out that BSO prior to menopause not only is associated with higher rates of all-cause mortality and cognitive impairment but also with coronary heart disease, parkinsonism, osteoporosis, and other chronic conditions associated with aging, including metabolic, mental health, and arthritic disorders.²⁶

Oophorectomy trends tracked

Given these and other reports²⁷ that highlighted the health risks of premenopausal BSO in women at average risk for ovarian cancer, Rocca and colleagues recently assessed trends in the occurrence of unilateral oophorectomy or BSO versus ovarian conservation among all women residing in the Minnesota county (Olmsted) in which Mayo Clinic is located, and who underwent gynecologic surgery between 1950 and 2018.²⁸

The investigators limited their analysis to women who had undergone unilateral oophorectomy or BSO between ages 18 and 49 years (these women are assumed to have been premenopausal). The authors considered as indications for oophorectomy primary or metastatic ovarian cancer, risk-reducing BSO for women at elevated risk for ovarian cancer (for example, strong family history or known BRCA gene mutation), adnexal mass, endometriosis, torsion, and other benign gynecologic conditions that included pelvic pain, abscess, oophoritis, or ectopic pregnancy. When more than 1 indication for ovarian surgery was present, the authors used the most clinically important indication. Unilateral oophorectomy or BSO was considered not indicated if the surgery was performed during another primary procedure (usually hysterectomy) without indication, or if the surgeon referred to the ovarian surgery as elective.

Results. Among 5,154 women who had oophorectomies between 1950 and 2018, the proportion of these women who underwent unilateral oophorectomy and BSO was 40.6% and 59.4%, respectively.

For most years between 1950 and 1979, the incidence of unilateral oophorectomy was higher than BSO. However, from 1980 to 2004, the incidence of BSO increased more than 2-fold while the incidence of unilateral surgery declined. After 2005, however, both types of ovarian surgery declined. During the years 2005–2018, a marked decline in BSO occurred, with the reduced incidence in premenopausal BSO most notable among women undergoing hysterectomy or those without an indication for oophorectomy.

Historically, ObGyns were taught that the benefits of removing normal ovaries (to prevent ovarian cancer) in average-risk women at the time of hysterectomy outweighed the risks. We agree with the authors’ speculation that beginning with Parker’s 2005 publication,²³ ObGyns have become more conservative in performing unindicated BSO in women at average risk for ovarian cancer, now recognizing that the harms of this procedure often outweigh any benefits.²⁸

Women with BRCA1 and BRCA2 gene mutations are at elevated risk for ovarian, tubal, and breast malignancies. In this population, risk-reducing BSO dramatically lowers future risk of ovarian and tubal cancer.

Data addressing the effect of RRSO in BRCA1 and BRCA2 gene mutation carriers continue to be evaluated, with differences between the 2 mutations, but they suggest that the surgery reduces not only ovarian cancer and tubal cancer but also possibly breast cancer.²⁹

Continue to: Trends show decline in ET use in surgically menopausal women... 

Trends show decline in ET use in surgically menopausal women 

Suzuki Y, Huang Y, Melamed A, et al. Use of estrogen therapy after surgical menopause in women who are premenopausal. Obstet Gynecol. 2022;139:756-763. doi: 10.1097/AOG.0000000000004762.

In addition to highlighting the risks associated with premenopausal BSO in women at average risk for ovarian cancer, the reports referred to above also underscore that the use of replacement menopausal HT in premenopausal women who undergo BSO prevents morbidity and mortality that otherwise accompanies surgical menopause. In addition, the North American Menopause Society (NAMS) recommends replacement menopausal HT in the setting of induced early menopause when no contraindications are present.¹⁸

To assess the prevalence of HT use in surgically menopausal women, investigators at Columbia University College of Physicians and Surgeons used a national database that captures health insurance claims for some 280 million US patients, focusing on women aged 18 to 50 years who underwent BSO from 2008 to 2019.³⁰ The great majority of women in this database have private insurance. Although the authors used the term estrogen therapy in their article, this term refers to systemic estrogen alone or with progestogen, as well as vaginal ET (personal communication with Jason Wright, MD, a coauthor of the study, May 19, 2022). In this Update section, we use the term HT to include use of any systemic HT or vaginal estrogen.

Prevalence of HT use changed over time period and patient age range

Among almost 61,980 evaluable women who had undergone BSO (median age, 45 years; 75.1% with concomitant hysterectomy; median follow-up time, 27 months), with no history of gynecologic or breast cancer, HT was used within 3 years of BSO by 64.5%. The highest percentage of women in this cohort who used HT peaked in 2008 (69.5%), declining to 58.2% by 2016. The median duration of HT use was 5.3 months. The prevalence of HT use 3 years after BSO declined with age, from 79.1% in women aged 18–29 to 60.0% in women aged 45–50.³⁰

This report, published in the June 2022 issue of Obstetrics and Gynecology, makes several sobering observations: Many surgically menopausal women aged 50 years and younger are not prescribed HT, the proportion of such women receiving a prescription for HT is declining over time, and the duration of HT use following BSO is short. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781-1792. doi: 10.1056/NEJMoa2201295.

Expert Commentary

In the nonpregnant population, medical management of hypertension >140/90 mm Hg is standard practice. By contrast, much higher blood pressures (BPs; up to 160/110 mm Hg) traditionally have been tolerated in pregnant patients with chronic hypertension without initiating treatment, and existing medications are often discontinued during pregnancy. Concern for impaired fetal growth as well as lack of data on improved outcomes have led to different recommendations for the management of mild chronic hypertension in pregnancy. However, chronic hypertension affects a substantial number of pregnant patients and is known to be a risk factor for severe short-term pregnancy and long-term health complications. With preliminary data suggesting that BPs >140/90 mm Hg prior to 20 weeks’ gestation are associated with an increase in adverse outcomes, Tita and colleagues sought to determine the effects of decreasing BP in pregnant patients with mild chronic hypertension.

Details about the study

This is an investigator-initiated, multicenter, pragmatic, open-label, randomized control trial of 2,408 patients with mild chronic hypertension. The active treatment group was treated with antihypertensive medication (including titration of existing medication), targeting a BP of <140/90 mm Hg. The control group only received medication for severe hypertension (≥160 mm Hg systolic or ≥105 mm Hg diastolic). The primary outcome of the study was a composite of preeclampsia with severe features, medically indicated preterm delivery prior to 35 weeks’ gestation (not spontaneous labor or rupture of membranes), placental abruption, and fetal or neonatal death. Birthweight that was less than the 10th percentile was used as a safety outcome. The hypothesis was that treatment would decrease the rate of adverse pregnancy and fetal/neonatal outcomes.

The patient population of singleton pregnancies at a gestational age of less than 23 weeks included 56% with known chronic hypertension on medications, 22% with known chronic hypertension without medications, and 22% with newly diagnosed (during pregnancy) chronic hypertension. The treatment group primarily received labetalol (61.7%) or nifedipine (35.6%); the maximum dose of a single agent was used as tolerated prior to adding a second agent. The control group only received an antihypertensive medication for severe hypertension.

Treatment of chronic hypertension demonstrated a decreased risk of the composite adverse outcome with an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<.001) and a number needed to treat (NNT) of 14.7. When analyzed separately, a similar risk reduction was noted for both preeclampsia with severe features and medically indicated preterm birth <35 weeks’ gestation. There was no statistical difference between the groups for birth weight <10th percentile and <5th percentile (adjusted risk ratio, 1.04 [0.82–1.31] vs 0.89 [0.62–1.26], respectively).

Planned subgroup analysis by type of chronic hypertension, race/ethnic group, diabetes status, gestational age at baseline, and body mass index (BMI) demonstrated a similar treatment effect to the overall composite primary outcome, with the exception of patients with newly diagnosed chronic hypertension or BMI ≥40 kg/m². Overall maternal and neonatal composite outcomes of severe complications did not differ between treatment and control groups; however, rates of severe preeclampsia, any preeclampsia, preterm birth rate, and birthweight <2,500 g were all lower in the treatment group.

Study strengths and weaknesses

The study strengths cited are a large sample size, multiple study sites, an independent data and safety monitoring board with close oversight, and centralized blinded confirmation of outcomes. Another strength is that the patient population of the study was similar to the overall population of pregnant patients in the United States with chronic hypertension in terms of age, race, and ethnicity.

The weaknesses of the study include the open-label design and the high ratio of screened to enrolled patients. Both of these issues appear related to the study design (ethics and logistics of a blinded treatment and gestational age cutoff) and the physiology of pregnancy (expected decrease in BP in the second trimester rendering patients ineligible due to lower BP). The study was also not powered to assess treatment effect in all of the subgroups, and further evaluation of patients with newly diagnosed chronic hypertension and BMI ≥ 40 kg/m² is needed. ●

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

The evaluation and management of chronic pelvic pain in patients with a history of Essure device (Bayer HealthCare Pharmaceuticals Inc, Whippany, New Jersey) insertion have posed many challenges for both clinicians and patients. The availability of high-quality, evidence-based clinical guidance has been limited. We have reviewed the currently available published data, and here provide an overview of takeaways, as well as share our perspective and approach on evaluating and managing chronic pelvic pain in this unique patient population.

The device

The Essure microinsert is a hysteroscopically placed device that facilitates permanent sterilization by occluding the bilateral proximal fallopian tubes. The microinsert has an inner and outer nitinol coil that attaches the device to the proximal fallopian tube to ensure retention. The inner coil releases polyethylene terephthalate fibers that cause tubal fiber proliferation to occlude the lumen of the fallopian tube and achieve sterilization.

The device was first approved by the US Food and Drug Administration (FDA) in 2002. In subsequent years, the device was well received and widely used, with approximately 750,000 women worldwide undergoing Essure placement.^1,2 Shortly after approval, many adverse events (AEs), including pelvic pain and abnormal uterine bleeding, were reported, resulting in a public meeting of the FDA Obstetrics and Gynecology Devices Panel in September 2015. A postmarket surveillance study on the device ensued to assess complication rates including unplanned pregnancy, pelvic pain, and surgery for removal. In February 2016, the FDA issued a black box warning and a patient decision checklist.^3,4 In December 2018, Bayer stopped selling and distributing Essure in the United States.⁵ A 4-year follow-up surveillance study on Essure was submitted to the FDA in March 2020.

Adverse outcomes

Common AEs related to the Essure device include heavy uterine bleeding, pelvic pain, and other quality-of-life symptoms such as fatigue and weight gain.^6-8 The main safety endpoints for the mandated FDA postmarket 522 surveillance studies were chronic lower abdominal and pelvic pain; abnormal uterine bleeding; hypersensitivity; allergic reaction, as well as autoimmune disorders incorporating inflammatory markers and human leukocyte antigen; and gynecologic surgery for device removal.⁹ Postmarket surveillence has shown that most AEs are related to placement complications or pelvic pain after Essure insertion. However, there have been several reports of autoimmune diseases categorized as serious AEs, such as new-onset systemic lupus erythematosus, rheumatoid arthritis, and worsening ulcerative colitis, after Essure insertion.⁵

Evaluation of symptoms

Prevalence of pelvic pain following device placement

We conducted a PubMed and MEDLINE search from January 2000 to May 2020, which identified 43 studies citing AEs related to device placement, including pelvic or abdominal pain, abnormal uterine bleeding, hypersensitivity, and autoimmune disorders. A particularly debilitating and frequently cited AE was new-onset pelvic pain or worsening of preexisting pelvic pain. Perforation of the uterus or fallopian tube, resulting in displacement of the device into the peritoneal cavity, or fragmentation of the microinsert was reported as a serious AE that occurred after device placement. However, due to the complexity of chronic pelvic pain pathogenesis, the effect of the insert on patients with existing chronic pelvic pain remains unknown.

Authors of a large retrospective study found that approximately 2.7% of 1,430 patients developed new-onset or worsening pelvic pain after device placement. New-onset pelvic pain in 1% of patients was thought to be secondary to device placement, without a coexisting pathology or diagnosis.¹⁰

In a retrospective study by Clark and colleagues, 22 of 50 women (44%) with pelvic pain after microinsert placement were found to have at least one other cause of pelvic pain. The most common alternative diagnoses were endometriosis, adenomyosis, salpingitis, and adhesive disease. Nine of the 50 patients (18%) were found to have endometriosis upon surgical removal of the microinsert.⁷

Another case series examined outcomes in 29 patients undergoing laparoscopic device removal due to new-onset pelvic pain. Intraoperative findings included endometriosis in 5 patients (17.2%) and pelvic adhesions in 3 (10.3%).² Chronic pelvic pain secondary to endometriosis may be exacerbated with Essure insertion due to discontinuation of hormonal birth control after device placement,⁷ and this diagnosis along with adenomyosis should be strongly considered in patients whose pelvic pain began when hormonal contraception was discontinued after placement of the device.

Continue to: Risk factors...

Authors of a retrospective cohort study found that patients with prior diagnosis of a chronic pain syndrome, low back pain, headaches, or fibromyalgia were 5 to 6 times more likely to report acute and chronic pain after hysteroscopic sterilization with Essure.¹¹ Since chronic pain is often thought to be driven by a hyperalgesic state of the central nervous system, as previously shown in patients with conditions such as vulvodynia, interstitial cystitis, and fibromyalgia,¹² a hyperalgesic state can potentially explain why some patients are more susceptible to developing worsening pain.

Van Limburg and colleagues conducted a retrospective cohort study with prospective follow-up on 284 women who underwent Essure sterilization. Among these patients, 48% reported negative AEs; risk factors included young age at placement, increasing gravidity, and no prior abdominal surgery.¹³

Onset of pain

The timing and onset of pelvic pain vary widely, suggesting there is no particular time frame for this AE after device placement.^2,6,14-18 A case series by Arjona and colleagues analyzed the incidence of chronic pelvic pain in 4,274 patients after Essure sterilization. Seven patients (0.16%) reported chronic pelvic pain that necessitated device removal. In 6 of the women, the pelvic pain began within 1 week of device placement. In 3 of the 6 cases, the surgeon reported the removal procedures as “difficult.” In all 6 cases, the level of pelvic pain increased with time and was not alleviated with standard analgesic medications.⁶

In another case series of 26 patients, the authors evaluated patients undergoing laparoscopic removal of Essure secondary to pelvic pain and reported that the time range for symptom presentation was immediate to 85 months. Thirteen of 26 patients (50%) reported pain onset within less than 1 month of device placement, 5 of 26 patients (19.2%) reported pain between 1 and 12 months after device placement, and 8 of 26 patients (30.8%) reported pain onset more than 12 months after microinsert placement.² In this study, 17.2% of operative reports indicated difficulty with device placement. It is unclear whether difficulty with placement was associated with development of subsequent abdominal or pelvic pain; however, the relevance of initial insertion difficulty diminished with longer follow-up.

Workup and evaluation

We found 5 studies that provided some framework for evaluating a patient with new-onset or worsening pelvic pain after microinsert placement. Overall, correct placement and functionality of the device should be confirmed by either hysterosalpingogram (HSG) or transvaginal ultrasonography (TVUS). The gold standard to determine tubal occlusion is the HSG. However, TVUS may be a dependable alternative, and either test can accurately demonstrate Essure location.¹⁹ Patients often prefer TVUS over HSG due to the low cost, minimal discomfort, and short examination time.¹ TVUS is a noninvasive and reasonable test to start the initial assessment. The Essure devices are highly echogenic on pelvic ultrasound and easily identifiable by the proximity of the device to the uterotubal junction and its relationship with the surrounding soft tissue. If the device perforates the peritoneal cavity, then the echogenic bowel can impede adequate visualization of the Essure microinsert. If the Essure insert is not visualized on TVUS, an HSG will not only confirm placement but also test insert functionality. After confirming correct placement of the device, the provider can proceed with standard workup for chronic pelvic pain.

If one or more of the devices are malpositioned, the devices are generally presumed to be the etiology of the new pain. Multiple case reports demonstrate pain due to Essure misconfiguration or perforation with subsequent resolution of symptoms after device removal.^18,20,21 A case study by Alcantara and colleagues described a patient with chronic pelvic pain and an Essure coil that was curved in an elliptical shape, not adhering to the anatomic course of the fallopian tube. The patient reported pain resolution after laparoscopic removal of the device.²⁰ Another case report by Mahmoud et al described a subserosal malpositioned device that caused acute pelvic pain 4 months after sterilization. The patient reported resolution of pain after the microinsert was removed via laparoscopy.²¹ These reports highlight the importance of considering malpositioned devices as the etiology of new pelvic pain after Essure placement.

Continue to: Device removal and patient outcomes...

Removal

Several studies that we evaluated included a discussion on the methods for Essure removal. which are divided into 2 general categories: hysteroscopy and laparoscopy.

Hysteroscopic removal is generally used when the device was placed less than 12 weeks prior to removal.^7,19 After 12 weeks, removal is more difficult due to fibrosis within the fallopian tubes. A risk with hysteroscopic removal is failure to remove all fibers, which allows inflammation and fibrosis to continue.⁷ This risk is mitigated via laparoscopic hysterectomy or mini-cornuectomy with bilateral salpingectomy, where the devices can be removed en bloc and without excessive traction.

Laparoscopic Essure removal procedures described in the literature include salpingostomy and traction on the device, salpingectomy, and salpingectomy with mini-cornuectomy. The incision and traction method is typically performed via a 2- to 3-cm incision on the antimesial edge of the fallopian tube along with a circumferential incision to surround the interstitial tubal area. The implant is carefully extracted from the fallopian tube and cornua, and a salpingectomy is then performed.²² The implant is removed prior to the salpingectomy to ensure that the Essure device is removed in its entirety prior to performing a salpingectomy.

A prospective observational study evaluated laparoscopic removal of Essure devices in 80 women with or without cornual excision. Results suggest that the incision and traction method poses more technical difficulties than the cornuectomy approach.²³ Surgeons reported significant difficulty controlling the tensile pressure with traction, whereas use of the cornuectomy approach eliminated this risk and decreased the risk of fragmentation and incomplete removal.^23,24

Charavil and colleagues demonstrated in a prospective observational study that a vaginal hysterectomy with bilateral salpingectomy is a feasible approach to Essure removal. Twenty-six vaginal hysterectomies with bilateral salpingectomy and Essure removal were performed without conversion to laparoscopy or laparotomy. The surgeons performed an en bloc removal of each hemiuterus along with the ipsilateral tube, which ensured complete removal of the Essure device. Each case was confirmed with an x-ray of the surgical specimen.²⁵

If device fragmentation occurs, there are different methods recommended for locating fragments. A case report of bilateral uterine perforation after uncomplicated Essure placement used a preoperative computed tomography (CT) scan to locate the Essure fragments, but no intraoperative imaging was performed to confirm complete fragment removal.²⁶ The patient continued reporting chronic pelvic pain and ultimately underwent exploratory laparotomy with intraoperative fluoroscopy. Using fluoroscopy, investigators identified omental fragments that were missed on preoperative CT imaging. Fluoroscopy is not commonly used intraoperatively, but it may have added benefit for localizing retained fragments.

A retrospective cohort study reviewed the use of intraoperative x-ray of the removed specimen to confirm complete Essure removal.²⁷ If an x-ray of the removed specimen showed incomplete removal, an intraoperative pelvic x-ray was performed to locate missing fragments. X-ray of the removed devices confirmed complete removal in 63 of 72 patients (87.5%). Six of 9 women with an unsatisfactory specimen x-ray had no residual fragments identified during pelvic x-ray, and the device removal was deemed adequate. The remaining 3 women had radiologic evidence of incomplete device removal and required additional dissection for complete removal. Overall, use of x-ray or fluoroscopy is a relatively safe and accessible way to ensure complete removal of the Essure device and is worth consideration, especially when retained device fragments are suspected.

Symptom resolution

We reviewed 5 studies that examined pain outcomes after removal of the Essure devices. Casey et al found that 23 of 26 patients (88.5%) reported significant pain relief at the postoperative visit, while 3 of 26 (11.5%) reported persistent pelvic pain.² Two of 3 case series examined other outcomes in addition to postoperative pelvic pain, including sexual function and activities of daily living.^7,14 In the first case series by Brito and colleagues, 8 of 11 patients (72.7%) reported an improvement in pelvic pain, ability to perform daily activities, sexual life, and overall quality of life after Essure removal. For the remaining 3 patients with persistent pelvic pain after surgical removal of the device, 2 patients reported worsening pain symptoms and dyspareunia.¹⁴ In this study, 5 of 11 patients reported a history of chronic pelvic pain at baseline. In a retrospective case series by Clark et al, 28 of 32 women (87.5%) reported some improvement in all domains, with 24 of 32 patients (75%) reporting almost total or complete improvement in quality of life, sexual life, pelvic pain, and scores related to activities of daily living. Pain and quality-of-life scores were similar for women who underwent uterine-preserving surgery and for those who underwent hysterectomy. Ten of 32 women (31.3%) reported persistent or worsening symptoms after the Essure removal surgery. In these patients, the authors recommended consideration of other autoimmune and hypersensitivity etiologies.⁷

In a retrospective cohort study by Kamencic et al from 2002 to 2013 of 1,430 patients who underwent Essure placement with postplacement imaging, 62 patients (4.3%) required a second surgery after Essure placement due to pelvic pain.¹⁰ This study also found that 4 of 62 patients (0.3%) had no other obvious cause for the pelvic pain. All 4 of these women had complete resolution of their pain with removal of the Essure microinsert device. A prospective observational study by Chene et al examined health-related quality-of-life outcomes in 80 women who underwent laparoscopic Essure removal for pelvic pain. This survey study demonstrated significant improvement in the quality of life in both psychological and physical aspects, and these results were maintained at 3- and 6-month follow-up examinations.²³

Summary

Although Essure products were withdrawn from the market in the United States in 2018, many patients still experience significant AEs associated with the device. The goal of the perspectives and data presented here is to assist clinicians in addressing and managing the pain experienced by patients after device insertion. ●

​​​​​​​

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

Oxytocin and prostaglandins are critically important regulators of uterine contraction. Obstetrician-gynecologists commonly prescribe oxytocin and prostaglandin agonists (misoprostol, dinoprostone) to stimulate uterine contraction for the induction of labor, prevention and treatment of postpartum hemorrhage, and treatment of miscarriage and fetal demise. The focus of this editorial is the clinical pharmacology of misoprostol.

Misoprostol is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of nonsteroidal anti-inflammatory drug–induced gastric ulcers and for patients at high risk for gastric ulcers, including those with a history of gastric ulcers. The approved misoprostol route and dose for this indication is oral administration of 200 µg four times daily with food.¹ Recent food intake and antacid use reduces the absorption of orally administered misoprostol. There are no FDA-approved indications for the use of misoprostol as a single agent in obstetrics and gynecology. The FDA has approved the combination of mifepristone and misoprostol for medication abortion in the first trimester. In contrast to misoprostol, PGE2 (dinoprostone) is approved by the FDA as a vaginal insert containing 10 mg of dinoprostone for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetric indication for induction of labor (Cervidil; Ferring Pharmaceuticals Inc, Parsippany, New Jersey).²

Pharmacology of misoprostol

Misoprostol is a prostaglandin E1 (PGE1) agonist analogue. Prostaglandin E1 (alprostadil) is rapidly metabolized, has a half-life in the range of minutes and is not orally active, requiring administration by intravenous infusion or injection. It is indicated to maintain a patent ductus arteriosus in newborns with ductal-dependent circulation and to treat erectile dysfunction.³ In contrast to PGE1, misoprostol has a methyl ester group at carbon-1 (C-1) that increases potency and duration of action. Misoprostol also has no hydroxyl group at C-15, replacing that moiety with the addition of both a methyl- and hydroxyl- group at C-16 (FIGURE). These molecular changes improve oral activity and increase duration of action.⁴ Pure misoprostol is a viscous oil. It is formulated into tables by dispersing the oil on hydroxypropyl methyl cellulose before compounding into tablets. Unlike naturally occurring prostaglandins (PGE1), misoprostol tablets are stabile at room temperature for years.⁴

Following absorption, the methyl ester at C-1 is enzymatically cleaved, yielding misoprostol acid, the active drug.⁴ Misoprostol binds to the E prostanoid receptor 3 (EP-3).⁵ Activation of myometrial EP-3 receptor induces an increase in intracellular phosphoinositol turnover and calcium mobilization, resulting in an increase in intracellular-free calcium, triggering actin-myosin contractility.⁶ The increase in free calcium is propagated cell-to-cell through gap junctions that link the myometrial cells to facilitate the generation of a coordinated contraction.

Misoprostol: Various routes of administration are not equal

Misoprostol can be given by an oral, buccal, vaginal, or rectal route of administration. To study the effect of the route of administration on uterine tone and contractility, investigators randomly assigned patients at 8 to 11 weeks’ gestation to receive misoprostol 400 µg as a single dose by the oral or vaginal route. Uterine tone and contractility were measured using an intrauterine pressure transducer. Compared to vaginal administration, oral administration of misprostol was associated with rapid attainment of peak plasma level at 30 minutes, followed by a decline in concentration by 60 minutes. This rapid onset and rapid offset of plasma concentration was paralleled by the onset of uterine tone within 8 minutes, but surprisingly no sustained uterine contractions.⁷ By contrast, following vaginal administration of misoprostol, serum levels rose slowly and peaked in 1 to 2 hours. Uterine tone increased within 21 minutes, and sustained uterine contractions were recorded for 4 hours.⁷ The rapid rise and fall in plasma misoprostol following oral administration and the more sustained plasma misoprostol concentration over 4 hours has been previously reported.⁸ In a second study involving patients 8 to 11 weeks’ gestation, the effect of a single dose of misoprostol 400 µg by an oral or vaginal route on uterine contractility was compared using an intrauterine pressure transducer.⁹ Confirming previous results, the time from misoprostol administration to increased uterine tone was more rapid with oral than with vaginal administration (8 min vs 19 min). Over the course of 4 hours, uterine contraction activity was greater with vaginal than with oral administration (454 vs 166 Montevideo units).⁹

Both studies reported that oral administration of misoprostol resulted in more rapid onset and offset of action than vaginal administration. Oral administration of a single dose of misoprostol 400 µg did not result in sustained uterine contractions in most patients in the first trimester. Vaginal administration produced a slower onset of increased uterine tone but sustained uterine contractions over 4 hours. Compared with vaginal administration of misoprostol, the rapid onset and offset of action of oral misoprostol may reduce the rate of tachysystole and changes in fetal heart rate observed with vaginal administration.¹⁰

An important finding is that buccal and vaginal administration of misoprostol have similar effects on uterine tone in the first trimester.¹¹ To study the effect of buccal and vaginal administration of misoprostol on uterine tone, patients 6 to 13 weeks’ gestation were randomly allocated to receive a single dose of misoprostol 400 µg by a buccal or vaginal route.¹¹ Uterine activity over 5 hours following administration was assessed using an intrauterine pressure transducer. Uterine tone 20 to 30 minutes after buccal or vaginal administration of misoprostol (400 µg) was 27 and 28 mm Hg, respectively. Peak uterine tone, as measured by an intrauterine pressure transducer, for buccal and vaginal administration of misoprostol was 49 mm Hg and 54 mm Hg, respectively. Total Alexandria units (AU) over 5 hours following buccal or vaginal administration was 6,537 AU and 6,090 AU, respectively.¹¹

An AU is calculated as the average amplitude of the contractions (mm Hg) multiplied by the average duration of the contractions (min) multiplied by average frequency of contraction over 10 minutes.¹² By contrast, a Montevideo unit does not include an assessment of contraction duration and is calculated as average amplitude of contractions (mm Hg) multiplied by frequency of uterine contractions over 10 minutes.¹²

In contrast to buccal or vaginal administration, rectal administration of misoprostol resulted in much lower peak uterine tone and contractility as measured by a pressure transducer. Uterine tone 20 to 30 minutes after vaginal and rectal administration of misoprostol (400 µg) was 28 and 19 mm Hg, respectively.¹¹ Peak uterine tone, as measured by an intrauterine pressure transducer, for vaginal and rectal administration of misoprostol was 54 and 31 mm Hg, respectively. AUs over 5 hours following vaginal and rectal administration was 6,090 AU and 2,768 AU, respectively.¹¹ Compared with buccal and vaginal administration of misoprostol, rectal administration produced less sustained uterine contractions in the first trimester of pregnancy. To achieve maximal sustained uterine contractions, buccal and vaginal routes of administration are superior to oral and rectal administration.

Continue to: Misoprostol and cervical ripening...

Misoprostol is commonly used to soften and ripen the cervix. Some of the cervical ripening effects of misoprostol are likely due to increased uterine tone. In addition, misoprostol may have a direct effect on the collagen structure of the cervix. To study the effect of misoprostol on the cervix, pregnant patients in the first trimester were randomly assigned to receive misoprostol 200 µg by vaginal self-administration, isosorbide mononitrate (IMN) 40 mg by vaginal self-administration or no treatment the evening prior to pregnancy termination.¹³ The following day, before uterine evacuation, a cervical biopsy was obtained for electron microscopy studies and immunohistochemistry to assess the presence of enzymes involved in collagen degradation, including matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 9 (MMP-9). Electron microscopy demonstrated that pretreatment with misoprostol resulted in a pronounced splitting and disorganization of collagen fibers.¹³ Compared with misoprostol treatment, IMN produced less splitting and disorganization of collagen fibers, and in the no treatment group, no marked changes in the collagen framework were observed.

Compared with no treatment, misoprostol and IMN pretreatment were associated with marked increases in MMP-1 and MMP-9 as assessed by immunohistochemistry. Misoprostol pretreatment also resulted in a significant increase in interleukin-8 concentration compared with IMN pretreatment and no treatment (8.8 vs 2.7 vs 2.4 pg/mg tissue), respectively.¹³ Other investigators have also reported that misoprostol increased cervical leukocyte influx and collagen disrupting enzymes MMP-8 and MMP-9.^14,15

An open-label clinical trial compared the efficacy of misoprostol versus Foley catheter for labor induction at term in 1,859 patients ≥ 37 weeks’ gestation with a Bishop score <6.¹⁶ Patients were randomly allocated to misoprostol (50 µg orally every 4 hours up to 3 times in 24 hours) versus placement of a 16 F or 18 F Foley catheter introduced through the cervix, filled with 30 mL of sodium chloride or water. The investigators reported that oral misoprostol and Foley catheter cervical ripening had similar safety and effectiveness for cervical ripening as a prelude to induction of labor, including no statistically significant differences in 5-minute Apgar score <7, umbilical cord artery pH ≤ 7.05, postpartum hemorrhage, or cesarean birth rate.¹⁶

Bottom line

Misoprostol and oxytocin are commonly prescribed in obstetric practice for cervical ripening and induction of labor, respectively. The dose and route of administration of misoprostol influences the effect on the uterus. For cervical ripening, where rapid onset and offset may help to reduce the risk of uterine tachysystole and worrisome fetal heart rate changes, low-dose (50 µg) oral administration of misoprostol may be a preferred dose and route. For the treatment of miscarriage and fetal demise, to stimulate sustained uterine contractions over many hours, buccal and vaginal administration of misoprostol are preferred. Rectal administration is generally inferior to buccal and vaginal administration for stimulating sustained uterine contractions and its uses should be limited. ●

For the infections we most commonly encounter in obstetric practice, I review in this article the selection of specific antibiotics. I focus on the key pathogens that cause these infections, the most useful diagnostic tests, and the most cost-effective antibiotic therapy. Relative cost estimates (high vs low) for drugs are based on information published on the GoodRx website (https://www.goodrx.com/). Actual charges to patients, of course, may vary widely depending on contractual relationships between hospitals, insurance companies, and wholesale vendors. The infections are listed in alphabetical order, not in order of frequency or severity.

1. Bacterial vaginosis

Bacterial vaginosis (BV) is a polymicrobial infection that results from perturbation of the normal vaginal flora due to conditions such as pregnancy, hormonal therapy, and changes in the menstrual cycle. It is characterized by a decrease in the vaginal concentration of Lactobacillus crispatus, followed by an increase in Prevotella bivia, Gardnerella vaginalis, Mobiluncus species, Atopobium vaginae, and Megasphaera type 1.^1,2

BV is characterized by a thin, white-gray malodorous (fishlike smell) discharge. The vaginal pH is >4.5. Clue cells are apparent on saline microscopy, and the whiff (amine) test is positive when potassium hydroxide is added to a drop of vaginal secretions. Diagnostic accuracy can be improved using one of the new vaginal panel assays such as BD MAX Vaginal Panel (Becton, Dickinson and Company).³

Antibiotic selection

Antibiotic treatment of BV is directed primarily at the anaerobic component of the infection. The preferred treatment is oral metronidazole 500 mg twice daily for 7 days. If the patient cannot tolerate metronidazole, oral clindamycin 300 mg twice daily for 7 days, can be used, although it is more expensive than metronidazole. Topical metronidazole vaginal gel (0.75%), 1 applicatorful daily for 5 days, is effective in treating the local vaginal infection, but it is not effective in preventing systemic complications such as preterm labor, chorioamnionitis, and puerperal endometritis.² It also is significantly more expensive than the oral formulation of metronidazole. Topical clindamycin cream, 1 applicatorful daily for 5 days, is even more expensive.

Tinidazole 2 g orally daily for 2 days is an effective alternative to oral metronidazole. Single-dose therapy with oral secnidazole (2 g), a 5-nitroimidazole with a longer half-life than metronidazole, has been effective in small studies, but experience with this drug in the United States is limited. Secnidazole is also very expensive.⁴

2. Candidiasis

Vulvovaginal candidiasis usually is caused by Candida albicans. Other less common species include C tropicalis, C glabrata, C auris, C lusitaniae, and C krusei. The most common clinical findings are vulvovaginal pruritus in association with a curdlike white vaginal discharge. The diagnosis can be established by confirmation of a normal vaginal pH and identification of budding yeast and hyphae on a potassium hydroxide preparation. As noted above for BV, the vaginal panel assay improves the accuracy of clinical diagnosis.³ Culture usually is indicated only in patients with infections that are refractory to therapy.

Continue to: Antibiotic selection...

Antibiotic selection

In the first trimester of pregnancy, vulvovaginal candidiasis should be treated with a topical medication such as clotrimazole cream 1% (50 mg intravaginally daily for 7 days), miconazole cream 2% (100 mg intravaginally daily for 7 days), or terconazole cream 0.4% (50 g intravaginally daily for 7 days). Single-dose formulations or 3-day courses of treatment may not be quite as effective in pregnant patients, but they do offer a more convenient dosing schedule.^2,5

Oral fluconazole should not be used in the first trimester of pregnancy because it has been associated with an increased risk for spontaneous abortion and with fetal cardiac septal defects. Beyond the first trimester, oral fluconazole offers an attractive option for treatment of vulvovaginal candidiasis. The appropriate dose is 150 mg initially, with a repeat dose in 3 days if symptoms persist.^2,5

Ibrexafungerp (300 mg twice daily for 1 day) was recently approved by the US Food and Drug Administration (FDA) for oral treatment of vulvovaginal candidiasis. However, this drug is teratogenic and is contraindicated during pregnancy and lactation. It also is significantly more expensive than fluconazole.⁶

3. Cesarean delivery prophylaxis

All women having a cesarean delivery (CD) should receive antibiotic prophylaxis to reduce the risk of endometritis and wound infection.

Antibiotic selection

In my opinion, the preferred regimen is intravenous cefazolin 2 g plus azithromycin 500 mg administered preoperatively.⁷ Cefazolin can be administered in a rapid bolus; azithromycin should be administered over 1 hour.

In an exceptionally rigorous investigation called the C/SOAP trial (Cesarean Section Optimal Antibiotic Prophylaxis trial), Tita and colleagues showed that the combination of cefazolin plus azithromycin was superior to single-agent prophylaxis (usually with cefazolin) in preventing the composite of endometritis, wound infection, or other infection occurring within 6 weeks of surgery.⁸ The additive effect of azithromycin was particularly pronounced in patients having CD after labor and rupture of membranes. Harper and associates subsequently validated the cost-effectiveness of this combination regimen using a decision analytic model.⁹

If the patient has a serious allergy to β-lactam antibiotics, the best alternative regimen for prophylaxis is clindamycin plus gentamicin. The appropriate single intravenous dose of clindamycin is 900 mg; the single dose of gentamicin should be 5 mg/kg of ideal body weight (IBW).⁷

4. Chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium. In pregnant women, it typically causes urethritis, endocervicitis, and inflammatory proctitis. Along with gonorrhea, it is the cause of an unusual infection/inflammation of the liver capsule, termed Fitz-Hugh-Curtis syndrome (perihepatitis). The diagnosis of chlamydia infection is best confirmed with a nucleic acid amplification test (NAAT). The NAAT simultaneously tests for chlamydia and gonorrhea in urine or in secretions obtained from the urethra, endocervix, and rectum.²

Antibiotic selection

The drug of choice for treating chlamydia in pregnancy is azithromycin 1,000 mg orally in a single dose. Erythromycin can be used as an alternative to azithromycin, but it usually is not well tolerated because of gastrointestinal adverse effects. In my practice, the preferred alternative for a patient who cannot tolerate azithromycin is amoxicillin 500 mg orally 3 times daily for 7 days.^2,10

Continue to: 5. Chorioamnionitis...

5. Chorioamnionitis

Chorioamnionitis is a polymicrobial infection caused by anaerobes, aerobic gram-negative bacilli (predominantly Escherichia coli), and aerobic gram-positive cocci (primarily group B streptococci [GBS]). The diagnosis usually is made based on clinical examination: maternal fever, maternal and fetal tachycardia, and no other localizing sign of infection. The diagnosis can be confirmed by obtaining a sample of amniotic fluid via amniocentesis or via aspiration through the intrauterine pressure catheter and demonstrating a positive Gram stain, low glucose concentration (<20 mg/dL), positive nitrites, positive leukocyte esterase, and ultimately, a positive bacteriologic culture.²

Antibiotic selection

The initial treatment of chorioamnionitis specifically targets the 2 major organisms that cause neonatal pneumonia, meningitis, and sepsis: GBS and E coli. For many years, the drugs of choice have been intravenous ampicillin (2 g every 6 hours) plus intravenous gentamicin (5 mg/kg of IBW every 24 hours). Gentamicin also can be administered intravenously at a dose of 1.5 mg/kg every 8 hours. I prefer the once-daily dosing for 3 reasons:

• Gentamicin works by a concentration-dependent mechanism; the higher the initial serum concentration, the better the killing effect.
• Once-daily dosing preserves long periods with low trough levels, an effect that minimizes ototoxicity and nephrotoxicity.
• Once-daily dosing is more convenient.

In a patient who has a contraindication to use of an aminoglycoside, aztreonam (2 g intravenously every 8 hours) may be combined with ampicillin.²

If the patient delivers vaginally, 1 dose of each drug should be administered postpartum, and then the antibiotics should be discontinued. If the patient delivers by cesarean, a single dose of a medication with strong anaerobic coverage should be administered immediately after the infant’s umbilical cord is clamped. Options include clindamycin (900 mg intravenously) or metronidazole (500 mg intravenously).¹¹

There are 2 key exceptions to the single postpartum dose rule, however. If the patient is obese (body mass index [BMI] >30 kg/m²) or if the membranes have been ruptured for more than 24 hours, antibiotics should be continued until she has been afebrile and asymptomatic for 24 hours.¹²

Two single agents are excellent alternatives to the combination ampicillin-gentamicin regimen. One is ampicillin-sulbactam, 3 g intravenously every 6 hours. The other is piperacillin-tazobactam, 3.375 g intravenously every 6 hours. These extended-spectrum penicillins provide exceptionally good coverage against the major pathogens that cause chorioamnionitis. Although more expensive than the combination regimen, they avoid the potential ototoxicity and nephrotoxicity associated with gentamicin.²

6. Endometritis

Puerperal endometritis is significantly more common after CD than after vaginal delivery. The infection is polymicrobial, and the principal pathogens are anaerobic gram-positive cocci, anaerobic gram-negative bacilli, aerobic gram-negative bacilli, and aerobic gram-positive cocci. The diagnosis usually is made almost exclusively based on clinical findings: fever within 24 to 36 hours of delivery, tachycardia, mild tachypnea, and lower abdominal/pelvic pain and tenderness in the absence of any other localizing sign of infection.¹³

Antibiotic selection

Effective treatment of endometritis requires administration of antibiotics that provide coverage against the broad range of pelvic pathogens. For many years, the gold standard of treatment has been the combination regimens of clindamycin plus gentamicin or metronidazole plus ampicillin plus gentamicin. These drugs are available in generic form and are relatively inexpensive. However, several broad-spectrum single agents are now available for treatment of endometritis. Although they are moderately more expensive than the generic combination regimens, they usually are very well tolerated, and they avoid the potential nephrotoxicity and ototoxicity associated with gentamicin. TABLE 1 summarizes the dosing regimens of these various agents and their potential weaknesses in coverage.^2,13

7. Gonorrhea

Gonorrhea is caused by the gram-negative diplococcus, Neisseria gonorrhoeae. The organism has a propensity to infect columnar epithelium and uroepithelium, and, typically, it causes a localized infection of the urethra, endocervix, and rectum. The organism also can cause an oropharyngeal infection, a disseminated infection (most commonly manifested by dermatitis and arthritis), and perihepatitis.

The diagnosis is best confirmed by a NAAT that can simultaneously test for gonorrhea and chlamydia in urine or in secretions obtained from the urethra, endocervix, and rectum.^2,10

Antibiotic selection

The drugs of choice for treating uncomplicated gonococcal infection in pregnancy are a single dose of ceftriaxone 500 mg intramuscularly, or cefixime 800 mg orally. If the patient is allergic to β-lactam antibiotics, the recommended treatment is gentamicin 240 mg intramuscularly in a single dose, combined with azithromycin 2,000 mg orally.¹⁴

8. Group B streptococci prophylaxis

The first-line agents for GBS prophylaxis are penicillin and ampicillin. Resistance of GBS to either of these antibiotics is extremely rare. The appropriate penicillin dose is 3 million U intravenously every 4 hours; the intravenous dose of ampicillin is 2 g initially, then 1 g every 4 hours. I prefer penicillin for prophylaxis because it has a narrower spectrum of activity and is less likely to cause antibiotic-associated diarrhea. The antibiotic should be continued until delivery of the neonate.^2,15,16

If the patient has a mild allergy to penicillin, the drug of choice is cefazolin 2 g intravenously initially, then 1 g every 8 hours. If the patient’s allergy to β-lactam antibiotics is severe, the alternative agents are vancomycin (20 mg/kg intravenously every 8 hours infused over 1–2 hours; maximum single dose of 2 g) and clindamycin (900 mg intravenously every 8 hours). The latter drug should be used only if sensitivity testing has confirmed that the GBS strain is sensitive to clindamycin. Resistance to clindamycin usually ranges from 10% to 15%.^2,15,16

9. Puerperal mastitis

The principal microorganisms that cause puerperal mastitis are the aerobic streptococci and staphylococci that form part of the normal skin flora. The diagnosis usually is made based on the characteristic clinical findings: erythema, tenderness, and warmth in an area of the breast accompanied by a purulent nipple discharge and fever and chills. The vast majority of cases can be treated with oral antibiotics on an outpatient basis. The key indications for hospitalization are severe illness, particularly in an immunocompromised patient, and suspicion of a breast abscess.²

Continue to: Antibiotic selection...

The initial drug of choice for treatment of mastitis is dicloxacillin sodium 500 mg every 6 hours for 7 to 10 days. If the patient has a mild allergy to penicillin, the appropriate alternative is cephalexin 500 mg every 8 hours for 7 to 10 days. If the patient’s allergy to penicillin is severe, 2 alternatives are possible. One is clindamycin 300 mg twice daily for 7 to 10 days; the other is trimethoprim-sulfamethoxazole double strength (800 mg/160 mg), twice daily for 7 to 10 days. The latter 2 drugs are also of great value if the patient fails to respond to initial therapy and/or infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.² I prefer the latter agent because it is less expensive than clindamycin and is less likely to cause antibiotic-induced diarrhea.

If hospitalization is required, the drug of choice is intravenous vancomycin. The appropriate dosage is 20 mg/kg every 8 to 12 hours (maximum single dose of 2 g).²

10. Syphilis

Syphilis is caused by the spirochete bacterium, Treponema pallidum. The diagnosis can be made by clinical examination if the characteristic findings listed in TABLE 2 are present.^2,17 However, most patients in our practice will have latent syphilis, and the diagnosis must be established based on serologic screening.¹⁷

Antibiotic selection

In pregnancy, the treatment of choice for syphilis is penicillin (TABLE 3).^2,10,17 Only penicillin has been proven effective in treating both maternal and fetal infection. If the patient has a history of allergy to penicillin, she should undergo skin testing to determine if she is truly allergic. If hypersensitivity is confirmed, the patient should be desensitized and then treated with the appropriate regimen outlined in TABLE 3. Of interest, within a short period of time after treatment, the patient’s sensitivity to penicillin will be reestablished, and she should not be treated again with penicillin unless she undergoes another desensitization process.^2,17

11. Trichomoniasis

Trichomoniasis is caused by the flagellated protozoan, Trichomonas vaginalis. The condition is characterized by a distinct yellowish-green vaginal discharge. The vaginal pH is >4.5, and motile flagellated organisms are easily visualized on saline microscopy. The vaginal panel assay also is a valuable diagnostic test.³

Antibiotic selection

The drug of choice for trichomoniasis is oral metronidazole 500 mg twice daily for 7 days. The patient’s sexual partner(s) should be treated concurrently to prevent reinfection. Most treatment failures are due to poor compliance with therapy on the part of either the patient or her partner(s); true drug resistance is uncommon. When antibiotic resistance is strongly suspected, the patient may be treated with a single 2-g oral dose of tinidazole.²

12. Urinary tract infections

Urethritis

Acute urethritis usually is caused by C trachomatis or N gonorrhoeae. The treatment of infections with these 2 organisms is discussed above.

Asymptomatic bacteriuria and acute cystitis

Bladder infections are caused primarily by E coli, Klebsiella pneumoniae, and Proteus species. Gram-positive cocci such as enterococci, Staphylococcus saprophyticus, and GBS are less common pathogens.¹⁸

The key diagnostic criterion for asymptomatic bacteriuria is a colony count greater than 100,000 organisms/mL of a single uropathogen on a clean-catch midstream urine specimen.¹⁸

The usual clinical manifestations of acute cystitis include frequency, urgency, hesitancy, suprapubic discomfort, and a low-grade fever. The diagnosis is most effectively confirmed by obtaining urine by catheterization and demonstrating a positive nitrite and positive leukocyte esterase reaction on dipstick examination. The finding of a urine pH of 8 or greater usually indicates an infection caused by Proteus species. When urine is obtained by catheterization, the criterion for defining a positive culture is greater than 100 colonies/mL.¹⁸

Antibiotic selection. In the first trimester, the preferred agents for treatment of a lower urinary tract infection are oral amoxicillin (875 mg twice daily) or cephalexin (500 mg every 8 hours). For an initial infection, a 3-day course of therapy usually is adequate. For a recurrent infection, a 7- to 10-day course is indicated.

Beyond the first trimester, nitrofurantoin monohydrate macrocrystals (100 mg orally twice daily) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily) are the preferred agents. Unless no other oral drug is likely to be effective, these 2 drugs should be avoided in the first trimester. The former has been associated with eye, heart, and cleft defects. The latter has been associated with neural tube defects, cardiac anomalies, choanal atresia, and diaphragmatic hernia.¹⁸

Acute pyelonephritis

Acute infections of the kidney usually are caused by the aerobic gram-negative bacilli: E coli, K pneumoniae, and Proteus species. Enterococci, S saprophyticus, and GBS are less likely to cause upper tract infection as opposed to bladder infection.

The typical clinical manifestations of acute pyelonephritis include high fever and chills in association with flank pain and tenderness. The diagnosis is best confirmed by obtaining urine by catheterization and documenting the presence of a positive nitrite and leukocyte esterase reaction. Again, an elevated urine pH is indicative of an infection secondary to Proteus species. The criterion for defining a positive culture from catheterized urine is greater than 100 colonies/mL.^2,18

Antibiotic selection. Patients in the first half of pregnancy who are hemodynamically stable and who show no signs of preterm labor may be treated with oral antibiotics as outpatients. The 2 drugs of choice are amoxicillin-clavulanate (875 mg twice daily for 7 to 10 days) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily for 7 to 10 days).

For unstable patients in the first half of pregnancy and for essentially all patients in the second half of pregnancy, parenteral treatment should be administered on an inpatient basis. My preference for treatment is ceftriaxone, 2 g intravenously every 24 hours. The drug provides excellent coverage against almost all the uropathogens. It has a convenient dosing schedule, and it usually is very well tolerated. Parenteral therapy should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. At this point, the patient can be transitioned to one of the oral regimens listed above and managed as an outpatient. If the patient is allergic to β-lactam antibiotics, an excellent alternative is aztreonam, 2 g intravenously every 8 hours.^2,18 ●

For the infections we most commonly encounter in obstetric practice, I review in this article the selection of specific antibiotics. I focus on the key pathogens that cause these infections, the most useful diagnostic tests, and the most cost-effective antibiotic therapy. Relative cost estimates (high vs low) for drugs are based on information published on the GoodRx website (https://www.goodrx.com/). Actual charges to patients, of course, may vary widely depending on contractual relationships between hospitals, insurance companies, and wholesale vendors. The infections are listed in alphabetical order, not in order of frequency or severity.

1. Bacterial vaginosis

Bacterial vaginosis (BV) is a polymicrobial infection that results from perturbation of the normal vaginal flora due to conditions such as pregnancy, hormonal therapy, and changes in the menstrual cycle. It is characterized by a decrease in the vaginal concentration of Lactobacillus crispatus, followed by an increase in Prevotella bivia, Gardnerella vaginalis, Mobiluncus species, Atopobium vaginae, and Megasphaera type 1.^1,2

BV is characterized by a thin, white-gray malodorous (fishlike smell) discharge. The vaginal pH is >4.5. Clue cells are apparent on saline microscopy, and the whiff (amine) test is positive when potassium hydroxide is added to a drop of vaginal secretions. Diagnostic accuracy can be improved using one of the new vaginal panel assays such as BD MAX Vaginal Panel (Becton, Dickinson and Company).³

Antibiotic selection

Antibiotic treatment of BV is directed primarily at the anaerobic component of the infection. The preferred treatment is oral metronidazole 500 mg twice daily for 7 days. If the patient cannot tolerate metronidazole, oral clindamycin 300 mg twice daily for 7 days, can be used, although it is more expensive than metronidazole. Topical metronidazole vaginal gel (0.75%), 1 applicatorful daily for 5 days, is effective in treating the local vaginal infection, but it is not effective in preventing systemic complications such as preterm labor, chorioamnionitis, and puerperal endometritis.² It also is significantly more expensive than the oral formulation of metronidazole. Topical clindamycin cream, 1 applicatorful daily for 5 days, is even more expensive.

Tinidazole 2 g orally daily for 2 days is an effective alternative to oral metronidazole. Single-dose therapy with oral secnidazole (2 g), a 5-nitroimidazole with a longer half-life than metronidazole, has been effective in small studies, but experience with this drug in the United States is limited. Secnidazole is also very expensive.⁴

2. Candidiasis

Vulvovaginal candidiasis usually is caused by Candida albicans. Other less common species include C tropicalis, C glabrata, C auris, C lusitaniae, and C krusei. The most common clinical findings are vulvovaginal pruritus in association with a curdlike white vaginal discharge. The diagnosis can be established by confirmation of a normal vaginal pH and identification of budding yeast and hyphae on a potassium hydroxide preparation. As noted above for BV, the vaginal panel assay improves the accuracy of clinical diagnosis.³ Culture usually is indicated only in patients with infections that are refractory to therapy.

Continue to: Antibiotic selection...

Antibiotic selection

In the first trimester of pregnancy, vulvovaginal candidiasis should be treated with a topical medication such as clotrimazole cream 1% (50 mg intravaginally daily for 7 days), miconazole cream 2% (100 mg intravaginally daily for 7 days), or terconazole cream 0.4% (50 g intravaginally daily for 7 days). Single-dose formulations or 3-day courses of treatment may not be quite as effective in pregnant patients, but they do offer a more convenient dosing schedule.^2,5

Oral fluconazole should not be used in the first trimester of pregnancy because it has been associated with an increased risk for spontaneous abortion and with fetal cardiac septal defects. Beyond the first trimester, oral fluconazole offers an attractive option for treatment of vulvovaginal candidiasis. The appropriate dose is 150 mg initially, with a repeat dose in 3 days if symptoms persist.^2,5

Ibrexafungerp (300 mg twice daily for 1 day) was recently approved by the US Food and Drug Administration (FDA) for oral treatment of vulvovaginal candidiasis. However, this drug is teratogenic and is contraindicated during pregnancy and lactation. It also is significantly more expensive than fluconazole.⁶

3. Cesarean delivery prophylaxis

All women having a cesarean delivery (CD) should receive antibiotic prophylaxis to reduce the risk of endometritis and wound infection.

Antibiotic selection

In my opinion, the preferred regimen is intravenous cefazolin 2 g plus azithromycin 500 mg administered preoperatively.⁷ Cefazolin can be administered in a rapid bolus; azithromycin should be administered over 1 hour.

In an exceptionally rigorous investigation called the C/SOAP trial (Cesarean Section Optimal Antibiotic Prophylaxis trial), Tita and colleagues showed that the combination of cefazolin plus azithromycin was superior to single-agent prophylaxis (usually with cefazolin) in preventing the composite of endometritis, wound infection, or other infection occurring within 6 weeks of surgery.⁸ The additive effect of azithromycin was particularly pronounced in patients having CD after labor and rupture of membranes. Harper and associates subsequently validated the cost-effectiveness of this combination regimen using a decision analytic model.⁹

If the patient has a serious allergy to β-lactam antibiotics, the best alternative regimen for prophylaxis is clindamycin plus gentamicin. The appropriate single intravenous dose of clindamycin is 900 mg; the single dose of gentamicin should be 5 mg/kg of ideal body weight (IBW).⁷

4. Chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium. In pregnant women, it typically causes urethritis, endocervicitis, and inflammatory proctitis. Along with gonorrhea, it is the cause of an unusual infection/inflammation of the liver capsule, termed Fitz-Hugh-Curtis syndrome (perihepatitis). The diagnosis of chlamydia infection is best confirmed with a nucleic acid amplification test (NAAT). The NAAT simultaneously tests for chlamydia and gonorrhea in urine or in secretions obtained from the urethra, endocervix, and rectum.²

Antibiotic selection

The drug of choice for treating chlamydia in pregnancy is azithromycin 1,000 mg orally in a single dose. Erythromycin can be used as an alternative to azithromycin, but it usually is not well tolerated because of gastrointestinal adverse effects. In my practice, the preferred alternative for a patient who cannot tolerate azithromycin is amoxicillin 500 mg orally 3 times daily for 7 days.^2,10

Continue to: 5. Chorioamnionitis...

5. Chorioamnionitis

Chorioamnionitis is a polymicrobial infection caused by anaerobes, aerobic gram-negative bacilli (predominantly Escherichia coli), and aerobic gram-positive cocci (primarily group B streptococci [GBS]). The diagnosis usually is made based on clinical examination: maternal fever, maternal and fetal tachycardia, and no other localizing sign of infection. The diagnosis can be confirmed by obtaining a sample of amniotic fluid via amniocentesis or via aspiration through the intrauterine pressure catheter and demonstrating a positive Gram stain, low glucose concentration (<20 mg/dL), positive nitrites, positive leukocyte esterase, and ultimately, a positive bacteriologic culture.²

Antibiotic selection

The initial treatment of chorioamnionitis specifically targets the 2 major organisms that cause neonatal pneumonia, meningitis, and sepsis: GBS and E coli. For many years, the drugs of choice have been intravenous ampicillin (2 g every 6 hours) plus intravenous gentamicin (5 mg/kg of IBW every 24 hours). Gentamicin also can be administered intravenously at a dose of 1.5 mg/kg every 8 hours. I prefer the once-daily dosing for 3 reasons:

• Gentamicin works by a concentration-dependent mechanism; the higher the initial serum concentration, the better the killing effect.
• Once-daily dosing preserves long periods with low trough levels, an effect that minimizes ototoxicity and nephrotoxicity.
• Once-daily dosing is more convenient.

In a patient who has a contraindication to use of an aminoglycoside, aztreonam (2 g intravenously every 8 hours) may be combined with ampicillin.²

If the patient delivers vaginally, 1 dose of each drug should be administered postpartum, and then the antibiotics should be discontinued. If the patient delivers by cesarean, a single dose of a medication with strong anaerobic coverage should be administered immediately after the infant’s umbilical cord is clamped. Options include clindamycin (900 mg intravenously) or metronidazole (500 mg intravenously).¹¹

There are 2 key exceptions to the single postpartum dose rule, however. If the patient is obese (body mass index [BMI] >30 kg/m²) or if the membranes have been ruptured for more than 24 hours, antibiotics should be continued until she has been afebrile and asymptomatic for 24 hours.¹²

Two single agents are excellent alternatives to the combination ampicillin-gentamicin regimen. One is ampicillin-sulbactam, 3 g intravenously every 6 hours. The other is piperacillin-tazobactam, 3.375 g intravenously every 6 hours. These extended-spectrum penicillins provide exceptionally good coverage against the major pathogens that cause chorioamnionitis. Although more expensive than the combination regimen, they avoid the potential ototoxicity and nephrotoxicity associated with gentamicin.²

6. Endometritis

Puerperal endometritis is significantly more common after CD than after vaginal delivery. The infection is polymicrobial, and the principal pathogens are anaerobic gram-positive cocci, anaerobic gram-negative bacilli, aerobic gram-negative bacilli, and aerobic gram-positive cocci. The diagnosis usually is made almost exclusively based on clinical findings: fever within 24 to 36 hours of delivery, tachycardia, mild tachypnea, and lower abdominal/pelvic pain and tenderness in the absence of any other localizing sign of infection.¹³

Antibiotic selection

Effective treatment of endometritis requires administration of antibiotics that provide coverage against the broad range of pelvic pathogens. For many years, the gold standard of treatment has been the combination regimens of clindamycin plus gentamicin or metronidazole plus ampicillin plus gentamicin. These drugs are available in generic form and are relatively inexpensive. However, several broad-spectrum single agents are now available for treatment of endometritis. Although they are moderately more expensive than the generic combination regimens, they usually are very well tolerated, and they avoid the potential nephrotoxicity and ototoxicity associated with gentamicin. TABLE 1 summarizes the dosing regimens of these various agents and their potential weaknesses in coverage.^2,13

7. Gonorrhea

Gonorrhea is caused by the gram-negative diplococcus, Neisseria gonorrhoeae. The organism has a propensity to infect columnar epithelium and uroepithelium, and, typically, it causes a localized infection of the urethra, endocervix, and rectum. The organism also can cause an oropharyngeal infection, a disseminated infection (most commonly manifested by dermatitis and arthritis), and perihepatitis.

The diagnosis is best confirmed by a NAAT that can simultaneously test for gonorrhea and chlamydia in urine or in secretions obtained from the urethra, endocervix, and rectum.^2,10

Antibiotic selection

The drugs of choice for treating uncomplicated gonococcal infection in pregnancy are a single dose of ceftriaxone 500 mg intramuscularly, or cefixime 800 mg orally. If the patient is allergic to β-lactam antibiotics, the recommended treatment is gentamicin 240 mg intramuscularly in a single dose, combined with azithromycin 2,000 mg orally.¹⁴

8. Group B streptococci prophylaxis

The first-line agents for GBS prophylaxis are penicillin and ampicillin. Resistance of GBS to either of these antibiotics is extremely rare. The appropriate penicillin dose is 3 million U intravenously every 4 hours; the intravenous dose of ampicillin is 2 g initially, then 1 g every 4 hours. I prefer penicillin for prophylaxis because it has a narrower spectrum of activity and is less likely to cause antibiotic-associated diarrhea. The antibiotic should be continued until delivery of the neonate.^2,15,16

If the patient has a mild allergy to penicillin, the drug of choice is cefazolin 2 g intravenously initially, then 1 g every 8 hours. If the patient’s allergy to β-lactam antibiotics is severe, the alternative agents are vancomycin (20 mg/kg intravenously every 8 hours infused over 1–2 hours; maximum single dose of 2 g) and clindamycin (900 mg intravenously every 8 hours). The latter drug should be used only if sensitivity testing has confirmed that the GBS strain is sensitive to clindamycin. Resistance to clindamycin usually ranges from 10% to 15%.^2,15,16

9. Puerperal mastitis

The principal microorganisms that cause puerperal mastitis are the aerobic streptococci and staphylococci that form part of the normal skin flora. The diagnosis usually is made based on the characteristic clinical findings: erythema, tenderness, and warmth in an area of the breast accompanied by a purulent nipple discharge and fever and chills. The vast majority of cases can be treated with oral antibiotics on an outpatient basis. The key indications for hospitalization are severe illness, particularly in an immunocompromised patient, and suspicion of a breast abscess.²

Continue to: Antibiotic selection...

The initial drug of choice for treatment of mastitis is dicloxacillin sodium 500 mg every 6 hours for 7 to 10 days. If the patient has a mild allergy to penicillin, the appropriate alternative is cephalexin 500 mg every 8 hours for 7 to 10 days. If the patient’s allergy to penicillin is severe, 2 alternatives are possible. One is clindamycin 300 mg twice daily for 7 to 10 days; the other is trimethoprim-sulfamethoxazole double strength (800 mg/160 mg), twice daily for 7 to 10 days. The latter 2 drugs are also of great value if the patient fails to respond to initial therapy and/or infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.² I prefer the latter agent because it is less expensive than clindamycin and is less likely to cause antibiotic-induced diarrhea.

If hospitalization is required, the drug of choice is intravenous vancomycin. The appropriate dosage is 20 mg/kg every 8 to 12 hours (maximum single dose of 2 g).²

10. Syphilis

Syphilis is caused by the spirochete bacterium, Treponema pallidum. The diagnosis can be made by clinical examination if the characteristic findings listed in TABLE 2 are present.^2,17 However, most patients in our practice will have latent syphilis, and the diagnosis must be established based on serologic screening.¹⁷

Antibiotic selection

In pregnancy, the treatment of choice for syphilis is penicillin (TABLE 3).^2,10,17 Only penicillin has been proven effective in treating both maternal and fetal infection. If the patient has a history of allergy to penicillin, she should undergo skin testing to determine if she is truly allergic. If hypersensitivity is confirmed, the patient should be desensitized and then treated with the appropriate regimen outlined in TABLE 3. Of interest, within a short period of time after treatment, the patient’s sensitivity to penicillin will be reestablished, and she should not be treated again with penicillin unless she undergoes another desensitization process.^2,17

11. Trichomoniasis

Trichomoniasis is caused by the flagellated protozoan, Trichomonas vaginalis. The condition is characterized by a distinct yellowish-green vaginal discharge. The vaginal pH is >4.5, and motile flagellated organisms are easily visualized on saline microscopy. The vaginal panel assay also is a valuable diagnostic test.³

Antibiotic selection

The drug of choice for trichomoniasis is oral metronidazole 500 mg twice daily for 7 days. The patient’s sexual partner(s) should be treated concurrently to prevent reinfection. Most treatment failures are due to poor compliance with therapy on the part of either the patient or her partner(s); true drug resistance is uncommon. When antibiotic resistance is strongly suspected, the patient may be treated with a single 2-g oral dose of tinidazole.²

12. Urinary tract infections

Urethritis

Acute urethritis usually is caused by C trachomatis or N gonorrhoeae. The treatment of infections with these 2 organisms is discussed above.

Asymptomatic bacteriuria and acute cystitis

Bladder infections are caused primarily by E coli, Klebsiella pneumoniae, and Proteus species. Gram-positive cocci such as enterococci, Staphylococcus saprophyticus, and GBS are less common pathogens.¹⁸

The key diagnostic criterion for asymptomatic bacteriuria is a colony count greater than 100,000 organisms/mL of a single uropathogen on a clean-catch midstream urine specimen.¹⁸

The usual clinical manifestations of acute cystitis include frequency, urgency, hesitancy, suprapubic discomfort, and a low-grade fever. The diagnosis is most effectively confirmed by obtaining urine by catheterization and demonstrating a positive nitrite and positive leukocyte esterase reaction on dipstick examination. The finding of a urine pH of 8 or greater usually indicates an infection caused by Proteus species. When urine is obtained by catheterization, the criterion for defining a positive culture is greater than 100 colonies/mL.¹⁸

Antibiotic selection. In the first trimester, the preferred agents for treatment of a lower urinary tract infection are oral amoxicillin (875 mg twice daily) or cephalexin (500 mg every 8 hours). For an initial infection, a 3-day course of therapy usually is adequate. For a recurrent infection, a 7- to 10-day course is indicated.

Beyond the first trimester, nitrofurantoin monohydrate macrocrystals (100 mg orally twice daily) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily) are the preferred agents. Unless no other oral drug is likely to be effective, these 2 drugs should be avoided in the first trimester. The former has been associated with eye, heart, and cleft defects. The latter has been associated with neural tube defects, cardiac anomalies, choanal atresia, and diaphragmatic hernia.¹⁸

Acute pyelonephritis

Acute infections of the kidney usually are caused by the aerobic gram-negative bacilli: E coli, K pneumoniae, and Proteus species. Enterococci, S saprophyticus, and GBS are less likely to cause upper tract infection as opposed to bladder infection.

The typical clinical manifestations of acute pyelonephritis include high fever and chills in association with flank pain and tenderness. The diagnosis is best confirmed by obtaining urine by catheterization and documenting the presence of a positive nitrite and leukocyte esterase reaction. Again, an elevated urine pH is indicative of an infection secondary to Proteus species. The criterion for defining a positive culture from catheterized urine is greater than 100 colonies/mL.^2,18

Antibiotic selection. Patients in the first half of pregnancy who are hemodynamically stable and who show no signs of preterm labor may be treated with oral antibiotics as outpatients. The 2 drugs of choice are amoxicillin-clavulanate (875 mg twice daily for 7 to 10 days) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily for 7 to 10 days).

For unstable patients in the first half of pregnancy and for essentially all patients in the second half of pregnancy, parenteral treatment should be administered on an inpatient basis. My preference for treatment is ceftriaxone, 2 g intravenously every 24 hours. The drug provides excellent coverage against almost all the uropathogens. It has a convenient dosing schedule, and it usually is very well tolerated. Parenteral therapy should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. At this point, the patient can be transitioned to one of the oral regimens listed above and managed as an outpatient. If the patient is allergic to β-lactam antibiotics, an excellent alternative is aztreonam, 2 g intravenously every 8 hours.^2,18 ●

For the infections we most commonly encounter in obstetric practice, I review in this article the selection of specific antibiotics. I focus on the key pathogens that cause these infections, the most useful diagnostic tests, and the most cost-effective antibiotic therapy. Relative cost estimates (high vs low) for drugs are based on information published on the GoodRx website (https://www.goodrx.com/). Actual charges to patients, of course, may vary widely depending on contractual relationships between hospitals, insurance companies, and wholesale vendors. The infections are listed in alphabetical order, not in order of frequency or severity.

1. Bacterial vaginosis

Bacterial vaginosis (BV) is a polymicrobial infection that results from perturbation of the normal vaginal flora due to conditions such as pregnancy, hormonal therapy, and changes in the menstrual cycle. It is characterized by a decrease in the vaginal concentration of Lactobacillus crispatus, followed by an increase in Prevotella bivia, Gardnerella vaginalis, Mobiluncus species, Atopobium vaginae, and Megasphaera type 1.^1,2

BV is characterized by a thin, white-gray malodorous (fishlike smell) discharge. The vaginal pH is >4.5. Clue cells are apparent on saline microscopy, and the whiff (amine) test is positive when potassium hydroxide is added to a drop of vaginal secretions. Diagnostic accuracy can be improved using one of the new vaginal panel assays such as BD MAX Vaginal Panel (Becton, Dickinson and Company).³

Antibiotic selection

Antibiotic treatment of BV is directed primarily at the anaerobic component of the infection. The preferred treatment is oral metronidazole 500 mg twice daily for 7 days. If the patient cannot tolerate metronidazole, oral clindamycin 300 mg twice daily for 7 days, can be used, although it is more expensive than metronidazole. Topical metronidazole vaginal gel (0.75%), 1 applicatorful daily for 5 days, is effective in treating the local vaginal infection, but it is not effective in preventing systemic complications such as preterm labor, chorioamnionitis, and puerperal endometritis.² It also is significantly more expensive than the oral formulation of metronidazole. Topical clindamycin cream, 1 applicatorful daily for 5 days, is even more expensive.

Tinidazole 2 g orally daily for 2 days is an effective alternative to oral metronidazole. Single-dose therapy with oral secnidazole (2 g), a 5-nitroimidazole with a longer half-life than metronidazole, has been effective in small studies, but experience with this drug in the United States is limited. Secnidazole is also very expensive.⁴

2. Candidiasis

Vulvovaginal candidiasis usually is caused by Candida albicans. Other less common species include C tropicalis, C glabrata, C auris, C lusitaniae, and C krusei. The most common clinical findings are vulvovaginal pruritus in association with a curdlike white vaginal discharge. The diagnosis can be established by confirmation of a normal vaginal pH and identification of budding yeast and hyphae on a potassium hydroxide preparation. As noted above for BV, the vaginal panel assay improves the accuracy of clinical diagnosis.³ Culture usually is indicated only in patients with infections that are refractory to therapy.

Continue to: Antibiotic selection...

Antibiotic selection

In the first trimester of pregnancy, vulvovaginal candidiasis should be treated with a topical medication such as clotrimazole cream 1% (50 mg intravaginally daily for 7 days), miconazole cream 2% (100 mg intravaginally daily for 7 days), or terconazole cream 0.4% (50 g intravaginally daily for 7 days). Single-dose formulations or 3-day courses of treatment may not be quite as effective in pregnant patients, but they do offer a more convenient dosing schedule.^2,5

Oral fluconazole should not be used in the first trimester of pregnancy because it has been associated with an increased risk for spontaneous abortion and with fetal cardiac septal defects. Beyond the first trimester, oral fluconazole offers an attractive option for treatment of vulvovaginal candidiasis. The appropriate dose is 150 mg initially, with a repeat dose in 3 days if symptoms persist.^2,5

Ibrexafungerp (300 mg twice daily for 1 day) was recently approved by the US Food and Drug Administration (FDA) for oral treatment of vulvovaginal candidiasis. However, this drug is teratogenic and is contraindicated during pregnancy and lactation. It also is significantly more expensive than fluconazole.⁶

3. Cesarean delivery prophylaxis

All women having a cesarean delivery (CD) should receive antibiotic prophylaxis to reduce the risk of endometritis and wound infection.

Antibiotic selection

In my opinion, the preferred regimen is intravenous cefazolin 2 g plus azithromycin 500 mg administered preoperatively.⁷ Cefazolin can be administered in a rapid bolus; azithromycin should be administered over 1 hour.

In an exceptionally rigorous investigation called the C/SOAP trial (Cesarean Section Optimal Antibiotic Prophylaxis trial), Tita and colleagues showed that the combination of cefazolin plus azithromycin was superior to single-agent prophylaxis (usually with cefazolin) in preventing the composite of endometritis, wound infection, or other infection occurring within 6 weeks of surgery.⁸ The additive effect of azithromycin was particularly pronounced in patients having CD after labor and rupture of membranes. Harper and associates subsequently validated the cost-effectiveness of this combination regimen using a decision analytic model.⁹

If the patient has a serious allergy to β-lactam antibiotics, the best alternative regimen for prophylaxis is clindamycin plus gentamicin. The appropriate single intravenous dose of clindamycin is 900 mg; the single dose of gentamicin should be 5 mg/kg of ideal body weight (IBW).⁷

4. Chlamydia

Chlamydia trachomatis is an obligate intracellular bacterium. In pregnant women, it typically causes urethritis, endocervicitis, and inflammatory proctitis. Along with gonorrhea, it is the cause of an unusual infection/inflammation of the liver capsule, termed Fitz-Hugh-Curtis syndrome (perihepatitis). The diagnosis of chlamydia infection is best confirmed with a nucleic acid amplification test (NAAT). The NAAT simultaneously tests for chlamydia and gonorrhea in urine or in secretions obtained from the urethra, endocervix, and rectum.²

Antibiotic selection

The drug of choice for treating chlamydia in pregnancy is azithromycin 1,000 mg orally in a single dose. Erythromycin can be used as an alternative to azithromycin, but it usually is not well tolerated because of gastrointestinal adverse effects. In my practice, the preferred alternative for a patient who cannot tolerate azithromycin is amoxicillin 500 mg orally 3 times daily for 7 days.^2,10

Continue to: 5. Chorioamnionitis...

5. Chorioamnionitis

Chorioamnionitis is a polymicrobial infection caused by anaerobes, aerobic gram-negative bacilli (predominantly Escherichia coli), and aerobic gram-positive cocci (primarily group B streptococci [GBS]). The diagnosis usually is made based on clinical examination: maternal fever, maternal and fetal tachycardia, and no other localizing sign of infection. The diagnosis can be confirmed by obtaining a sample of amniotic fluid via amniocentesis or via aspiration through the intrauterine pressure catheter and demonstrating a positive Gram stain, low glucose concentration (<20 mg/dL), positive nitrites, positive leukocyte esterase, and ultimately, a positive bacteriologic culture.²

Antibiotic selection

The initial treatment of chorioamnionitis specifically targets the 2 major organisms that cause neonatal pneumonia, meningitis, and sepsis: GBS and E coli. For many years, the drugs of choice have been intravenous ampicillin (2 g every 6 hours) plus intravenous gentamicin (5 mg/kg of IBW every 24 hours). Gentamicin also can be administered intravenously at a dose of 1.5 mg/kg every 8 hours. I prefer the once-daily dosing for 3 reasons:

• Gentamicin works by a concentration-dependent mechanism; the higher the initial serum concentration, the better the killing effect.
• Once-daily dosing preserves long periods with low trough levels, an effect that minimizes ototoxicity and nephrotoxicity.
• Once-daily dosing is more convenient.

In a patient who has a contraindication to use of an aminoglycoside, aztreonam (2 g intravenously every 8 hours) may be combined with ampicillin.²

If the patient delivers vaginally, 1 dose of each drug should be administered postpartum, and then the antibiotics should be discontinued. If the patient delivers by cesarean, a single dose of a medication with strong anaerobic coverage should be administered immediately after the infant’s umbilical cord is clamped. Options include clindamycin (900 mg intravenously) or metronidazole (500 mg intravenously).¹¹

There are 2 key exceptions to the single postpartum dose rule, however. If the patient is obese (body mass index [BMI] >30 kg/m²) or if the membranes have been ruptured for more than 24 hours, antibiotics should be continued until she has been afebrile and asymptomatic for 24 hours.¹²

Two single agents are excellent alternatives to the combination ampicillin-gentamicin regimen. One is ampicillin-sulbactam, 3 g intravenously every 6 hours. The other is piperacillin-tazobactam, 3.375 g intravenously every 6 hours. These extended-spectrum penicillins provide exceptionally good coverage against the major pathogens that cause chorioamnionitis. Although more expensive than the combination regimen, they avoid the potential ototoxicity and nephrotoxicity associated with gentamicin.²

6. Endometritis

Puerperal endometritis is significantly more common after CD than after vaginal delivery. The infection is polymicrobial, and the principal pathogens are anaerobic gram-positive cocci, anaerobic gram-negative bacilli, aerobic gram-negative bacilli, and aerobic gram-positive cocci. The diagnosis usually is made almost exclusively based on clinical findings: fever within 24 to 36 hours of delivery, tachycardia, mild tachypnea, and lower abdominal/pelvic pain and tenderness in the absence of any other localizing sign of infection.¹³

Antibiotic selection

Effective treatment of endometritis requires administration of antibiotics that provide coverage against the broad range of pelvic pathogens. For many years, the gold standard of treatment has been the combination regimens of clindamycin plus gentamicin or metronidazole plus ampicillin plus gentamicin. These drugs are available in generic form and are relatively inexpensive. However, several broad-spectrum single agents are now available for treatment of endometritis. Although they are moderately more expensive than the generic combination regimens, they usually are very well tolerated, and they avoid the potential nephrotoxicity and ototoxicity associated with gentamicin. TABLE 1 summarizes the dosing regimens of these various agents and their potential weaknesses in coverage.^2,13

7. Gonorrhea

Gonorrhea is caused by the gram-negative diplococcus, Neisseria gonorrhoeae. The organism has a propensity to infect columnar epithelium and uroepithelium, and, typically, it causes a localized infection of the urethra, endocervix, and rectum. The organism also can cause an oropharyngeal infection, a disseminated infection (most commonly manifested by dermatitis and arthritis), and perihepatitis.

The diagnosis is best confirmed by a NAAT that can simultaneously test for gonorrhea and chlamydia in urine or in secretions obtained from the urethra, endocervix, and rectum.^2,10

Antibiotic selection

The drugs of choice for treating uncomplicated gonococcal infection in pregnancy are a single dose of ceftriaxone 500 mg intramuscularly, or cefixime 800 mg orally. If the patient is allergic to β-lactam antibiotics, the recommended treatment is gentamicin 240 mg intramuscularly in a single dose, combined with azithromycin 2,000 mg orally.¹⁴

8. Group B streptococci prophylaxis

The first-line agents for GBS prophylaxis are penicillin and ampicillin. Resistance of GBS to either of these antibiotics is extremely rare. The appropriate penicillin dose is 3 million U intravenously every 4 hours; the intravenous dose of ampicillin is 2 g initially, then 1 g every 4 hours. I prefer penicillin for prophylaxis because it has a narrower spectrum of activity and is less likely to cause antibiotic-associated diarrhea. The antibiotic should be continued until delivery of the neonate.^2,15,16

If the patient has a mild allergy to penicillin, the drug of choice is cefazolin 2 g intravenously initially, then 1 g every 8 hours. If the patient’s allergy to β-lactam antibiotics is severe, the alternative agents are vancomycin (20 mg/kg intravenously every 8 hours infused over 1–2 hours; maximum single dose of 2 g) and clindamycin (900 mg intravenously every 8 hours). The latter drug should be used only if sensitivity testing has confirmed that the GBS strain is sensitive to clindamycin. Resistance to clindamycin usually ranges from 10% to 15%.^2,15,16

9. Puerperal mastitis

The principal microorganisms that cause puerperal mastitis are the aerobic streptococci and staphylococci that form part of the normal skin flora. The diagnosis usually is made based on the characteristic clinical findings: erythema, tenderness, and warmth in an area of the breast accompanied by a purulent nipple discharge and fever and chills. The vast majority of cases can be treated with oral antibiotics on an outpatient basis. The key indications for hospitalization are severe illness, particularly in an immunocompromised patient, and suspicion of a breast abscess.²

Continue to: Antibiotic selection...

The initial drug of choice for treatment of mastitis is dicloxacillin sodium 500 mg every 6 hours for 7 to 10 days. If the patient has a mild allergy to penicillin, the appropriate alternative is cephalexin 500 mg every 8 hours for 7 to 10 days. If the patient’s allergy to penicillin is severe, 2 alternatives are possible. One is clindamycin 300 mg twice daily for 7 to 10 days; the other is trimethoprim-sulfamethoxazole double strength (800 mg/160 mg), twice daily for 7 to 10 days. The latter 2 drugs are also of great value if the patient fails to respond to initial therapy and/or infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.² I prefer the latter agent because it is less expensive than clindamycin and is less likely to cause antibiotic-induced diarrhea.

If hospitalization is required, the drug of choice is intravenous vancomycin. The appropriate dosage is 20 mg/kg every 8 to 12 hours (maximum single dose of 2 g).²

10. Syphilis

Syphilis is caused by the spirochete bacterium, Treponema pallidum. The diagnosis can be made by clinical examination if the characteristic findings listed in TABLE 2 are present.^2,17 However, most patients in our practice will have latent syphilis, and the diagnosis must be established based on serologic screening.¹⁷

Antibiotic selection

In pregnancy, the treatment of choice for syphilis is penicillin (TABLE 3).^2,10,17 Only penicillin has been proven effective in treating both maternal and fetal infection. If the patient has a history of allergy to penicillin, she should undergo skin testing to determine if she is truly allergic. If hypersensitivity is confirmed, the patient should be desensitized and then treated with the appropriate regimen outlined in TABLE 3. Of interest, within a short period of time after treatment, the patient’s sensitivity to penicillin will be reestablished, and she should not be treated again with penicillin unless she undergoes another desensitization process.^2,17

11. Trichomoniasis

Trichomoniasis is caused by the flagellated protozoan, Trichomonas vaginalis. The condition is characterized by a distinct yellowish-green vaginal discharge. The vaginal pH is >4.5, and motile flagellated organisms are easily visualized on saline microscopy. The vaginal panel assay also is a valuable diagnostic test.³

Antibiotic selection

The drug of choice for trichomoniasis is oral metronidazole 500 mg twice daily for 7 days. The patient’s sexual partner(s) should be treated concurrently to prevent reinfection. Most treatment failures are due to poor compliance with therapy on the part of either the patient or her partner(s); true drug resistance is uncommon. When antibiotic resistance is strongly suspected, the patient may be treated with a single 2-g oral dose of tinidazole.²

12. Urinary tract infections

Urethritis

Acute urethritis usually is caused by C trachomatis or N gonorrhoeae. The treatment of infections with these 2 organisms is discussed above.

Asymptomatic bacteriuria and acute cystitis

Bladder infections are caused primarily by E coli, Klebsiella pneumoniae, and Proteus species. Gram-positive cocci such as enterococci, Staphylococcus saprophyticus, and GBS are less common pathogens.¹⁸

The key diagnostic criterion for asymptomatic bacteriuria is a colony count greater than 100,000 organisms/mL of a single uropathogen on a clean-catch midstream urine specimen.¹⁸

The usual clinical manifestations of acute cystitis include frequency, urgency, hesitancy, suprapubic discomfort, and a low-grade fever. The diagnosis is most effectively confirmed by obtaining urine by catheterization and demonstrating a positive nitrite and positive leukocyte esterase reaction on dipstick examination. The finding of a urine pH of 8 or greater usually indicates an infection caused by Proteus species. When urine is obtained by catheterization, the criterion for defining a positive culture is greater than 100 colonies/mL.¹⁸

Antibiotic selection. In the first trimester, the preferred agents for treatment of a lower urinary tract infection are oral amoxicillin (875 mg twice daily) or cephalexin (500 mg every 8 hours). For an initial infection, a 3-day course of therapy usually is adequate. For a recurrent infection, a 7- to 10-day course is indicated.

Beyond the first trimester, nitrofurantoin monohydrate macrocrystals (100 mg orally twice daily) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily) are the preferred agents. Unless no other oral drug is likely to be effective, these 2 drugs should be avoided in the first trimester. The former has been associated with eye, heart, and cleft defects. The latter has been associated with neural tube defects, cardiac anomalies, choanal atresia, and diaphragmatic hernia.¹⁸

Acute pyelonephritis

Acute infections of the kidney usually are caused by the aerobic gram-negative bacilli: E coli, K pneumoniae, and Proteus species. Enterococci, S saprophyticus, and GBS are less likely to cause upper tract infection as opposed to bladder infection.

The typical clinical manifestations of acute pyelonephritis include high fever and chills in association with flank pain and tenderness. The diagnosis is best confirmed by obtaining urine by catheterization and documenting the presence of a positive nitrite and leukocyte esterase reaction. Again, an elevated urine pH is indicative of an infection secondary to Proteus species. The criterion for defining a positive culture from catheterized urine is greater than 100 colonies/mL.^2,18

Antibiotic selection. Patients in the first half of pregnancy who are hemodynamically stable and who show no signs of preterm labor may be treated with oral antibiotics as outpatients. The 2 drugs of choice are amoxicillin-clavulanate (875 mg twice daily for 7 to 10 days) or trimethoprim-sulfamethoxazole double strength (800 mg/160 mg twice daily for 7 to 10 days).

For unstable patients in the first half of pregnancy and for essentially all patients in the second half of pregnancy, parenteral treatment should be administered on an inpatient basis. My preference for treatment is ceftriaxone, 2 g intravenously every 24 hours. The drug provides excellent coverage against almost all the uropathogens. It has a convenient dosing schedule, and it usually is very well tolerated. Parenteral therapy should be continued until the patient has been afebrile and asymptomatic for 24 to 48 hours. At this point, the patient can be transitioned to one of the oral regimens listed above and managed as an outpatient. If the patient is allergic to β-lactam antibiotics, an excellent alternative is aztreonam, 2 g intravenously every 8 hours.^2,18 ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

CASE Part 1: CPR initiated during induction of labor

A 32-year-old gravida 4 para 3-0-0-3 is undergoing induction of labor with intravenous (IV) oxytocin at 39 weeks of gestation. She has no significant medical or obstetric history. Fifteen minutes after reaching complete cervical dilation, she says “I don’t feel right,” then suddenly loses consciousness. The nurse finds no detectable pulse, calls a “code blue,” and initiates cardiopulmonary resuscitation (CPR). The obstetrician is notified, appears promptly, assesses the situation, and delivers a 3.6-kg baby via vacuum extraction. Apgar score is 2/10 at 1 minute and 6/10 at 5 minutes. After delivery of the placenta, there is uterine atony and brisk hemorrhage with 2 L of blood loss.

Management of AFE: A rare complication

This case demonstrates a classic presentation of amniotic fluid embolism (AFE) syndrome—a patient in labor or within 30 minutes after delivery has sudden onset of cardiorespiratory collapse followed by disseminated intravascular coagulation (DIC). AFE is rare, affecting only about 2 to 6 per 100,000 births, but classic cases have a reported maternal mortality rate that exceeds 50%.¹ It is thought to reflect a complex, systemic proinflammatory response to maternal intravasation of pregnancy material, such as trophoblast, thromboplastins, fetal cells, or amniotic fluid. Because the syndrome is not necessarily directly caused by emboli or by amniotic fluid per se,² it has been proposed that AFE be called “anaphylactoid syndrome of pregnancy,” but this terminology has not yet been widely adopted.³

Guidelines from the Society for Maternal-Fetal Medicine (SMFM) recommend several time-critical steps for the initial stabilization and management of patients with AFE.⁴ However, because AFE is rare, most obstetric providers may not encounter a case for many years or even decades after they have received training, so it is unrealistic to expect that they will remember these guidelines when they are needed. For this reason, when AFE occurs, it is important to have a readily accessible cognitive aid, such as a checklist that summarizes the key management steps. The SMFM provides a checklist for initial management of AFE that can be used at your institution; it is presented in the FIGURE and provides the outline for this discussion.⁵

Provide CPR immediately

Most AFE cases are accompanied by cardiorespiratory arrest. If the patient has no pulse, call a “code” to mobilize additional help and immediately start CPR. Use a backboard to make cardiac compressions most effective and manually displace the uterus or tilt the patient to avoid supine hypotension. Designate a timekeeper to call out 1-minute intervals and record critical data, such as medication administration and laboratory orders/results.

Expedite delivery

Immediate delivery is needed if maternal cardiac activity is not restored within 4 minutes of starting CPR, with a target to have delivery completed within 5 minutes. Operative vaginal delivery may be an option if delivery is imminent, as in the case presented, but cesarean delivery (CD) will be needed in most cases. This was previously called “perimortem cesarean” delivery, but the term “resuscitative hysterotomy” has been proposed because the primary goal is to improve the effectiveness of CPR⁶ and prevent both maternal and perinatal death. CPR is less effective in pregnant women because the pregnant uterus takes a substantial fraction of the maternal cardiac output, as well as compresses the vena cava. Some experts suggest that, rather than waiting 4 minutes, CD should be started as soon as an obstetrician or other surgeon is present, unless there is an immediate response to electrical cardioversion.^6,7

In most cases, immediate CD should be performed wherever the patient is located rather than using precious minutes to move the patient to an operating room. Antiseptic preparation is expedited by simply pouring povidone-iodine or chlorhexidine over the lower abdomen if readily available; if not available, skip this step. Enter the abdomen and uterus as rapidly as possible using only a scalpel to make generous midline incisions.

If CPR is not required, proceed with cesarean or operative vaginal delivery as soon as the mother has been stabilized. These procedures should be performed using standard safety precautions outlined in the SMFM patient safety checklists for cesarean or operative vaginal delivery.^8,9

Continue to: Anticipate hemorrhage...

Be prepared for uterine atony, coagulopathy, and catastrophic hemorrhage. Initiate IV oxytocin prophylaxis as soon as the infant is delivered. Have a low threshold for giving other uterotonic agents such as methylergonovine, carboprost, or misoprostol. If hemorrhage or DIC occurs, give tranexamic acid. Have the anesthesiologist or trauma team (if available) insert an intraosseous line for fluid resuscitation if peripheral IV access is inadequate.

Massive transfusion is often needed to treat DIC, which occurs in most AFE cases. Anticipate—do not wait—for DIC to occur. We propose activating your hospital’s massive transfusion protocol (MTP) as soon as you diagnose AFE so that blood products will be available as soon as possible. A typical MTP provides several units of red blood cells, a pheresis pack of platelets, and fresh/frozen plasma (FFP). If clinically indicated, administer cryoprecipitate instead of FFP to minimize volume overload, which may occur with FFP.

CASE Part 2: MTP initiated to treat DIC

The MTP is initiated. Laboratory results immediately pre-transfusion include hemoglobin 11.3 g/dL, platelet count 46,000 per mm³, fibrinogen 87 mg/dL, and an elevated prothrombin time international normalized ratio.

Expect heart failure

The initial hemodynamic picture in AFE is right heart failure, which should optimally be managed by a specialist from anesthesiology, cardiology, or critical care as soon as they are available. An emergency department physician may manage the hemodynamics until a specialist arrives. Avoidance of fluid overload is one important principle. If fluid challenges are needed for hypovolemic shock, boluses should be restricted to 500 mL rather than the traditional 1000 mL.

Pharmacologic treatment may include vasopressors, inotropic agents, and pulmonary vasodilators. Example medications and dosages recommended by SMFM are summarized in the checklist (FIGURE).⁵

After the initial phase of recovery, the hemodynamic picture often changes from right heart failure to left heart failure. Management of left heart failure is not covered in the SMFM checklist because, by the time it appears, the patient will usually be in the intensive care unit, managed by the critical care team. Management of left heart failure generally includes diuresis as needed for cardiogenic pulmonary edema, optimization of cardiac preload, and inotropic agents or vasopressors if needed to maintain cardiac output or perfusion pressure.⁴

Debrief, learning opportunities

Complex emergencies such as AFE are rarely handled 100% perfectly, even those with a good outcome, so they present opportunities for team learning and improvement. The team should conduct a 10- to 15-minute debrief soon after the patient is stabilized. Make an explicit statement that the main goal of the debrief is to gather suggestions as to how systems and processes could be improved for next time, not to find fault or lay blame on individuals. Encourage all personnel involved in the initial management to attend and discuss what went well and what did not. Another goal is to provide support for individuals who may feel traumatized by the dramatic, frightening events surrounding an AFE and by the poor patient outcome or guarded prognosis that frequently follows. Another goal is to discuss the plan for providing support and disclosure to the patient and family.

The vast majority of AFE cases meet criteria to be designated as “sentinel events,” because of patient transfer to the intensive care unit, multi-unit blood transfusion, other severe maternal morbidities, or maternal death. Therefore, most AFE cases will trigger a root cause analysis (RCA) or other formal sentinel event analysis conducted by the hospital’s Safety or Quality Department. As with the immediate post-event debrief, the first goal of the RCA is to identify systems issues that may have resulted in suboptimal care and that can be modified to improve future care. Specific issues regarding the checklist should also be addressed:

• Was the checklist used?
• Was the checklist available?
• Are there items on the checklist that need to be modified, added, or deleted?

The RCA concludes with the development of a performance improvement plan.

Ultimately, we encourage all AFE cases be reported to the registry maintained by the Amniotic Fluid Embolism Foundation at https://www.afesupport.org/, regardless of whether the outcome was favorable for the mother and newborn. The registry includes over 130 AFE cases since 2013 from around the world. Researchers periodically report on the registry findings.¹⁰ If providers report cases with both good and bad outcomes, the registry may provide future insights regarding which adjunctive or empiric treatments may or may not be promising.

Continue to: Empiric treatments...

From time-to-time, new regimens for empiric treatment of AFE are reported. It is important to recognize that these reports are generally uncontrolled case reports of favorable outcomes and that, without a control group, it is impossible to determine to what extent the treatment contributed to the outcome or was merely incidental. Given the rarity of AFE, it seems unlikely that there will ever be a randomized clinical trial or even a controlled prospective study comparing treatment regimens.

The “A-OK” regimen is an empiric treatment that has garnered some interest after an initial case report.¹¹ It consists of an anticholinergic agent (atropine 0.2 mg IV), a selective 5-HT3 receptor antagonist (ondansetron 8 mg IV), and a nonsteroidal anti-inflammatory drug (ketorolac 15 mg IV). We have some reservations about this regimen, however, because atropine is relatively contraindicated if the patient has tachycardia (which is common in patients with hemorrhage) and ketorolac may suppress platelet function, which might be harmful for patients with DIC or thrombocytopenia.

Another empiric treatment is the “50-50-500” regimen, which includes an H1 antihistamine (diphenhydramine 50 mg IV), an H2 antihistamine (famotidine 50 mg IV), and a corticosteroid (hydrocortisone 500 mg IV). This regimen aims to suppress histamine-mediated and cell-mediated inflammatory responses, based on the notion that proinflammatory responses likely mediate much of the underlying pathophysiology of the AFE syndrome.

We would emphasize that these empiric regimens are not clinically validated, US Food and Drug Administration approved for treatment of AFE, or considered standard of care. Future reports of these and other regimens will be needed to evaluate their efficacy, limitations, and risks. Again, we encourage providers to report all AFE cases to the AFE Foundation registry, regardless of whether the treatments are successful.

CASE Conclusion

The hemorrhage stops after administration of oxytocin, carboprost, 6 units of cryoprecipitate, and a 6-unit platelet pheresis pack. The patient is transferred to the intensive care unit where she eventually requires a total of 10 units of red cells, 8 more units of cryoprecipitate, and another platelet pheresis pack. She is discharged to home in stable condition on postpartum day 4.

Be prepared, have the checklist ready

Because AFE is rare, most members of the health care team will have no prior experience managing a real case. It may have been years or decades since they had any education on AFE or they last read a review article such as this one. It is even possible the anesthesiologist, cardiologist, or critical care specialist has never heard of AFE. Thus if they rely on memory alone, there is substantial risk of forgetting items, getting dosages wrong, or other errors. With this in mind, what is the best way to prepare the team to expeditiously employ the management steps outlined here?

Use of a checklist that summarizes these key steps for early management, such as the SMFM checklist in the FIGURE, will help ensure that all relevant steps are performed in every AFE case. It is designed to be printed on a single sheet of letter-sized paper, and we propose that every labor and delivery (L&D) unit keep laminated copies of this checklist in several places where they will be immediately available should an AFE occur. Copies can be kept on the anesthesia carts in the L&D operating rooms, in an emergency procedures binder on the unit, and on the “crash carts” and hemorrhage supply carts in the L&D unit. Effective implementation of an AFE checklist requires all personnel know where to readily find it and have some familiarity with its contents.

An interdisciplinary team comprising representatives from nursing, obstetrics, and anesthesia should meet to discuss whether the checklist needs to be modified to fit the local hospital formulary or other unique local circumstances. The team should develop an implementation plan that includes where to keep checklist copies, a process to periodically ensure that the copies are still present and readable, a roll-out plan to inform all personnel about the checklist process, and most importantly a training plan that includes incorporating AFE cases into the schedule of multidisciplinary simulations and drills for obstetric emergencies. Other implementation strategies are outlined in the SMFM document.⁵

Ultimately an organized, systematic approach is recommended for management of AFE. There is no single best treatment of AFE; it is supportive and directed toward the underlying pathophysiology, which may vary from patient to patient. Therefore, although a checklist, in conjunction with regular education and simulation activities, may help optimize care and improve outcomes, there is still a high risk of maternal morbidity and mortality from AFE. ●

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Minimizing dietary consumption of simple sugars may help alleviate symptoms of gastroesophageal reflux disease (GERD), new data suggest.

People who consumed lower quantities of simple sugars experienced significant improvement in total acid exposure time, number of reflux episodes, and subjective reports of heartburn and reflux symptoms, compared with those consuming higher amounts of simple sugars, the authors report.

The authors call their study the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic GERD and one of only a few to investigate any type of dietary intervention for GERD.

“There’s really almost no rigorous scientific evidence on any of the foods or ingredients or nutrients that are often recommended to avoid if you have GERD,” corresponding author Heidi J. Silver, RD, PhD, told this news organization. Dr. Silver is research professor of medicine at Vanderbilt University School of Medicine and director of the Vanderbilt Diet, Body Composition, and Human Metabolism Core in Nashville, Tenn.

Even the avoidance of fatty foods, which has been long promoted as part of GERD management, has little evidence to support it.

“With fat, there’s some belief that it may slow down gastric emptying. Therefore, if you had slower gastric emptying, you would have a longer time for the food to put pressure on the lower esophageal sphincter and create an environment for reflux. So, it’s kind of conceptually what is thought but not really tested,” she notes.

The findings were published online in the American Journal of Gastroenterology.
 

Greatest symptom reduction with low simple carb intake

To test the role of dietary carbohydrates, Dr. Silver and her colleagues randomly assigned 98 U.S. veterans with symptomatic GERD to intake of one of four diets with varying carbohydrate types and amounts for 9 weeks: high total/high simple (the control group), high total/low simple, low total/high simple, or low total/low simple. The total caloric intake was approximately the same for all groups.

At baseline, the average total carbohydrate consumption was 43.7% of calories, and the average simple sugar intake was 116.5 g/d. The two “low-total” groups averaged about a 10% reduction in carbohydrate calories. The “low-simple” groups reduced simple sugars by about half.

There were no changes in body weight in the control group, whereas all three of the other groups lost some weight, ranging from 1.5-2.0 kg (3.3-4.4 lb) despite calorie totals designed for weight maintenance.

There was a significant effect of diet on the two primary outcomes, total esophageal acid exposure time, and total number of reflux episodes, as measured by 24-hour ambulatory pH monitoring. The change in total acid exposure time was significantly greater for the high total/low simple group, compared with the high total/high simple group.

The participants’ ratings of symptoms assessed by the Gastroesophageal Reflux Disease Questionnaire and the GERD Symptom Assessment Scale, including heartburn frequency and severity, pain in throat/chest, and sleep disturbance, improved in all modified diet groups, compared with the control group. The mean degree of improvement in heartburn and regurgitation was twice as great for the modified diets, compared with the controls, and was greatest for the two “low-simple” carb groups.

Dr. Silver and colleagues hypothesize that the differential effects of the diets may relate to the way that dietary carbohydrates are sensed in the gastrointestinal tract after being enzymatically degraded into monosaccharides, possibly affecting lower esophageal tone via the effects of gut-derived hormones including ghrelin and glucagon-like peptide 1 that are secreted in response to macronutrient intake.

Although more data are needed about the effects of carbohydrates in GERD, Dr. Silver advised, “I do think it would be smart for clinicians, when they’re discussing diet, that they bring up the simple sugars. There’s no potential harm in reducing simple sugars. You’re only benefiting yourself in multiple ways. We know that the consumption of simple sugars is extremely excessive, not just in America but worldwide.”

Asked to comment, Philip O. Katz, MD, professor of medicine and director of the GI Function Laboratories at Weill Cornell Medicine, New York, told this news organization that “this is one of the better-designed studies with a lot of care looking at a lot of endpoints that are intriguing and useful.”

“What it says to me is there is potential for nonpharmacologic interventions for GERD that include diet change for helping patients,” he said. “This shows promise for a diet that doesn’t just concentrate on fat or acidic products and is a possible way of augmenting reflux treatment.”

However, Dr. Katz cautioned, “I don’t think anybody should do more with a 9-week study than look at it as good potential.”

“I would tell patients that this is something that they might try, but I wouldn’t make it a rigid requirement based on these data,” he added. “If I were involved in this study, the next thing I would do is transition it to real life and look at compliance to see if results were sustained at 18 weeks or 6 months.”
 

Diet part of an ‘overall reflux program’

Overall, Dr. Katz, who was the first author of the American College of Gastroenterology’s Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease, pointed out that the main nonpharmacologic advice for GERD management includes “Eat smaller meals, don’t eat before bed, don’t lie down after you eat, and reduce any individually known trigger foods.”

Essentially, he views dietary interventions as complementary to medication and other interventions.

“When people really have GERD – not just heartburn – dietary change is an adjunct,” Dr. Katz said. “GERD is a real disease, like diabetes. For some with GERD, maybe this is the only thing they need to do. But, in general, this will be an adjunct to augment an overall reflux program.”

And that program, both Dr. Silver and Dr. Katz said, should include referral to a dietitian or nutritionist.

“If you’re going to invest time in getting your patients to change their diet, it should be done with professional help, a qualified nutritionist who can work with the patient. This should not be a fad,” Dr. Katz said.

Dr. Silver noted, “In contrast to a physician, the dietitian looks at everything the person is eating. If they’re consuming a lot of simple sugars, I certainly would make that recommendation to reduce, along with other recommendations for GERD. It could be easily incorporated. We included examples in the paper of what we did to achieve that reduction and some things clinicians could focus on.”

One obvious approach, she said, is to advise patients to cut the amount of sugared soda they’re drinking, if not eliminate it entirely.

The study was funded by a VA Merit Award. Dr. Silver has no further disclosures. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca.

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

Results from a randomized controlled trial conducted in China found low-dose benzbromarone to be more effective in lowering serum urate levels than low-dose febuxostat (Uloric), with a similar safety profile, in gout with renal uric acid underexcretion.

Benzbromarone is not approved in the United States because of concerns of acute liver injury but is approved in several other countries, including China, Brazil, and New Zealand.

“The results suggest that low dosing of benzbromarone may warrant stronger consideration as a safe and effective therapy to achieve serum urate target in gout without moderate chronic kidney disease,” the study team writes.

“Benzbromarone is severely hepatotoxic in some individuals and unlikely to ever gain approval in the United States,” one of the study’s investigators, Robert Terkeltaub, MD, professor of medicine, University of California, San Diego, told this news organization.

However, this study “illustrates the value and impact of uricosuric therapy in general in gout, including potentially as an initial urate-lowering monotherapy strategy, and the sheer number of subjects reaching urate target with low-dose uricosuric monotherapy was impressive,” Dr. Terkeltaub said.

The study was published online  in Arthritis & Rheumatology.

“Renal uric acid underexcretion is the chief mechanism driving hyperuricemia in gout, yet the standard urate-lowering therapy recommendation is first-line xanthine oxidase inhibition irrespective of the cause of hyperuricemia,” the study team explains in their article.

Their prospective, randomized, single-center, open-labeled trial was conducted at the Gout Clinic of the Affiliated Hospital of Qingdao University, China.

A total of 196 relatively young healthy men with gout and uric acid underexcretion were randomly assigned to receive low-dose benzbromarone (25 mg/d) or low-dose febuxostat (20 mg/d) for 12 weeks.

Renal uric acid underexcretion was defined as fractional excretion of urate less than 5.5% and uric acid excretion less than or equal to 600 mg/d/1.73 m2.

A “major aspect” of this comparative effectiveness trial was its specific focus on gout-associated renal uric acid underexcretion, where the uricosuric targeted the dominant abnormality promoting the hyperuricemia, Dr. Terkeltaub told this news organization.

In addition, all participants received daily urine alkalinization with oral sodium bicarbonate. “This is not always done in clinical practice, nor in clinical trials of uricosuric agents,” Dr. Terkeltaub said.

The results showed that more participants in the benzbromarone group achieved the serum urate target of less than 6 mg/dL, compared with those in the febuxostat group (primary endpoint, 61% vs. 32%, P < .001).

Adverse events, including gout flares and urolithiasis, did not differ significantly between the two groups, with the exception of more transaminase elevation in the febuxostat group (15% vs. 4%; P = .008).

“We did not find severe hepatotoxicity with low-dose benzbromarone, but ethnic background may affect drug responses, and severe hepatotoxicity of benzbromarone has rarely been reported in Asia,” the authors write.

The incidence of urolithiasis was numerically, but not significantly, higher in the benzbromarone group (5% vs. 2%).

This study found no significant changes in participants’ triglyceride levels, though a previous study suggested febuxostat could increase serum triglycerides.

The investigators caution that the study only included patients who had baseline serum urate levels ranging from 8.0 to 10 mg/dL, who were relatively young and with few comorbidities.

The authors further noted that the “... results may not be generalizable to patients with higher serum urate levels or impaired kidney function, as well [as] patients from other geographical regions, age, and ethnicity groups. The study only included men, and the findings may not be generalizable to women with gout.”

‘Very useful’ in select cases

Weighing in on the results, Valderilio Feijó Azevedo, MD, PhD, adjunct professor of rheumatology, Federal University of Paraná, Brazil, noted that in some specific clinical circumstances, benzbromarone has been “a very useful medication, alone or combined, to treat gout patients.”

“We have great experience with the drug in Brazil. However, it is not used to treat all patients. Patients must be very well-selected in our clinical practice,” Dr. Azevedo said in an interview.

“For most patients, benzbromarone is effective for those who have failed to achieve serum uric acid goals with allopurinol treatment. We do not use it to treat patients with asymptomatic hyperuricemia. In general, we avoid patients with hepatic dysfunction due to previous hepatotoxicity reports. In every patient, we do active monitoring of enzymes,” Dr. Azevedo explained.

“We also avoid using it in patients with severe kidney disease. However, we have used it in some patients with estimated glomerular filtration rate less than 30. We also avoid dosage over 200 mg per day. On average, we use 100 mg per day combined with allopurinol or alone,” said Dr. Azevedo, who was not involved with the study.

Also weighing in, Michael Pillinger, MD, rheumatologist at NYU Langone Health, noted that while benzbromarone is not used in the United States, “in many parts of the world, it is used and is felt to be effective.” Dr. Pillinger was not associated with this current research.

This study, Dr. Pillinger said, “does underline the fact that an alternative drug that lowers urate by promoting urate excretion, if it could gain [U.S. Food and Drug Association] approval and if it were safe, could present a viable new option for therapy.”

He added, “If one conclusion to the study is that determining the basis of hyperuricemia is helpful in guiding benzbromarone use, that implies an additional layer of effort for physicians and patients in a disease that is already notoriously known for patient noncompliance – and in a case where febuxostat and allopurinol will work for both overproducers and underexcreters and would not need this additional assessment.”

The study was sponsored by Shandong Provincial Key Research and Development Plan, the National Natural Science Foundation of China, and Shandong Provincial Science Foundation for Outstanding Youth Scholarship. Dr. Terkeltaub was supported by the National Institutes of Health and the VA Research Service. Dr. Terkeltaub has received research funding from AstraZeneca, and has consulted with Horizon, Selecta, SOBI, Dyve BioSciences, Fortress, AstraZeneca, Allena, Fortress Biotech, and LG Life Sciences. Dr. Azevedo and Dr. Pillinger have no reported no relevant financial relationships.

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

Results from a randomized controlled trial conducted in China found low-dose benzbromarone to be more effective in lowering serum urate levels than low-dose febuxostat (Uloric), with a similar safety profile, in gout with renal uric acid underexcretion.

Benzbromarone is not approved in the United States because of concerns of acute liver injury but is approved in several other countries, including China, Brazil, and New Zealand.

“The results suggest that low dosing of benzbromarone may warrant stronger consideration as a safe and effective therapy to achieve serum urate target in gout without moderate chronic kidney disease,” the study team writes.

“Benzbromarone is severely hepatotoxic in some individuals and unlikely to ever gain approval in the United States,” one of the study’s investigators, Robert Terkeltaub, MD, professor of medicine, University of California, San Diego, told this news organization.

However, this study “illustrates the value and impact of uricosuric therapy in general in gout, including potentially as an initial urate-lowering monotherapy strategy, and the sheer number of subjects reaching urate target with low-dose uricosuric monotherapy was impressive,” Dr. Terkeltaub said.

The study was published online  in Arthritis & Rheumatology.

“Renal uric acid underexcretion is the chief mechanism driving hyperuricemia in gout, yet the standard urate-lowering therapy recommendation is first-line xanthine oxidase inhibition irrespective of the cause of hyperuricemia,” the study team explains in their article.

Their prospective, randomized, single-center, open-labeled trial was conducted at the Gout Clinic of the Affiliated Hospital of Qingdao University, China.

A total of 196 relatively young healthy men with gout and uric acid underexcretion were randomly assigned to receive low-dose benzbromarone (25 mg/d) or low-dose febuxostat (20 mg/d) for 12 weeks.

Renal uric acid underexcretion was defined as fractional excretion of urate less than 5.5% and uric acid excretion less than or equal to 600 mg/d/1.73 m2.

A “major aspect” of this comparative effectiveness trial was its specific focus on gout-associated renal uric acid underexcretion, where the uricosuric targeted the dominant abnormality promoting the hyperuricemia, Dr. Terkeltaub told this news organization.

In addition, all participants received daily urine alkalinization with oral sodium bicarbonate. “This is not always done in clinical practice, nor in clinical trials of uricosuric agents,” Dr. Terkeltaub said.

The results showed that more participants in the benzbromarone group achieved the serum urate target of less than 6 mg/dL, compared with those in the febuxostat group (primary endpoint, 61% vs. 32%, P < .001).

Adverse events, including gout flares and urolithiasis, did not differ significantly between the two groups, with the exception of more transaminase elevation in the febuxostat group (15% vs. 4%; P = .008).

“We did not find severe hepatotoxicity with low-dose benzbromarone, but ethnic background may affect drug responses, and severe hepatotoxicity of benzbromarone has rarely been reported in Asia,” the authors write.

The incidence of urolithiasis was numerically, but not significantly, higher in the benzbromarone group (5% vs. 2%).

This study found no significant changes in participants’ triglyceride levels, though a previous study suggested febuxostat could increase serum triglycerides.

The investigators caution that the study only included patients who had baseline serum urate levels ranging from 8.0 to 10 mg/dL, who were relatively young and with few comorbidities.

The authors further noted that the “... results may not be generalizable to patients with higher serum urate levels or impaired kidney function, as well [as] patients from other geographical regions, age, and ethnicity groups. The study only included men, and the findings may not be generalizable to women with gout.”

‘Very useful’ in select cases

Weighing in on the results, Valderilio Feijó Azevedo, MD, PhD, adjunct professor of rheumatology, Federal University of Paraná, Brazil, noted that in some specific clinical circumstances, benzbromarone has been “a very useful medication, alone or combined, to treat gout patients.”

“We have great experience with the drug in Brazil. However, it is not used to treat all patients. Patients must be very well-selected in our clinical practice,” Dr. Azevedo said in an interview.

“For most patients, benzbromarone is effective for those who have failed to achieve serum uric acid goals with allopurinol treatment. We do not use it to treat patients with asymptomatic hyperuricemia. In general, we avoid patients with hepatic dysfunction due to previous hepatotoxicity reports. In every patient, we do active monitoring of enzymes,” Dr. Azevedo explained.

“We also avoid using it in patients with severe kidney disease. However, we have used it in some patients with estimated glomerular filtration rate less than 30. We also avoid dosage over 200 mg per day. On average, we use 100 mg per day combined with allopurinol or alone,” said Dr. Azevedo, who was not involved with the study.

Also weighing in, Michael Pillinger, MD, rheumatologist at NYU Langone Health, noted that while benzbromarone is not used in the United States, “in many parts of the world, it is used and is felt to be effective.” Dr. Pillinger was not associated with this current research.

This study, Dr. Pillinger said, “does underline the fact that an alternative drug that lowers urate by promoting urate excretion, if it could gain [U.S. Food and Drug Association] approval and if it were safe, could present a viable new option for therapy.”

He added, “If one conclusion to the study is that determining the basis of hyperuricemia is helpful in guiding benzbromarone use, that implies an additional layer of effort for physicians and patients in a disease that is already notoriously known for patient noncompliance – and in a case where febuxostat and allopurinol will work for both overproducers and underexcreters and would not need this additional assessment.”

The study was sponsored by Shandong Provincial Key Research and Development Plan, the National Natural Science Foundation of China, and Shandong Provincial Science Foundation for Outstanding Youth Scholarship. Dr. Terkeltaub was supported by the National Institutes of Health and the VA Research Service. Dr. Terkeltaub has received research funding from AstraZeneca, and has consulted with Horizon, Selecta, SOBI, Dyve BioSciences, Fortress, AstraZeneca, Allena, Fortress Biotech, and LG Life Sciences. Dr. Azevedo and Dr. Pillinger have no reported no relevant financial relationships.

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

Results from a randomized controlled trial conducted in China found low-dose benzbromarone to be more effective in lowering serum urate levels than low-dose febuxostat (Uloric), with a similar safety profile, in gout with renal uric acid underexcretion.

Benzbromarone is not approved in the United States because of concerns of acute liver injury but is approved in several other countries, including China, Brazil, and New Zealand.

“The results suggest that low dosing of benzbromarone may warrant stronger consideration as a safe and effective therapy to achieve serum urate target in gout without moderate chronic kidney disease,” the study team writes.

“Benzbromarone is severely hepatotoxic in some individuals and unlikely to ever gain approval in the United States,” one of the study’s investigators, Robert Terkeltaub, MD, professor of medicine, University of California, San Diego, told this news organization.

However, this study “illustrates the value and impact of uricosuric therapy in general in gout, including potentially as an initial urate-lowering monotherapy strategy, and the sheer number of subjects reaching urate target with low-dose uricosuric monotherapy was impressive,” Dr. Terkeltaub said.

The study was published online  in Arthritis & Rheumatology.

“Renal uric acid underexcretion is the chief mechanism driving hyperuricemia in gout, yet the standard urate-lowering therapy recommendation is first-line xanthine oxidase inhibition irrespective of the cause of hyperuricemia,” the study team explains in their article.

Their prospective, randomized, single-center, open-labeled trial was conducted at the Gout Clinic of the Affiliated Hospital of Qingdao University, China.

A total of 196 relatively young healthy men with gout and uric acid underexcretion were randomly assigned to receive low-dose benzbromarone (25 mg/d) or low-dose febuxostat (20 mg/d) for 12 weeks.

Renal uric acid underexcretion was defined as fractional excretion of urate less than 5.5% and uric acid excretion less than or equal to 600 mg/d/1.73 m2.

A “major aspect” of this comparative effectiveness trial was its specific focus on gout-associated renal uric acid underexcretion, where the uricosuric targeted the dominant abnormality promoting the hyperuricemia, Dr. Terkeltaub told this news organization.

In addition, all participants received daily urine alkalinization with oral sodium bicarbonate. “This is not always done in clinical practice, nor in clinical trials of uricosuric agents,” Dr. Terkeltaub said.

The results showed that more participants in the benzbromarone group achieved the serum urate target of less than 6 mg/dL, compared with those in the febuxostat group (primary endpoint, 61% vs. 32%, P < .001).

Adverse events, including gout flares and urolithiasis, did not differ significantly between the two groups, with the exception of more transaminase elevation in the febuxostat group (15% vs. 4%; P = .008).

“We did not find severe hepatotoxicity with low-dose benzbromarone, but ethnic background may affect drug responses, and severe hepatotoxicity of benzbromarone has rarely been reported in Asia,” the authors write.

The incidence of urolithiasis was numerically, but not significantly, higher in the benzbromarone group (5% vs. 2%).

This study found no significant changes in participants’ triglyceride levels, though a previous study suggested febuxostat could increase serum triglycerides.

The investigators caution that the study only included patients who had baseline serum urate levels ranging from 8.0 to 10 mg/dL, who were relatively young and with few comorbidities.

The authors further noted that the “... results may not be generalizable to patients with higher serum urate levels or impaired kidney function, as well [as] patients from other geographical regions, age, and ethnicity groups. The study only included men, and the findings may not be generalizable to women with gout.”

‘Very useful’ in select cases

Weighing in on the results, Valderilio Feijó Azevedo, MD, PhD, adjunct professor of rheumatology, Federal University of Paraná, Brazil, noted that in some specific clinical circumstances, benzbromarone has been “a very useful medication, alone or combined, to treat gout patients.”

“We have great experience with the drug in Brazil. However, it is not used to treat all patients. Patients must be very well-selected in our clinical practice,” Dr. Azevedo said in an interview.

“For most patients, benzbromarone is effective for those who have failed to achieve serum uric acid goals with allopurinol treatment. We do not use it to treat patients with asymptomatic hyperuricemia. In general, we avoid patients with hepatic dysfunction due to previous hepatotoxicity reports. In every patient, we do active monitoring of enzymes,” Dr. Azevedo explained.

“We also avoid using it in patients with severe kidney disease. However, we have used it in some patients with estimated glomerular filtration rate less than 30. We also avoid dosage over 200 mg per day. On average, we use 100 mg per day combined with allopurinol or alone,” said Dr. Azevedo, who was not involved with the study.

Also weighing in, Michael Pillinger, MD, rheumatologist at NYU Langone Health, noted that while benzbromarone is not used in the United States, “in many parts of the world, it is used and is felt to be effective.” Dr. Pillinger was not associated with this current research.

This study, Dr. Pillinger said, “does underline the fact that an alternative drug that lowers urate by promoting urate excretion, if it could gain [U.S. Food and Drug Association] approval and if it were safe, could present a viable new option for therapy.”

He added, “If one conclusion to the study is that determining the basis of hyperuricemia is helpful in guiding benzbromarone use, that implies an additional layer of effort for physicians and patients in a disease that is already notoriously known for patient noncompliance – and in a case where febuxostat and allopurinol will work for both overproducers and underexcreters and would not need this additional assessment.”

The study was sponsored by Shandong Provincial Key Research and Development Plan, the National Natural Science Foundation of China, and Shandong Provincial Science Foundation for Outstanding Youth Scholarship. Dr. Terkeltaub was supported by the National Institutes of Health and the VA Research Service. Dr. Terkeltaub has received research funding from AstraZeneca, and has consulted with Horizon, Selecta, SOBI, Dyve BioSciences, Fortress, AstraZeneca, Allena, Fortress Biotech, and LG Life Sciences. Dr. Azevedo and Dr. Pillinger have no reported no relevant financial relationships.

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

Sitting at his desk in Sea Girt, N.J., John Schwind is eager to demonstrate his ReadiMask 365. He holds up what looks like a white sheet of memo paper, peels off a protective liner, and sticks the mask first to his nose. He glides his fingers down his face, over his cheeks, and to his chin, sealing the mask and then demonstrating how easy it is to talk with it in place.

The mask’s medical adhesive sticks directly to the face, without causing breakouts, he said. It doesn’t let air leak and won’t fog his glasses. It’s strapless, so it won’t hurt his ears or make them stick out.

This fall, Mr. Schwind, the CEO of Global Safety First, is hoping to take home $150,000 as one of the two top winners of the federal Mask Innovation Challenge. He has made it to the top 10 but realizes he still has a ton of competition.

After the challenge launched in late 2021, nearly 1,500 submissions were received, says Kumiko Lippold, PhD, a health scientist and manager of the Mask Innovation Challenge. The challenge is run by Dr. Lippold and others at the Division of Research, Innovation, and Ventures (DRIVe), which is part of the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services.

Like the rest of us, Dr. Lippold knows that masks desperately need a makeover. The point of the challenge is to inspire and design masks that are comfortable, even with long wear, and that provide excellent protection. The aim is not only to get us through this pandemic but also future pandemics and other public health emergencies. “We are focused on building masks for the next pandemic, the next wildfires,” she says.

The project is a partnership among BARDA’s DRIVe, the National Institute for Occupational Safety and Health (NIOSH), and the National Institute of Standards and Technology (NIST).

While NIOSH is a partner in the challenge, giving feedback to mask developers, “the mask challenge is entirely separate from the NIOSH approval process,” Dr. Lippold says. Companies can then pursue NIOSH approval on their own, later, if they wish. The agency certifies only masks and respirators.
 

Preview of masks to come

“We’ve seen some really amazing things,” Dr. Lippold said of the new designs. She didn’t want to play favorites, so she gave an overview of innovations. Some designs have transparent materials, or partially see-through materials, so facial expressions can be read. “We’ve also seen really unique bio-based materials that are derived from natural products. We’ve seen sensors in some.”

One mask model has origami folds, which increase overall surface and breathing area. Some 3D-printed masks promise a custom fit and take into account whether a person’s nose bridge is low or high.
 

And the finalists are ...

ReadiMask 365: “I can wear this all day long,” Mr. Schwind said of his new design. It has a nano fiber filter and is flexible. Besides the one in the BARDA challenge, the company has other ReadiMasks on the market. “The most important thing is comfort,” he says. “Second is protection. If they don’t feel they have a good seal, users don’t have confidence in the mask.”

He offers various sizes of ReadiMasks, from small sizes designed for women with smaller faces to extra-large, “for NFL linemen.”

ClearMask: “We are the original clear mask,” says Aaron Hsu, CEO and co-founder of ClearMask in Baltimore. The company began in 2017, and the clear design was inspired by a company co-founder who is deaf. She was scheduled to have surgery, and her sign language interpreter did not show up, leaving her to try to communicate in the operating room with masked health care providers. There were no transparent masks available then, Mr. Hsu says.

“Being able to work with BARDA and getting their wisdom is invaluable,” he says.

The makers of ClearMask think masks are here to stay, at least for some. “I think a certain percentage of the population will continue to wear them, regardless,” said Mr. Hsu. He predicts health care settings will become stricter about wearing masks.

“Even now, when you even walk in to a hospital, you might be required to wear a mask,” he says, even as a visitor. His company’s masks are easy to adjust and are secured around the head, so your ears don’t get sore, he says.

4C Air: The BreSafe transparent mask is semi-transparent and is made of a nanomaterial that provides high levels of filtration and breathability with some transparency.

Air99: Based on origami principles, the Airgami mask is meant to improve fit, breathability, and aesthetics over existing masks. “Airgami fits better, works better and looks better,” says Min Xiao, a company spokesperson. “It won’t fall off the nose or collapse onto the mouth, and eyeglasses fog less, she says. Voices are less muffled.” It’s also reusable, rinseable and can be heat disinfected, she says. It went on the market in November 2020.

Air Flo Labs: Flo Mask Pro, like the company’s other designs, conducted over 100 3D facial scans across many ethnicities to produce a better fit, says Kevin Ngo, its creator. For the adult masks, two nose bridge sizes are offered. And users can choose a Pro Filter, with 99% filtration, or an Everyday, which is meant to be much more breathable than other masks. “Our silicone gasket is incredibly soft and gentle on the skin,” Mr. Ngo says. “In addition,we offer indents for glasses, which prevent any fogging.” The company began shipping in May; several thousand masks are in use now, Mr. Ngo said.

Georgetown University: This team’s smart mask is made of metallic foams that can be cleaned and reused.

Levi Strauss: The form of the mask can be made by any basic garment factory. It aims to activate the apparel supply chain as another source of low-cost, high-performance masks.

Matregenix: This mask, made of a transparent nanofiber, allows for easier communication while having high filtration.

SEAL Lab: The SINEW mask stands for Smart, Individualized, Near-Face, Extended Wear. The mask used technology to overcome flaws of traditional respirators, with the same degree of protection. It doesn’t make contact with the skin of the wearer’s face.

StaySafeNow: A team from Harvard University developed Crystal Guard, a reusable, cost-effective clear mask. Its developers say it’s meant to be especially useful for essential workers, teachers, and others who have to communicate to do their work.
 

Bye-bye N95?

“From our perspective, our goal with the mask challenge was not to replace the N95 respirator,” Dr. Lippold says. N95 masks, which NIOSH certifies, are valuable and protect people in high-risk settings. “With the mask challenge, our goal was really to provide the public with a comparable alternative that really meets their specific level of risk.” Working in a health care setting carries a different risk, she says, than going to the grocery store.

“A common complaint with the N95 is that they are very uncomfortable.” It’s a major barrier to compliance, “and we wanted to address that gap. We didn’t directly compare [the entries] to an N95,” she says, although their testing was similar to NIOSH’s. A number of finalists say they will pursue NIOSH approval, she says.

Meanwhile, some of the finalists’ masks are for sale. Air Flo Labs, for instance, has its Flo Mask Pro for sale online, noting that BARDA allowed it to release the test results from NIOSH and NIST.
 

Getting from 1,500 to 10

In the first phase of the challenge, Dr. Lippold says, “the goal was to engage as wide an audience as possible.” With the second phase, the bar was set a bit higher. Instead of just submitting ideas on paper, companies had to submit prototypes for lab testing. “We got about 80 submissions,” she says.

Those 80 were whittled down to 10 finalists. Teams had sent prototypes, and experts, including those from NIOSH and NIST, rated them, sometimes looking at multiple copies of the masks. Experts looked at how well the masks filtered the air, how breathable they were, and other data. Once the feedback was given to the mask companies, they entered a redesign period. “Scientists can take this data and basically make these prototypes better,” Dr. Lippold says.

The final round of testing will be in September, and the winners will be announced in the fall. The opportunity allowed companies to have their products go through testing they might not otherwise have been able to get, she says.

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

Sitting at his desk in Sea Girt, N.J., John Schwind is eager to demonstrate his ReadiMask 365. He holds up what looks like a white sheet of memo paper, peels off a protective liner, and sticks the mask first to his nose. He glides his fingers down his face, over his cheeks, and to his chin, sealing the mask and then demonstrating how easy it is to talk with it in place.

The mask’s medical adhesive sticks directly to the face, without causing breakouts, he said. It doesn’t let air leak and won’t fog his glasses. It’s strapless, so it won’t hurt his ears or make them stick out.

This fall, Mr. Schwind, the CEO of Global Safety First, is hoping to take home $150,000 as one of the two top winners of the federal Mask Innovation Challenge. He has made it to the top 10 but realizes he still has a ton of competition.

After the challenge launched in late 2021, nearly 1,500 submissions were received, says Kumiko Lippold, PhD, a health scientist and manager of the Mask Innovation Challenge. The challenge is run by Dr. Lippold and others at the Division of Research, Innovation, and Ventures (DRIVe), which is part of the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services.

Like the rest of us, Dr. Lippold knows that masks desperately need a makeover. The point of the challenge is to inspire and design masks that are comfortable, even with long wear, and that provide excellent protection. The aim is not only to get us through this pandemic but also future pandemics and other public health emergencies. “We are focused on building masks for the next pandemic, the next wildfires,” she says.

The project is a partnership among BARDA’s DRIVe, the National Institute for Occupational Safety and Health (NIOSH), and the National Institute of Standards and Technology (NIST).

While NIOSH is a partner in the challenge, giving feedback to mask developers, “the mask challenge is entirely separate from the NIOSH approval process,” Dr. Lippold says. Companies can then pursue NIOSH approval on their own, later, if they wish. The agency certifies only masks and respirators.
 

Preview of masks to come

“We’ve seen some really amazing things,” Dr. Lippold said of the new designs. She didn’t want to play favorites, so she gave an overview of innovations. Some designs have transparent materials, or partially see-through materials, so facial expressions can be read. “We’ve also seen really unique bio-based materials that are derived from natural products. We’ve seen sensors in some.”

One mask model has origami folds, which increase overall surface and breathing area. Some 3D-printed masks promise a custom fit and take into account whether a person’s nose bridge is low or high.
 

And the finalists are ...

ReadiMask 365: “I can wear this all day long,” Mr. Schwind said of his new design. It has a nano fiber filter and is flexible. Besides the one in the BARDA challenge, the company has other ReadiMasks on the market. “The most important thing is comfort,” he says. “Second is protection. If they don’t feel they have a good seal, users don’t have confidence in the mask.”

He offers various sizes of ReadiMasks, from small sizes designed for women with smaller faces to extra-large, “for NFL linemen.”

ClearMask: “We are the original clear mask,” says Aaron Hsu, CEO and co-founder of ClearMask in Baltimore. The company began in 2017, and the clear design was inspired by a company co-founder who is deaf. She was scheduled to have surgery, and her sign language interpreter did not show up, leaving her to try to communicate in the operating room with masked health care providers. There were no transparent masks available then, Mr. Hsu says.

“Being able to work with BARDA and getting their wisdom is invaluable,” he says.

The makers of ClearMask think masks are here to stay, at least for some. “I think a certain percentage of the population will continue to wear them, regardless,” said Mr. Hsu. He predicts health care settings will become stricter about wearing masks.

“Even now, when you even walk in to a hospital, you might be required to wear a mask,” he says, even as a visitor. His company’s masks are easy to adjust and are secured around the head, so your ears don’t get sore, he says.

4C Air: The BreSafe transparent mask is semi-transparent and is made of a nanomaterial that provides high levels of filtration and breathability with some transparency.

Air99: Based on origami principles, the Airgami mask is meant to improve fit, breathability, and aesthetics over existing masks. “Airgami fits better, works better and looks better,” says Min Xiao, a company spokesperson. “It won’t fall off the nose or collapse onto the mouth, and eyeglasses fog less, she says. Voices are less muffled.” It’s also reusable, rinseable and can be heat disinfected, she says. It went on the market in November 2020.

Air Flo Labs: Flo Mask Pro, like the company’s other designs, conducted over 100 3D facial scans across many ethnicities to produce a better fit, says Kevin Ngo, its creator. For the adult masks, two nose bridge sizes are offered. And users can choose a Pro Filter, with 99% filtration, or an Everyday, which is meant to be much more breathable than other masks. “Our silicone gasket is incredibly soft and gentle on the skin,” Mr. Ngo says. “In addition,we offer indents for glasses, which prevent any fogging.” The company began shipping in May; several thousand masks are in use now, Mr. Ngo said.

Georgetown University: This team’s smart mask is made of metallic foams that can be cleaned and reused.

Levi Strauss: The form of the mask can be made by any basic garment factory. It aims to activate the apparel supply chain as another source of low-cost, high-performance masks.

Matregenix: This mask, made of a transparent nanofiber, allows for easier communication while having high filtration.

SEAL Lab: The SINEW mask stands for Smart, Individualized, Near-Face, Extended Wear. The mask used technology to overcome flaws of traditional respirators, with the same degree of protection. It doesn’t make contact with the skin of the wearer’s face.

StaySafeNow: A team from Harvard University developed Crystal Guard, a reusable, cost-effective clear mask. Its developers say it’s meant to be especially useful for essential workers, teachers, and others who have to communicate to do their work.
 

Bye-bye N95?

“From our perspective, our goal with the mask challenge was not to replace the N95 respirator,” Dr. Lippold says. N95 masks, which NIOSH certifies, are valuable and protect people in high-risk settings. “With the mask challenge, our goal was really to provide the public with a comparable alternative that really meets their specific level of risk.” Working in a health care setting carries a different risk, she says, than going to the grocery store.

“A common complaint with the N95 is that they are very uncomfortable.” It’s a major barrier to compliance, “and we wanted to address that gap. We didn’t directly compare [the entries] to an N95,” she says, although their testing was similar to NIOSH’s. A number of finalists say they will pursue NIOSH approval, she says.

Meanwhile, some of the finalists’ masks are for sale. Air Flo Labs, for instance, has its Flo Mask Pro for sale online, noting that BARDA allowed it to release the test results from NIOSH and NIST.
 

Getting from 1,500 to 10

In the first phase of the challenge, Dr. Lippold says, “the goal was to engage as wide an audience as possible.” With the second phase, the bar was set a bit higher. Instead of just submitting ideas on paper, companies had to submit prototypes for lab testing. “We got about 80 submissions,” she says.

Those 80 were whittled down to 10 finalists. Teams had sent prototypes, and experts, including those from NIOSH and NIST, rated them, sometimes looking at multiple copies of the masks. Experts looked at how well the masks filtered the air, how breathable they were, and other data. Once the feedback was given to the mask companies, they entered a redesign period. “Scientists can take this data and basically make these prototypes better,” Dr. Lippold says.

The final round of testing will be in September, and the winners will be announced in the fall. The opportunity allowed companies to have their products go through testing they might not otherwise have been able to get, she says.

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

Sitting at his desk in Sea Girt, N.J., John Schwind is eager to demonstrate his ReadiMask 365. He holds up what looks like a white sheet of memo paper, peels off a protective liner, and sticks the mask first to his nose. He glides his fingers down his face, over his cheeks, and to his chin, sealing the mask and then demonstrating how easy it is to talk with it in place.

The mask’s medical adhesive sticks directly to the face, without causing breakouts, he said. It doesn’t let air leak and won’t fog his glasses. It’s strapless, so it won’t hurt his ears or make them stick out.

This fall, Mr. Schwind, the CEO of Global Safety First, is hoping to take home $150,000 as one of the two top winners of the federal Mask Innovation Challenge. He has made it to the top 10 but realizes he still has a ton of competition.

After the challenge launched in late 2021, nearly 1,500 submissions were received, says Kumiko Lippold, PhD, a health scientist and manager of the Mask Innovation Challenge. The challenge is run by Dr. Lippold and others at the Division of Research, Innovation, and Ventures (DRIVe), which is part of the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services.

Like the rest of us, Dr. Lippold knows that masks desperately need a makeover. The point of the challenge is to inspire and design masks that are comfortable, even with long wear, and that provide excellent protection. The aim is not only to get us through this pandemic but also future pandemics and other public health emergencies. “We are focused on building masks for the next pandemic, the next wildfires,” she says.

The project is a partnership among BARDA’s DRIVe, the National Institute for Occupational Safety and Health (NIOSH), and the National Institute of Standards and Technology (NIST).

While NIOSH is a partner in the challenge, giving feedback to mask developers, “the mask challenge is entirely separate from the NIOSH approval process,” Dr. Lippold says. Companies can then pursue NIOSH approval on their own, later, if they wish. The agency certifies only masks and respirators.
 

Preview of masks to come

“We’ve seen some really amazing things,” Dr. Lippold said of the new designs. She didn’t want to play favorites, so she gave an overview of innovations. Some designs have transparent materials, or partially see-through materials, so facial expressions can be read. “We’ve also seen really unique bio-based materials that are derived from natural products. We’ve seen sensors in some.”

One mask model has origami folds, which increase overall surface and breathing area. Some 3D-printed masks promise a custom fit and take into account whether a person’s nose bridge is low or high.
 

And the finalists are ...

ReadiMask 365: “I can wear this all day long,” Mr. Schwind said of his new design. It has a nano fiber filter and is flexible. Besides the one in the BARDA challenge, the company has other ReadiMasks on the market. “The most important thing is comfort,” he says. “Second is protection. If they don’t feel they have a good seal, users don’t have confidence in the mask.”

He offers various sizes of ReadiMasks, from small sizes designed for women with smaller faces to extra-large, “for NFL linemen.”

ClearMask: “We are the original clear mask,” says Aaron Hsu, CEO and co-founder of ClearMask in Baltimore. The company began in 2017, and the clear design was inspired by a company co-founder who is deaf. She was scheduled to have surgery, and her sign language interpreter did not show up, leaving her to try to communicate in the operating room with masked health care providers. There were no transparent masks available then, Mr. Hsu says.

“Being able to work with BARDA and getting their wisdom is invaluable,” he says.

The makers of ClearMask think masks are here to stay, at least for some. “I think a certain percentage of the population will continue to wear them, regardless,” said Mr. Hsu. He predicts health care settings will become stricter about wearing masks.

“Even now, when you even walk in to a hospital, you might be required to wear a mask,” he says, even as a visitor. His company’s masks are easy to adjust and are secured around the head, so your ears don’t get sore, he says.

4C Air: The BreSafe transparent mask is semi-transparent and is made of a nanomaterial that provides high levels of filtration and breathability with some transparency.

Air99: Based on origami principles, the Airgami mask is meant to improve fit, breathability, and aesthetics over existing masks. “Airgami fits better, works better and looks better,” says Min Xiao, a company spokesperson. “It won’t fall off the nose or collapse onto the mouth, and eyeglasses fog less, she says. Voices are less muffled.” It’s also reusable, rinseable and can be heat disinfected, she says. It went on the market in November 2020.

Air Flo Labs: Flo Mask Pro, like the company’s other designs, conducted over 100 3D facial scans across many ethnicities to produce a better fit, says Kevin Ngo, its creator. For the adult masks, two nose bridge sizes are offered. And users can choose a Pro Filter, with 99% filtration, or an Everyday, which is meant to be much more breathable than other masks. “Our silicone gasket is incredibly soft and gentle on the skin,” Mr. Ngo says. “In addition,we offer indents for glasses, which prevent any fogging.” The company began shipping in May; several thousand masks are in use now, Mr. Ngo said.

Georgetown University: This team’s smart mask is made of metallic foams that can be cleaned and reused.

Levi Strauss: The form of the mask can be made by any basic garment factory. It aims to activate the apparel supply chain as another source of low-cost, high-performance masks.

Matregenix: This mask, made of a transparent nanofiber, allows for easier communication while having high filtration.

SEAL Lab: The SINEW mask stands for Smart, Individualized, Near-Face, Extended Wear. The mask used technology to overcome flaws of traditional respirators, with the same degree of protection. It doesn’t make contact with the skin of the wearer’s face.

StaySafeNow: A team from Harvard University developed Crystal Guard, a reusable, cost-effective clear mask. Its developers say it’s meant to be especially useful for essential workers, teachers, and others who have to communicate to do their work.
 

Bye-bye N95?

“From our perspective, our goal with the mask challenge was not to replace the N95 respirator,” Dr. Lippold says. N95 masks, which NIOSH certifies, are valuable and protect people in high-risk settings. “With the mask challenge, our goal was really to provide the public with a comparable alternative that really meets their specific level of risk.” Working in a health care setting carries a different risk, she says, than going to the grocery store.

“A common complaint with the N95 is that they are very uncomfortable.” It’s a major barrier to compliance, “and we wanted to address that gap. We didn’t directly compare [the entries] to an N95,” she says, although their testing was similar to NIOSH’s. A number of finalists say they will pursue NIOSH approval, she says.

Meanwhile, some of the finalists’ masks are for sale. Air Flo Labs, for instance, has its Flo Mask Pro for sale online, noting that BARDA allowed it to release the test results from NIOSH and NIST.
 

Getting from 1,500 to 10

In the first phase of the challenge, Dr. Lippold says, “the goal was to engage as wide an audience as possible.” With the second phase, the bar was set a bit higher. Instead of just submitting ideas on paper, companies had to submit prototypes for lab testing. “We got about 80 submissions,” she says.

Those 80 were whittled down to 10 finalists. Teams had sent prototypes, and experts, including those from NIOSH and NIST, rated them, sometimes looking at multiple copies of the masks. Experts looked at how well the masks filtered the air, how breathable they were, and other data. Once the feedback was given to the mask companies, they entered a redesign period. “Scientists can take this data and basically make these prototypes better,” Dr. Lippold says.

The final round of testing will be in September, and the winners will be announced in the fall. The opportunity allowed companies to have their products go through testing they might not otherwise have been able to get, she says.

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

The stress of losing a family member can hasten the death of patients with heart failure, suggests a large Swedish study that points to the need for greater integration of psychosocial risk factors in the treatment of HF.

The adjusted relative risk of dying was nearly 30% higher among bereaved patients with HF (1.29; 95% confidence interval, 1.27-1.30) and slightly higher for those grieving the loss of more than one family member (RR, 1.35).

The highest risk was in the first week after the loss (RR, 1.78) but persisted after 5 years of follow-up (RR, 1.30).

“Heart failure is a very difficult condition and has a very poor prognosis comparable to many, many cancers,” senior author Krisztina László, PhD, Karolinska Institutet, Stockholm, said in an interview. “So it’s important for us to be aware of these increased risks and to understand them better.”

The early risk for death could be related to stress-induced cardiomyopathy, or Takotsubo syndrome, as well as activation of the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system, and sympathetic nervous system, she explained. Higher long-term risks may reflect chronic stress, leading to poorly managed disease and an unhealthy lifestyle.

“If we understand better the underlying mechanisms maybe we can give more specific advice,” Dr. László said. “At this stage, I think having an awareness of the risk and trying to follow patients or at least not let them fall out of usual care, asking questions, trying to understand what their needs are, maybe that is what we can do well.”

A recent position paper by the European Association of Preventive Cardiology pointed out that psychosocial risk factors, like depression and social isolation, can exacerbate heart failure and calls for better integration of psychosocial factors in the treatment of patients with chronic HF.

“We don’t do a very good job of it, but I think they are very important,” observed Stuart D. Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., and was not involved in the study.

“When we hear about a spouse dying, we might call and give condolences, but it’s probably a group of patients that for the next 6 months or so we need to watch more closely and see if there are things we can impact both medically as well as socially to perhaps prevent some of this increase in mortality,” he told this news organization.

Although several studies have linked bereavement with adverse health outcomes, this is just one of two studies to look specifically at its role in HF prognosis, Dr. László noted. A 2013 study of 66,000 male veterans reported that widowers had nearly a 38% higher all-cause mortality risk than did married veterans.

The present study extends those findings to 490,527 patients in the Swedish Heart Failure Registry between 2000 and 2018 and/or in the Swedish Patient Register with a primary diagnosis of HF between 1987 and 2018. During a mean follow-up of 3.7 years, 12% of participants had a family member die, and 383,674 participants died.

Results showed the HF mortality risk increased 10% after the death of a child, 20% with the death of a spouse/partner, 13% with a sibling’s death, and 5% with the death of a grandchild.

No increased risk was seen after the death of a parent, which is likely owed to a median patient age of about 75 years and “is in line with our expectations of the life cycle,” Dr. László said.

An association between bereavement and mortality risk was observed in cases of loss caused by cardiovascular disease (RR, 1.34) and other natural causes (RR, 1.27) but also in cases of unnatural deaths, such as suicide (RR, 1.13).

The overall findings were similar regardless of left ventricular ejection fraction and New York Heart Association functional class and were not affected by sex or country of birth.

Dr. Russell agreed that the death of a parent would be expected among these older patients with HF but said that “if the mechanism of this truly is kind of this increased stress hormones and Takotsubo-type mechanism, you’d think it would be worse if it was your kid that died. That shocked me a bit.”

The strong association between mortality and the loss of a spouse or partner was not surprising, given that they’re an important source of mutual social support, he added.

“If it’s a 75-year-old whose spouse dies, we need to make sure that we have the children’s phone number or other people that we can reach out to and say: ‘Can you check on them?’ ” he said. “And we need to make sure that somebody else is coming in with them because I would guess that probably at least half of what patients hear in a clinic visit goes in one ear and out the other and it’s going to make that much better. So we need to find who that new support person is for the patient.”

Asked whether there are efforts underway to incorporate psychosocial factors into current U.S. guidelines, Dr. Russell replied, “certainly within heart failure, I don’t think we’re really discussing it and, that may be the best part of this paper. It really makes us think about a different way of approaching these older patients.”

Dr. László said that future studies are needed to investigate whether less severe sources of stress may also contribute to poor HF prognosis.

“In our population, 12% of patients were affected, which is quite high, but there are patients with heart failure who experience on a daily basis other sources of stress, which are less severe but chronic and affect large numbers,” she said. “This may also have important public health implications and will be an important next step.”

The authors noted that they were unable to eliminate residual confounding by genetic factors or unmeasured socioeconomic-, lifestyle-, or health-related factors shared by family members. Other limitations are limited power to detect a modest effect in some of the subanalyses and that the findings may be generalizable only to countries with social and cultural contexts and health-related factors similar to those of Sweden.

The study was supported by grants from the Swedish Council for Working Life and Social Research, the Karolinska Institutet’s Research Foundation, and the China Scholarship Council. Dr. László is also supported by a grant from the Heart and Lung Foundation. All other authors and Dr. Russell reported no relevant financial relationships.

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

The stress of losing a family member can hasten the death of patients with heart failure, suggests a large Swedish study that points to the need for greater integration of psychosocial risk factors in the treatment of HF.

The adjusted relative risk of dying was nearly 30% higher among bereaved patients with HF (1.29; 95% confidence interval, 1.27-1.30) and slightly higher for those grieving the loss of more than one family member (RR, 1.35).

The highest risk was in the first week after the loss (RR, 1.78) but persisted after 5 years of follow-up (RR, 1.30).

“Heart failure is a very difficult condition and has a very poor prognosis comparable to many, many cancers,” senior author Krisztina László, PhD, Karolinska Institutet, Stockholm, said in an interview. “So it’s important for us to be aware of these increased risks and to understand them better.”

The early risk for death could be related to stress-induced cardiomyopathy, or Takotsubo syndrome, as well as activation of the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system, and sympathetic nervous system, she explained. Higher long-term risks may reflect chronic stress, leading to poorly managed disease and an unhealthy lifestyle.

“If we understand better the underlying mechanisms maybe we can give more specific advice,” Dr. László said. “At this stage, I think having an awareness of the risk and trying to follow patients or at least not let them fall out of usual care, asking questions, trying to understand what their needs are, maybe that is what we can do well.”

A recent position paper by the European Association of Preventive Cardiology pointed out that psychosocial risk factors, like depression and social isolation, can exacerbate heart failure and calls for better integration of psychosocial factors in the treatment of patients with chronic HF.

“We don’t do a very good job of it, but I think they are very important,” observed Stuart D. Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., and was not involved in the study.

“When we hear about a spouse dying, we might call and give condolences, but it’s probably a group of patients that for the next 6 months or so we need to watch more closely and see if there are things we can impact both medically as well as socially to perhaps prevent some of this increase in mortality,” he told this news organization.

Although several studies have linked bereavement with adverse health outcomes, this is just one of two studies to look specifically at its role in HF prognosis, Dr. László noted. A 2013 study of 66,000 male veterans reported that widowers had nearly a 38% higher all-cause mortality risk than did married veterans.

The present study extends those findings to 490,527 patients in the Swedish Heart Failure Registry between 2000 and 2018 and/or in the Swedish Patient Register with a primary diagnosis of HF between 1987 and 2018. During a mean follow-up of 3.7 years, 12% of participants had a family member die, and 383,674 participants died.

Results showed the HF mortality risk increased 10% after the death of a child, 20% with the death of a spouse/partner, 13% with a sibling’s death, and 5% with the death of a grandchild.

No increased risk was seen after the death of a parent, which is likely owed to a median patient age of about 75 years and “is in line with our expectations of the life cycle,” Dr. László said.

An association between bereavement and mortality risk was observed in cases of loss caused by cardiovascular disease (RR, 1.34) and other natural causes (RR, 1.27) but also in cases of unnatural deaths, such as suicide (RR, 1.13).

The overall findings were similar regardless of left ventricular ejection fraction and New York Heart Association functional class and were not affected by sex or country of birth.

Dr. Russell agreed that the death of a parent would be expected among these older patients with HF but said that “if the mechanism of this truly is kind of this increased stress hormones and Takotsubo-type mechanism, you’d think it would be worse if it was your kid that died. That shocked me a bit.”

The strong association between mortality and the loss of a spouse or partner was not surprising, given that they’re an important source of mutual social support, he added.

“If it’s a 75-year-old whose spouse dies, we need to make sure that we have the children’s phone number or other people that we can reach out to and say: ‘Can you check on them?’ ” he said. “And we need to make sure that somebody else is coming in with them because I would guess that probably at least half of what patients hear in a clinic visit goes in one ear and out the other and it’s going to make that much better. So we need to find who that new support person is for the patient.”

Asked whether there are efforts underway to incorporate psychosocial factors into current U.S. guidelines, Dr. Russell replied, “certainly within heart failure, I don’t think we’re really discussing it and, that may be the best part of this paper. It really makes us think about a different way of approaching these older patients.”

Dr. László said that future studies are needed to investigate whether less severe sources of stress may also contribute to poor HF prognosis.

“In our population, 12% of patients were affected, which is quite high, but there are patients with heart failure who experience on a daily basis other sources of stress, which are less severe but chronic and affect large numbers,” she said. “This may also have important public health implications and will be an important next step.”

The authors noted that they were unable to eliminate residual confounding by genetic factors or unmeasured socioeconomic-, lifestyle-, or health-related factors shared by family members. Other limitations are limited power to detect a modest effect in some of the subanalyses and that the findings may be generalizable only to countries with social and cultural contexts and health-related factors similar to those of Sweden.

The study was supported by grants from the Swedish Council for Working Life and Social Research, the Karolinska Institutet’s Research Foundation, and the China Scholarship Council. Dr. László is also supported by a grant from the Heart and Lung Foundation. All other authors and Dr. Russell reported no relevant financial relationships.

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

The stress of losing a family member can hasten the death of patients with heart failure, suggests a large Swedish study that points to the need for greater integration of psychosocial risk factors in the treatment of HF.

The adjusted relative risk of dying was nearly 30% higher among bereaved patients with HF (1.29; 95% confidence interval, 1.27-1.30) and slightly higher for those grieving the loss of more than one family member (RR, 1.35).

The highest risk was in the first week after the loss (RR, 1.78) but persisted after 5 years of follow-up (RR, 1.30).

“Heart failure is a very difficult condition and has a very poor prognosis comparable to many, many cancers,” senior author Krisztina László, PhD, Karolinska Institutet, Stockholm, said in an interview. “So it’s important for us to be aware of these increased risks and to understand them better.”

The early risk for death could be related to stress-induced cardiomyopathy, or Takotsubo syndrome, as well as activation of the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system, and sympathetic nervous system, she explained. Higher long-term risks may reflect chronic stress, leading to poorly managed disease and an unhealthy lifestyle.

“If we understand better the underlying mechanisms maybe we can give more specific advice,” Dr. László said. “At this stage, I think having an awareness of the risk and trying to follow patients or at least not let them fall out of usual care, asking questions, trying to understand what their needs are, maybe that is what we can do well.”

A recent position paper by the European Association of Preventive Cardiology pointed out that psychosocial risk factors, like depression and social isolation, can exacerbate heart failure and calls for better integration of psychosocial factors in the treatment of patients with chronic HF.

“We don’t do a very good job of it, but I think they are very important,” observed Stuart D. Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., and was not involved in the study.

“When we hear about a spouse dying, we might call and give condolences, but it’s probably a group of patients that for the next 6 months or so we need to watch more closely and see if there are things we can impact both medically as well as socially to perhaps prevent some of this increase in mortality,” he told this news organization.

Although several studies have linked bereavement with adverse health outcomes, this is just one of two studies to look specifically at its role in HF prognosis, Dr. László noted. A 2013 study of 66,000 male veterans reported that widowers had nearly a 38% higher all-cause mortality risk than did married veterans.

The present study extends those findings to 490,527 patients in the Swedish Heart Failure Registry between 2000 and 2018 and/or in the Swedish Patient Register with a primary diagnosis of HF between 1987 and 2018. During a mean follow-up of 3.7 years, 12% of participants had a family member die, and 383,674 participants died.

Results showed the HF mortality risk increased 10% after the death of a child, 20% with the death of a spouse/partner, 13% with a sibling’s death, and 5% with the death of a grandchild.

No increased risk was seen after the death of a parent, which is likely owed to a median patient age of about 75 years and “is in line with our expectations of the life cycle,” Dr. László said.

An association between bereavement and mortality risk was observed in cases of loss caused by cardiovascular disease (RR, 1.34) and other natural causes (RR, 1.27) but also in cases of unnatural deaths, such as suicide (RR, 1.13).

The overall findings were similar regardless of left ventricular ejection fraction and New York Heart Association functional class and were not affected by sex or country of birth.

Dr. Russell agreed that the death of a parent would be expected among these older patients with HF but said that “if the mechanism of this truly is kind of this increased stress hormones and Takotsubo-type mechanism, you’d think it would be worse if it was your kid that died. That shocked me a bit.”

The strong association between mortality and the loss of a spouse or partner was not surprising, given that they’re an important source of mutual social support, he added.

“If it’s a 75-year-old whose spouse dies, we need to make sure that we have the children’s phone number or other people that we can reach out to and say: ‘Can you check on them?’ ” he said. “And we need to make sure that somebody else is coming in with them because I would guess that probably at least half of what patients hear in a clinic visit goes in one ear and out the other and it’s going to make that much better. So we need to find who that new support person is for the patient.”

Asked whether there are efforts underway to incorporate psychosocial factors into current U.S. guidelines, Dr. Russell replied, “certainly within heart failure, I don’t think we’re really discussing it and, that may be the best part of this paper. It really makes us think about a different way of approaching these older patients.”

Dr. László said that future studies are needed to investigate whether less severe sources of stress may also contribute to poor HF prognosis.

“In our population, 12% of patients were affected, which is quite high, but there are patients with heart failure who experience on a daily basis other sources of stress, which are less severe but chronic and affect large numbers,” she said. “This may also have important public health implications and will be an important next step.”

The authors noted that they were unable to eliminate residual confounding by genetic factors or unmeasured socioeconomic-, lifestyle-, or health-related factors shared by family members. Other limitations are limited power to detect a modest effect in some of the subanalyses and that the findings may be generalizable only to countries with social and cultural contexts and health-related factors similar to those of Sweden.

The study was supported by grants from the Swedish Council for Working Life and Social Research, the Karolinska Institutet’s Research Foundation, and the China Scholarship Council. Dr. László is also supported by a grant from the Heart and Lung Foundation. All other authors and Dr. Russell reported no relevant financial relationships.

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