In contrast to previous studies, screening for abdominal aortic aneurysms in older men does not appear to have a significant effect on overall mortality, according to a prospective, randomized study.

Mortality from ruptured AAA remains high in older men, which has prompted four previous large randomized trials to explore whether screening men aged 65 years and older might reduce mortality.

In contrast to previous studies, screening for abdominal aortic aneurysms in older men does not appear to have a significant effect on overall mortality, according to a prospective, randomized study.

Mortality from ruptured AAA remains high in older men, which has prompted four previous large randomized trials to explore whether screening men aged 65 years and older might reduce mortality.

In contrast to previous studies, screening for abdominal aortic aneurysms in older men does not appear to have a significant effect on overall mortality, according to a prospective, randomized study.

Mortality from ruptured AAA remains high in older men, which has prompted four previous large randomized trials to explore whether screening men aged 65 years and older might reduce mortality.

The genitourinary syndrome of menopause (GSM) is a constellation of symptoms and signs of a hypoestrogenic state resulting in some or all of the following: vaginal dryness, burning, irritation, dyspareunia, urinary urgency, dysuria, and recurrent urinary tract infections.¹ In 2014, the International Society for the Study of Women’s Sexual Health and the North American Menopause Society endorsed “GSM” as a new term to replace the less comprehensive description, vulvovaginal atrophy (VVA).¹

The prevalence of GSM is around 50%, but it may increase each year after menopause, reaching up to 84.2%.^2,3 Only about half of women affected seek medical care, with the most commonly reported symptoms being vaginal dryness and dyspareunia.^3,4

Nonhormonal vaginal moisturizers andlubricants remain first-line treatment. The benefits are temporary and short lived because these options do not change the physiologic makeup of the vaginal wall; these treatments therefore provide relief only if the GSM symptoms are limited or mild.⁵

In this Update on pelvic floor dysfunction, we review 2 randomized, placebo-controlled trials of hormonal options (vaginal estrogen and oral ospemifene) and examine the latest information regarding fractional CO₂ vaginal laser treatment. Also included are evidence-based guidelines for vaginal estrogen use and recommendations and conclusions for use of vaginal estrogen in women with a history of estrogen-dependent breast cancer. (The terms used in the studies described [ie, VVA versus GSM] have been maintained for accuracy of reporting.)

Low-dose estrogen vaginal cream ameliorates moderate to severe VVA with limited adverse events

Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H. Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy. Menopause. 2009;16(4):735-741.

In a multicenter, double-blind, randomized, placebo-controlled study, Freedman and colleagues evaluated the efficacy of a 1-g dose of synthetic conjugated estrogens A (SCE-A) cream versus placebo in postmenopausal women with moderate to severe VVA.

Details of the study

The investigators enrolled 305 participants aged 30 to 80 years (mean [SD] age, 60 [6.6] years) who were naturally or surgically postmenopausal. The enrollment criteria included ≤5% superficial cells on vaginal smear, vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA (vaginal dryness, soreness, irritation/itching, pain with intercourse, or bleeding after intercourse).

Participants were randomly assigned in a 1:1:1:1 ratio to twice-weekly therapy with 1 g (0.625 mg/g) SCE-A vaginal cream, 2 g SCE-A vaginal cream, 1 g placebo, or 2 g placebo. Study visits occurred on days 14, 21, 28, 56, and 84 (12-week end point). The 3 co-primary outcomes were cytology, vaginal pH, and most bothersome symptom (MBS). Primary outcomes and safety/adverse events (AEs) were recorded at each study visit, and transvaginal ultrasound and endometrial biopsy were performed for women with a uterus at the beginning and end of the study.

Mean change and percent change in the 3 primary outcomes were assessed between baseline and each study visit. MBS was scored on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). The principal indicators of efficacy were the changes from baseline to the end of treatment (12 weeks) for each of the 3 end points. Since the 1-g and 2-g SCE-A dose groups showed a similar degree of efficacy on all 3 co-primary end points, approval from the US Food and Drug Administration (FDA) was sought only for the lower dose, in keeping with the use of the lowest effective dose; therefore, results from only the 1-g SCE-A dose group and matching placebo group were presented in the article. A sample size calculation determined that at least 111 participants in each group were needed to provide 90% power for statistical testing.

Estrogen reduced MBS severity, improved vaginal indices

The modified intent-to-treat (MITT) cohort was used for outcome analysis, and data from 275 participants were available at the 12-week end point. At baseline, 132 participants (48%) indicated vaginal dryness and 86 women (31.3%) indicated pain during intercourse as the MBS. In the SCE-A group at baseline, the vaginal maturation index (VMI) was 31.31 compared with 31.84 in the placebo group. At 12 weeks, the SCE-A group had a mean reduction of 1.71 in overall MBS severity compared with the placebo group’s mean reduction of 1.11 (P<.0001). The SCE-A group had a greater increase in the VMI (with a mean change of 31.46 vs 5.16 in the placebo group [P<.0001]) and a greater decrease in the vaginal pH (mean pH at the end of treatment for the SCE-A group was 4.84, a decrease of 1.48, and for the placebo group was 5.96, a decrease of 0.31 [P<.0001]).

Adverse events. The incidence of AEs was similar for the 1-g SCE-A group and the 1-g placebo group, with no AE occurring at a rate of higher than 5%. There were 15 (10%) treatment-related AEs in the estrogen group and 16 (10.3%) in the placebo group. The SCE-A group had 3 AEs (2%) leading to discontinuation, while the placebo group had 2 AEs (1.3%) leading to discontinuation. There were no clinically significant endometrial biopsy findings at the conclusion of the study.

Strengths and limitations. This study evaluated clinical and physiologic outcomes as well as uterine response to transvaginal estrogen. The use of MBS allows symptoms to be scored objectively compared with prior subjective symptom assessment, which varied widely. However, fewer indicated symptoms will permit limited conclusions.

Ospemifene improves vaginal physiology and dyspareunia

Bachmann GA, Komi JO; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486.

Bachmann and colleagues evaluated the efficacy and safety of ospemifene for the treatment of VVA. This is one of the efficacy studies on which FDA approval was based. Ospemifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist/antagonist.

Details of the study

The study included 826 postmenopausal women randomly assigned to 30 mg/day of ospemifene, 60 mg/day of ospemifene, or placebo for 12 weeks. Participants were aged 40 to 80 years and met the criteria for VVA (defined as ≤5% superficial cells on vaginal smear [maturation index], vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA). All women were given a nonhormonal lubricant for use as needed.

There were 4 co-primary end points: percentage of superficial cells on the vaginal smear, percentage of parabasal cells on the vaginal smear, vaginal pH, and self-assessed MBS using a Likert scale (0, none; 1, mild; 2, moderate; 3, severe). The symptom score was calculated as the change from baseline to week 12 for each MBS. Safety was assessed by patient report; if a participant had an intact uterus and cervix, Pap test, endometrial thickness, and endometrial histologic analysis were performed at baseline and at 12 weeks. Baseline characteristics were similar among all treatment groups. A total of 46% of participants reported dyspareunia as their MBS, and 39% reported vaginal dryness.

Two dose levels of ospemifene effectively relieve symptoms

After 12 weeks of treatment, both the 30-mg and the 60-mg dose of ospemifene produced a statistically significant improvement in vaginal dryness and objective results of maturation index and vaginal pH compared with placebo. Vaginal dryness decreased in the ospemifene 30-mg group (1.22) and in the ospemifene 60-mg group (1.26) compared with placebo (0.84) (P = .04 for the 30-mg group and P = .021 for the 60-mg group). The percentage of superficial cells was increased in both treatment groups compared with placebo (7.8% for the 30-mg group, 10.8% for the 60-mg group, 2.2% for the placebo group; P<.001 for both). The percentage of parabasal cells decreased in both treatment groups compared with participants who received placebo (21.9% in the 30-mg group, 30.1% in the 60-mg group, and 3.98% in the placebo group; P<.001 for both). Both treatment groups had a decrease in vaginal pH versus the placebo group as well (0.67 decrease in the 30-mg group, 1.01 decrease in the 60-mg group, and 0.10 decrease in the placebo group; P<.001 for both). The 60-mg/day ospemifene dose improved dyspareunia compared with placebo and was more effective than the 30-mg dose for all end points.

Adverse effects. Hot flashes were reported in 9.6% of the 30-mg ospemifene group and in 8.3% of the 60-mg group, compared with 3.4% in the placebo group. The increased percentage of participants with hot flashes in the ospemifene groups did not lead to increased discontinuation with the study. Urinary tract infections, defined by symptoms only, were more common in the ospemifene groups (4.6% in the 30-mg group, 7.2% in the 60-mg group, and 2.2% in the placebo group). In each group, 5% of patients discontinued the study because of AEs. There were 5 serious AEs in the 30-mg ospemifene group, 4 serious AEs in the placebo group, and none in the 60-mg group. No venous thromboembolic events were reported.

Strengths and limitations. Vaginal physiology as well as common symptoms of GSM were assessed in this large study. However, AEs were self-reported. While ospemifene was found safe and well tolerated when the study was extended for an additional 52 weeks (in women without a uterus) and 40 weeks (in women with a uterus), longer follow-up is needed to determine  endometrial safety.^7,8

Fractional CO2 laser for VVA shows efficacy, patient satisfaction

Sokol ER, Karram MM. An assessment of the safety and efficacy of a fractional CO2 laser system for the treatment of vulvovaginal atrophy. Menopause. 2016;23(10):1102–1107.

In this first US pilot study, postmenopausal women received 3 fractional CO₂ laser treatments, 6 weeks apart. The investigators evaluated the safety and efficacy of the treatment for GSM.

Details of the study

Thirty women (mean age, 58.6 years) who were nonsmokers, postmenopausal, had less than stage 2 prolapse, no vaginal procedures for the past 6 months, and did not use vaginal creams, moisturizers, lubricants, or homeopathic preparations for the past 3 months were enrolled. Participants received 3 laser treatments with the SmartXide2, MonaLisa Touch (DEKA M.E.L.A. SRL, Florence, Italy) device at 6-week intervals followed by a 3-month follow-up.

The primary outcome was visual analog scale (VAS) change in 6 categories (vaginal pain, burning, itching, dryness, dyspareunia, and dysuria) assessed from baseline to after each treatment, including 3 months after the final treatment, using an 11-point scale with 0 the lowest (no symptoms) and 10 the highest (extreme bother). Secondary outcomes were Vaginal Health Index (VHI) score, maximal tolerable dilator size, Female Sexual Function Index (FSFI) questionnaire score, general quality of life, degree of difficulty performing the procedure, participant satisfaction, vaginal pH, adverse effects, and treatment discomfort assessed using the VAS.  

Improved VVA symptoms and vaginal caliber

Twenty-seven women completed the study. There was a statistically significant change in all 6 symptom categories measured with the VAS. Improvement change (SD) on the VAS was 1.7 (3.2) for pain, 1.4 (2.9) for burning, 1.4 (1.9) for itching, 1.0 (2.4) for dysuria, comparing baseline scores to scores after 3 treatments (all with P<.05). A greater improvement was noted for dryness, 6.1 (2.7), and for dyspareunia, 5.4 (2.9) (both P<.001). There was also a statistically significant change in overall improvement on the VHI and the FSFI. The mean (SD) VHI score at baseline was 14.4 (2.9; range, 8 to 20) and the mean (SD) after 3 laser treatments was 21.4 (2.9; range, 16 to 25), with an overall mean (SD) improvement of 7.0 (3.1; P<.001).

Twenty-six participants completed a follow-up FSFI, with a mean (SD) baseline score of 11.3 (7.3; range, 2 to 25) and a follow-up mean (SD) score of 8.8 (7.3; range, −3.7 to 27.2) (P<.001). There was an increase in dilator size of 83% when comparing baseline to follow-up. At baseline, 24 participants (80%) could comfortably accept an XS or S dilator, and at follow-up 23 of 24 women (96%) could comfortably accept an M or L dilator.

Adverse effects. At their follow-up, 96% of participants were satisfied or extremely satisfied with treatment. Two women reported mild-to-moderate pain lasting 2 to 3 days, and 2 had minor bleeding; however, no women withdrew or discontinued treatment because of adverse events.

Study limitations. This study evaluated the majority of GSM symptoms as well as change in vaginal caliber after a nonhormonal therapy. The cohort was small and had no placebo group. In addition, with the limited observation period, it is difficult to determine the duration of effect and long-term safety of repeated treatments.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The genitourinary syndrome of menopause (GSM) is a constellation of symptoms and signs of a hypoestrogenic state resulting in some or all of the following: vaginal dryness, burning, irritation, dyspareunia, urinary urgency, dysuria, and recurrent urinary tract infections.¹ In 2014, the International Society for the Study of Women’s Sexual Health and the North American Menopause Society endorsed “GSM” as a new term to replace the less comprehensive description, vulvovaginal atrophy (VVA).¹

The prevalence of GSM is around 50%, but it may increase each year after menopause, reaching up to 84.2%.^2,3 Only about half of women affected seek medical care, with the most commonly reported symptoms being vaginal dryness and dyspareunia.^3,4

Nonhormonal vaginal moisturizers andlubricants remain first-line treatment. The benefits are temporary and short lived because these options do not change the physiologic makeup of the vaginal wall; these treatments therefore provide relief only if the GSM symptoms are limited or mild.⁵

In this Update on pelvic floor dysfunction, we review 2 randomized, placebo-controlled trials of hormonal options (vaginal estrogen and oral ospemifene) and examine the latest information regarding fractional CO₂ vaginal laser treatment. Also included are evidence-based guidelines for vaginal estrogen use and recommendations and conclusions for use of vaginal estrogen in women with a history of estrogen-dependent breast cancer. (The terms used in the studies described [ie, VVA versus GSM] have been maintained for accuracy of reporting.)

Low-dose estrogen vaginal cream ameliorates moderate to severe VVA with limited adverse events

Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H. Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy. Menopause. 2009;16(4):735-741.

In a multicenter, double-blind, randomized, placebo-controlled study, Freedman and colleagues evaluated the efficacy of a 1-g dose of synthetic conjugated estrogens A (SCE-A) cream versus placebo in postmenopausal women with moderate to severe VVA.

Details of the study

The investigators enrolled 305 participants aged 30 to 80 years (mean [SD] age, 60 [6.6] years) who were naturally or surgically postmenopausal. The enrollment criteria included ≤5% superficial cells on vaginal smear, vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA (vaginal dryness, soreness, irritation/itching, pain with intercourse, or bleeding after intercourse).

Participants were randomly assigned in a 1:1:1:1 ratio to twice-weekly therapy with 1 g (0.625 mg/g) SCE-A vaginal cream, 2 g SCE-A vaginal cream, 1 g placebo, or 2 g placebo. Study visits occurred on days 14, 21, 28, 56, and 84 (12-week end point). The 3 co-primary outcomes were cytology, vaginal pH, and most bothersome symptom (MBS). Primary outcomes and safety/adverse events (AEs) were recorded at each study visit, and transvaginal ultrasound and endometrial biopsy were performed for women with a uterus at the beginning and end of the study.

Mean change and percent change in the 3 primary outcomes were assessed between baseline and each study visit. MBS was scored on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). The principal indicators of efficacy were the changes from baseline to the end of treatment (12 weeks) for each of the 3 end points. Since the 1-g and 2-g SCE-A dose groups showed a similar degree of efficacy on all 3 co-primary end points, approval from the US Food and Drug Administration (FDA) was sought only for the lower dose, in keeping with the use of the lowest effective dose; therefore, results from only the 1-g SCE-A dose group and matching placebo group were presented in the article. A sample size calculation determined that at least 111 participants in each group were needed to provide 90% power for statistical testing.

Estrogen reduced MBS severity, improved vaginal indices

The modified intent-to-treat (MITT) cohort was used for outcome analysis, and data from 275 participants were available at the 12-week end point. At baseline, 132 participants (48%) indicated vaginal dryness and 86 women (31.3%) indicated pain during intercourse as the MBS. In the SCE-A group at baseline, the vaginal maturation index (VMI) was 31.31 compared with 31.84 in the placebo group. At 12 weeks, the SCE-A group had a mean reduction of 1.71 in overall MBS severity compared with the placebo group’s mean reduction of 1.11 (P<.0001). The SCE-A group had a greater increase in the VMI (with a mean change of 31.46 vs 5.16 in the placebo group [P<.0001]) and a greater decrease in the vaginal pH (mean pH at the end of treatment for the SCE-A group was 4.84, a decrease of 1.48, and for the placebo group was 5.96, a decrease of 0.31 [P<.0001]).

Adverse events. The incidence of AEs was similar for the 1-g SCE-A group and the 1-g placebo group, with no AE occurring at a rate of higher than 5%. There were 15 (10%) treatment-related AEs in the estrogen group and 16 (10.3%) in the placebo group. The SCE-A group had 3 AEs (2%) leading to discontinuation, while the placebo group had 2 AEs (1.3%) leading to discontinuation. There were no clinically significant endometrial biopsy findings at the conclusion of the study.

Strengths and limitations. This study evaluated clinical and physiologic outcomes as well as uterine response to transvaginal estrogen. The use of MBS allows symptoms to be scored objectively compared with prior subjective symptom assessment, which varied widely. However, fewer indicated symptoms will permit limited conclusions.

Ospemifene improves vaginal physiology and dyspareunia

Bachmann GA, Komi JO; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486.

Bachmann and colleagues evaluated the efficacy and safety of ospemifene for the treatment of VVA. This is one of the efficacy studies on which FDA approval was based. Ospemifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist/antagonist.

Details of the study

The study included 826 postmenopausal women randomly assigned to 30 mg/day of ospemifene, 60 mg/day of ospemifene, or placebo for 12 weeks. Participants were aged 40 to 80 years and met the criteria for VVA (defined as ≤5% superficial cells on vaginal smear [maturation index], vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA). All women were given a nonhormonal lubricant for use as needed.

There were 4 co-primary end points: percentage of superficial cells on the vaginal smear, percentage of parabasal cells on the vaginal smear, vaginal pH, and self-assessed MBS using a Likert scale (0, none; 1, mild; 2, moderate; 3, severe). The symptom score was calculated as the change from baseline to week 12 for each MBS. Safety was assessed by patient report; if a participant had an intact uterus and cervix, Pap test, endometrial thickness, and endometrial histologic analysis were performed at baseline and at 12 weeks. Baseline characteristics were similar among all treatment groups. A total of 46% of participants reported dyspareunia as their MBS, and 39% reported vaginal dryness.

Two dose levels of ospemifene effectively relieve symptoms

After 12 weeks of treatment, both the 30-mg and the 60-mg dose of ospemifene produced a statistically significant improvement in vaginal dryness and objective results of maturation index and vaginal pH compared with placebo. Vaginal dryness decreased in the ospemifene 30-mg group (1.22) and in the ospemifene 60-mg group (1.26) compared with placebo (0.84) (P = .04 for the 30-mg group and P = .021 for the 60-mg group). The percentage of superficial cells was increased in both treatment groups compared with placebo (7.8% for the 30-mg group, 10.8% for the 60-mg group, 2.2% for the placebo group; P<.001 for both). The percentage of parabasal cells decreased in both treatment groups compared with participants who received placebo (21.9% in the 30-mg group, 30.1% in the 60-mg group, and 3.98% in the placebo group; P<.001 for both). Both treatment groups had a decrease in vaginal pH versus the placebo group as well (0.67 decrease in the 30-mg group, 1.01 decrease in the 60-mg group, and 0.10 decrease in the placebo group; P<.001 for both). The 60-mg/day ospemifene dose improved dyspareunia compared with placebo and was more effective than the 30-mg dose for all end points.

Adverse effects. Hot flashes were reported in 9.6% of the 30-mg ospemifene group and in 8.3% of the 60-mg group, compared with 3.4% in the placebo group. The increased percentage of participants with hot flashes in the ospemifene groups did not lead to increased discontinuation with the study. Urinary tract infections, defined by symptoms only, were more common in the ospemifene groups (4.6% in the 30-mg group, 7.2% in the 60-mg group, and 2.2% in the placebo group). In each group, 5% of patients discontinued the study because of AEs. There were 5 serious AEs in the 30-mg ospemifene group, 4 serious AEs in the placebo group, and none in the 60-mg group. No venous thromboembolic events were reported.

Strengths and limitations. Vaginal physiology as well as common symptoms of GSM were assessed in this large study. However, AEs were self-reported. While ospemifene was found safe and well tolerated when the study was extended for an additional 52 weeks (in women without a uterus) and 40 weeks (in women with a uterus), longer follow-up is needed to determine  endometrial safety.^7,8

Fractional CO2 laser for VVA shows efficacy, patient satisfaction

Sokol ER, Karram MM. An assessment of the safety and efficacy of a fractional CO2 laser system for the treatment of vulvovaginal atrophy. Menopause. 2016;23(10):1102–1107.

In this first US pilot study, postmenopausal women received 3 fractional CO₂ laser treatments, 6 weeks apart. The investigators evaluated the safety and efficacy of the treatment for GSM.

Details of the study

Thirty women (mean age, 58.6 years) who were nonsmokers, postmenopausal, had less than stage 2 prolapse, no vaginal procedures for the past 6 months, and did not use vaginal creams, moisturizers, lubricants, or homeopathic preparations for the past 3 months were enrolled. Participants received 3 laser treatments with the SmartXide2, MonaLisa Touch (DEKA M.E.L.A. SRL, Florence, Italy) device at 6-week intervals followed by a 3-month follow-up.

The primary outcome was visual analog scale (VAS) change in 6 categories (vaginal pain, burning, itching, dryness, dyspareunia, and dysuria) assessed from baseline to after each treatment, including 3 months after the final treatment, using an 11-point scale with 0 the lowest (no symptoms) and 10 the highest (extreme bother). Secondary outcomes were Vaginal Health Index (VHI) score, maximal tolerable dilator size, Female Sexual Function Index (FSFI) questionnaire score, general quality of life, degree of difficulty performing the procedure, participant satisfaction, vaginal pH, adverse effects, and treatment discomfort assessed using the VAS.  

Improved VVA symptoms and vaginal caliber

Twenty-seven women completed the study. There was a statistically significant change in all 6 symptom categories measured with the VAS. Improvement change (SD) on the VAS was 1.7 (3.2) for pain, 1.4 (2.9) for burning, 1.4 (1.9) for itching, 1.0 (2.4) for dysuria, comparing baseline scores to scores after 3 treatments (all with P<.05). A greater improvement was noted for dryness, 6.1 (2.7), and for dyspareunia, 5.4 (2.9) (both P<.001). There was also a statistically significant change in overall improvement on the VHI and the FSFI. The mean (SD) VHI score at baseline was 14.4 (2.9; range, 8 to 20) and the mean (SD) after 3 laser treatments was 21.4 (2.9; range, 16 to 25), with an overall mean (SD) improvement of 7.0 (3.1; P<.001).

Twenty-six participants completed a follow-up FSFI, with a mean (SD) baseline score of 11.3 (7.3; range, 2 to 25) and a follow-up mean (SD) score of 8.8 (7.3; range, −3.7 to 27.2) (P<.001). There was an increase in dilator size of 83% when comparing baseline to follow-up. At baseline, 24 participants (80%) could comfortably accept an XS or S dilator, and at follow-up 23 of 24 women (96%) could comfortably accept an M or L dilator.

Adverse effects. At their follow-up, 96% of participants were satisfied or extremely satisfied with treatment. Two women reported mild-to-moderate pain lasting 2 to 3 days, and 2 had minor bleeding; however, no women withdrew or discontinued treatment because of adverse events.

Study limitations. This study evaluated the majority of GSM symptoms as well as change in vaginal caliber after a nonhormonal therapy. The cohort was small and had no placebo group. In addition, with the limited observation period, it is difficult to determine the duration of effect and long-term safety of repeated treatments.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The genitourinary syndrome of menopause (GSM) is a constellation of symptoms and signs of a hypoestrogenic state resulting in some or all of the following: vaginal dryness, burning, irritation, dyspareunia, urinary urgency, dysuria, and recurrent urinary tract infections.¹ In 2014, the International Society for the Study of Women’s Sexual Health and the North American Menopause Society endorsed “GSM” as a new term to replace the less comprehensive description, vulvovaginal atrophy (VVA).¹

The prevalence of GSM is around 50%, but it may increase each year after menopause, reaching up to 84.2%.^2,3 Only about half of women affected seek medical care, with the most commonly reported symptoms being vaginal dryness and dyspareunia.^3,4

Nonhormonal vaginal moisturizers andlubricants remain first-line treatment. The benefits are temporary and short lived because these options do not change the physiologic makeup of the vaginal wall; these treatments therefore provide relief only if the GSM symptoms are limited or mild.⁵

In this Update on pelvic floor dysfunction, we review 2 randomized, placebo-controlled trials of hormonal options (vaginal estrogen and oral ospemifene) and examine the latest information regarding fractional CO₂ vaginal laser treatment. Also included are evidence-based guidelines for vaginal estrogen use and recommendations and conclusions for use of vaginal estrogen in women with a history of estrogen-dependent breast cancer. (The terms used in the studies described [ie, VVA versus GSM] have been maintained for accuracy of reporting.)

Low-dose estrogen vaginal cream ameliorates moderate to severe VVA with limited adverse events

Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H. Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy. Menopause. 2009;16(4):735-741.

In a multicenter, double-blind, randomized, placebo-controlled study, Freedman and colleagues evaluated the efficacy of a 1-g dose of synthetic conjugated estrogens A (SCE-A) cream versus placebo in postmenopausal women with moderate to severe VVA.

Details of the study

The investigators enrolled 305 participants aged 30 to 80 years (mean [SD] age, 60 [6.6] years) who were naturally or surgically postmenopausal. The enrollment criteria included ≤5% superficial cells on vaginal smear, vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA (vaginal dryness, soreness, irritation/itching, pain with intercourse, or bleeding after intercourse).

Participants were randomly assigned in a 1:1:1:1 ratio to twice-weekly therapy with 1 g (0.625 mg/g) SCE-A vaginal cream, 2 g SCE-A vaginal cream, 1 g placebo, or 2 g placebo. Study visits occurred on days 14, 21, 28, 56, and 84 (12-week end point). The 3 co-primary outcomes were cytology, vaginal pH, and most bothersome symptom (MBS). Primary outcomes and safety/adverse events (AEs) were recorded at each study visit, and transvaginal ultrasound and endometrial biopsy were performed for women with a uterus at the beginning and end of the study.

Mean change and percent change in the 3 primary outcomes were assessed between baseline and each study visit. MBS was scored on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). The principal indicators of efficacy were the changes from baseline to the end of treatment (12 weeks) for each of the 3 end points. Since the 1-g and 2-g SCE-A dose groups showed a similar degree of efficacy on all 3 co-primary end points, approval from the US Food and Drug Administration (FDA) was sought only for the lower dose, in keeping with the use of the lowest effective dose; therefore, results from only the 1-g SCE-A dose group and matching placebo group were presented in the article. A sample size calculation determined that at least 111 participants in each group were needed to provide 90% power for statistical testing.

Estrogen reduced MBS severity, improved vaginal indices

The modified intent-to-treat (MITT) cohort was used for outcome analysis, and data from 275 participants were available at the 12-week end point. At baseline, 132 participants (48%) indicated vaginal dryness and 86 women (31.3%) indicated pain during intercourse as the MBS. In the SCE-A group at baseline, the vaginal maturation index (VMI) was 31.31 compared with 31.84 in the placebo group. At 12 weeks, the SCE-A group had a mean reduction of 1.71 in overall MBS severity compared with the placebo group’s mean reduction of 1.11 (P<.0001). The SCE-A group had a greater increase in the VMI (with a mean change of 31.46 vs 5.16 in the placebo group [P<.0001]) and a greater decrease in the vaginal pH (mean pH at the end of treatment for the SCE-A group was 4.84, a decrease of 1.48, and for the placebo group was 5.96, a decrease of 0.31 [P<.0001]).

Adverse events. The incidence of AEs was similar for the 1-g SCE-A group and the 1-g placebo group, with no AE occurring at a rate of higher than 5%. There were 15 (10%) treatment-related AEs in the estrogen group and 16 (10.3%) in the placebo group. The SCE-A group had 3 AEs (2%) leading to discontinuation, while the placebo group had 2 AEs (1.3%) leading to discontinuation. There were no clinically significant endometrial biopsy findings at the conclusion of the study.

Strengths and limitations. This study evaluated clinical and physiologic outcomes as well as uterine response to transvaginal estrogen. The use of MBS allows symptoms to be scored objectively compared with prior subjective symptom assessment, which varied widely. However, fewer indicated symptoms will permit limited conclusions.

Ospemifene improves vaginal physiology and dyspareunia

Bachmann GA, Komi JO; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486.

Bachmann and colleagues evaluated the efficacy and safety of ospemifene for the treatment of VVA. This is one of the efficacy studies on which FDA approval was based. Ospemifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist/antagonist.

Details of the study

The study included 826 postmenopausal women randomly assigned to 30 mg/day of ospemifene, 60 mg/day of ospemifene, or placebo for 12 weeks. Participants were aged 40 to 80 years and met the criteria for VVA (defined as ≤5% superficial cells on vaginal smear [maturation index], vaginal pH >5.0, and at least 1 moderate or severe symptom of VVA). All women were given a nonhormonal lubricant for use as needed.

There were 4 co-primary end points: percentage of superficial cells on the vaginal smear, percentage of parabasal cells on the vaginal smear, vaginal pH, and self-assessed MBS using a Likert scale (0, none; 1, mild; 2, moderate; 3, severe). The symptom score was calculated as the change from baseline to week 12 for each MBS. Safety was assessed by patient report; if a participant had an intact uterus and cervix, Pap test, endometrial thickness, and endometrial histologic analysis were performed at baseline and at 12 weeks. Baseline characteristics were similar among all treatment groups. A total of 46% of participants reported dyspareunia as their MBS, and 39% reported vaginal dryness.

Two dose levels of ospemifene effectively relieve symptoms

After 12 weeks of treatment, both the 30-mg and the 60-mg dose of ospemifene produced a statistically significant improvement in vaginal dryness and objective results of maturation index and vaginal pH compared with placebo. Vaginal dryness decreased in the ospemifene 30-mg group (1.22) and in the ospemifene 60-mg group (1.26) compared with placebo (0.84) (P = .04 for the 30-mg group and P = .021 for the 60-mg group). The percentage of superficial cells was increased in both treatment groups compared with placebo (7.8% for the 30-mg group, 10.8% for the 60-mg group, 2.2% for the placebo group; P<.001 for both). The percentage of parabasal cells decreased in both treatment groups compared with participants who received placebo (21.9% in the 30-mg group, 30.1% in the 60-mg group, and 3.98% in the placebo group; P<.001 for both). Both treatment groups had a decrease in vaginal pH versus the placebo group as well (0.67 decrease in the 30-mg group, 1.01 decrease in the 60-mg group, and 0.10 decrease in the placebo group; P<.001 for both). The 60-mg/day ospemifene dose improved dyspareunia compared with placebo and was more effective than the 30-mg dose for all end points.

Adverse effects. Hot flashes were reported in 9.6% of the 30-mg ospemifene group and in 8.3% of the 60-mg group, compared with 3.4% in the placebo group. The increased percentage of participants with hot flashes in the ospemifene groups did not lead to increased discontinuation with the study. Urinary tract infections, defined by symptoms only, were more common in the ospemifene groups (4.6% in the 30-mg group, 7.2% in the 60-mg group, and 2.2% in the placebo group). In each group, 5% of patients discontinued the study because of AEs. There were 5 serious AEs in the 30-mg ospemifene group, 4 serious AEs in the placebo group, and none in the 60-mg group. No venous thromboembolic events were reported.

Strengths and limitations. Vaginal physiology as well as common symptoms of GSM were assessed in this large study. However, AEs were self-reported. While ospemifene was found safe and well tolerated when the study was extended for an additional 52 weeks (in women without a uterus) and 40 weeks (in women with a uterus), longer follow-up is needed to determine  endometrial safety.^7,8

Fractional CO2 laser for VVA shows efficacy, patient satisfaction

Sokol ER, Karram MM. An assessment of the safety and efficacy of a fractional CO2 laser system for the treatment of vulvovaginal atrophy. Menopause. 2016;23(10):1102–1107.

In this first US pilot study, postmenopausal women received 3 fractional CO₂ laser treatments, 6 weeks apart. The investigators evaluated the safety and efficacy of the treatment for GSM.

Details of the study

Thirty women (mean age, 58.6 years) who were nonsmokers, postmenopausal, had less than stage 2 prolapse, no vaginal procedures for the past 6 months, and did not use vaginal creams, moisturizers, lubricants, or homeopathic preparations for the past 3 months were enrolled. Participants received 3 laser treatments with the SmartXide2, MonaLisa Touch (DEKA M.E.L.A. SRL, Florence, Italy) device at 6-week intervals followed by a 3-month follow-up.

The primary outcome was visual analog scale (VAS) change in 6 categories (vaginal pain, burning, itching, dryness, dyspareunia, and dysuria) assessed from baseline to after each treatment, including 3 months after the final treatment, using an 11-point scale with 0 the lowest (no symptoms) and 10 the highest (extreme bother). Secondary outcomes were Vaginal Health Index (VHI) score, maximal tolerable dilator size, Female Sexual Function Index (FSFI) questionnaire score, general quality of life, degree of difficulty performing the procedure, participant satisfaction, vaginal pH, adverse effects, and treatment discomfort assessed using the VAS.  

Improved VVA symptoms and vaginal caliber

Twenty-seven women completed the study. There was a statistically significant change in all 6 symptom categories measured with the VAS. Improvement change (SD) on the VAS was 1.7 (3.2) for pain, 1.4 (2.9) for burning, 1.4 (1.9) for itching, 1.0 (2.4) for dysuria, comparing baseline scores to scores after 3 treatments (all with P<.05). A greater improvement was noted for dryness, 6.1 (2.7), and for dyspareunia, 5.4 (2.9) (both P<.001). There was also a statistically significant change in overall improvement on the VHI and the FSFI. The mean (SD) VHI score at baseline was 14.4 (2.9; range, 8 to 20) and the mean (SD) after 3 laser treatments was 21.4 (2.9; range, 16 to 25), with an overall mean (SD) improvement of 7.0 (3.1; P<.001).

Twenty-six participants completed a follow-up FSFI, with a mean (SD) baseline score of 11.3 (7.3; range, 2 to 25) and a follow-up mean (SD) score of 8.8 (7.3; range, −3.7 to 27.2) (P<.001). There was an increase in dilator size of 83% when comparing baseline to follow-up. At baseline, 24 participants (80%) could comfortably accept an XS or S dilator, and at follow-up 23 of 24 women (96%) could comfortably accept an M or L dilator.

Adverse effects. At their follow-up, 96% of participants were satisfied or extremely satisfied with treatment. Two women reported mild-to-moderate pain lasting 2 to 3 days, and 2 had minor bleeding; however, no women withdrew or discontinued treatment because of adverse events.

Study limitations. This study evaluated the majority of GSM symptoms as well as change in vaginal caliber after a nonhormonal therapy. The cohort was small and had no placebo group. In addition, with the limited observation period, it is difficult to determine the duration of effect and long-term safety of repeated treatments.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

PORTLAND, OR—Researchers have completed a double-blinded, placebo-controlled trial examining the potential benefits of a new formulation of exenatide in patients with Parkinson’s disease, according to an overview provided at the Fourth World Parkinson Congress. Results will be published in early 2017. If the findings are similar to those of the early proof-of-concept trial, then “this will be the first-ever demonstration of long-term disease modification and slowing of neurodegeneration in patients with Parkinson’s disease,” said Richard Wyse, MD, Director of Research at the Cure Parkinson’s Trust in London.

Exenatide is a treatment for type 2 diabetes that the Cure Parkinson’s Trust selected for study. As part of the charity’s international PD Linked Clinical Trials initiative, investigators conducted an open-label trial that suggested that 12 months of treatment with exenatide improved motor and nonmotor function in patients with mid-stage Parkinson’s disease. A follow-up study examined the same participants at 12 months after the end of the original study (ie, one year after the active group stopped receiving exenatide). Motor function and cognition were better among patients previously exposed to exenatide, compared with controls. These findings prompted the initiation of the recently completed study.

The Linked Clinical Trials Initiative

The goal of the Linked Clinical Trials initiative is to identify approved treatments for various conditions that may slow, stop, or reverse Parkinson’s disease. The initiative began in 2012 after research indicated that, among people with hypertension, patients who took the calcium channel blocker isradipine were approximately 30% less likely to develop Parkinson’s disease than those who did not. The Cure Parkinson’s Trust brought together international experts in calcium channels and funded research into the brains of healthy controls and patients with Parkinson’s disease. This research helped inform the design of a phase II trial that identified the maximum tolerable dose of isradipine. A phase III trial of isradipine’s efficacy in Parkinson’s disease is ongoing.

To date, the Cure Parkinson’s Trust has evaluated approximately 100 biologic targets relevant to Parkinson’s disease and has funded laboratory screens of more than 100,000 drugs for activity on some of these targets. Researchers have so far compiled detailed dossiers on more than 100 drugs that appear to have strong biochemical evidence for a disease-modifying effect in Parkinson’s disease. These drugs include parkin agonists, parkin interacting substrate (PARIS) inhibitors, mitochondrial and GLP-1 modulators, and various anti-inflammatory and alpha synuclein therapeutic approaches.

An international committee established by the charity regularly assesses these drug dossiers. During annual meetings, committee members prioritize the medicines for proof-of-concept trials. Their decisions are based on the therapies’ safety, efficacy, preclinical data, mechanism of action, and bioavailability. The process ensures that the selected drugs “have strong credentials for their disease-modifying potential in patients with Parkinson’s disease, and that they are also proven to be safe,” said Dr. Wyse.

Since 2012, between four and 10 therapies per year have been prioritized to enter clinical trials. Exenatide is one of these drugs. Six additional clinical trials are under way, and four more trials are in the advanced planning stages. Four of the trials are expected to conclude in 2017, and other trials in this program will launch soon.

Examining Drugs and Combination Therapies

Exenatide is not the only diabetes treatment that the initiative has considered. Among the other drugs in this program are liraglutide and lixisenatide, two injectable medicines for diabetes in the same drug class as exenatide. The liraglutide trial is already under way. In a study scheduled to begin soon, researchers will examine whether lixisenatide has benefits for patients in the early stage of Parkinson’s disease. Participants will begin treatment soon after their initial diagnosis, said Dr. Wyse.

Researchers in 23 UK centers are analyzing whether simvastatin’s anti-inflammatory properties could provide neuroprotection in Parkinson’s disease. The drug is approved to treat high cholesterol. Recruitment for a European trial of deferiprone, an iron chelator, is under way. Investigators are conducting a proof-of-concept trial in Boston, London, Tübingen, Los Angeles, and San Francisco to determine whether EPI-589, which was designed to treat pediatric mitochondrial diseases, may benefit patients with Parkinson’s disease.

Clinical trials for other drugs are in the planning stages. These treatments include N-acetyl cysteine, a therapy for cystic fibrosis and chronic obstructive pulmonary disease; nilotinib, a leukemia treatment; ursodeoxycholic acid, which treats liver disease; and the diabetes drugs alogliptin and MSDC-0160, all of which have strong biochemical rationales for disease-modifying potential in Parkinson’s disease, said Dr. Wyse.

Furthermore, the Cure Parkinson’s Trust plans to investigate the efficacy of various drug combinations. “The effective combinations of disease-modifying therapies are likely to involve two dissimilar biological approaches that work well individually, but complement each other,” said Dr. Wyse. For example, an alpha synuclein antiaggregation therapy might be more effective if it is administered with a mitochondrial therapy that increases energy availability.

“The need for effective disease-modifying therapies for Parkinson’s disease is urgent,” said Dr. Wyse. The Linked Clinical Trials initiative has prompted the initiation of clinical trials for various drugs that otherwise may not have been investigated as disease-modifying therapies for Parkinson’s disease, and many more trials are planned for the future. “It is the funding, not the science, that is slowing down the delivery of these fundamental new therapies for Parkinson’s disease,” Dr. Wyse concluded.

—Erik Greb

Suggested Reading

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123(6):2730-2736.

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4(3):337-344.

Brundin P, Barker RA, Conn PJ, et al. Linked clinical trials--the development of new clinical learning studies in Parkinson’s disease using screening of multiple prospective new treatments. J Parkinsons Dis. 2013;3(3):231-239.

Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831.

Roy A, Pahan K. Prospects of statins in Parkinson disease. Neuroscientist. 2011;17(3):244-255.

PORTLAND, OR—Researchers have completed a double-blinded, placebo-controlled trial examining the potential benefits of a new formulation of exenatide in patients with Parkinson’s disease, according to an overview provided at the Fourth World Parkinson Congress. Results will be published in early 2017. If the findings are similar to those of the early proof-of-concept trial, then “this will be the first-ever demonstration of long-term disease modification and slowing of neurodegeneration in patients with Parkinson’s disease,” said Richard Wyse, MD, Director of Research at the Cure Parkinson’s Trust in London.

Exenatide is a treatment for type 2 diabetes that the Cure Parkinson’s Trust selected for study. As part of the charity’s international PD Linked Clinical Trials initiative, investigators conducted an open-label trial that suggested that 12 months of treatment with exenatide improved motor and nonmotor function in patients with mid-stage Parkinson’s disease. A follow-up study examined the same participants at 12 months after the end of the original study (ie, one year after the active group stopped receiving exenatide). Motor function and cognition were better among patients previously exposed to exenatide, compared with controls. These findings prompted the initiation of the recently completed study.

The Linked Clinical Trials Initiative

The goal of the Linked Clinical Trials initiative is to identify approved treatments for various conditions that may slow, stop, or reverse Parkinson’s disease. The initiative began in 2012 after research indicated that, among people with hypertension, patients who took the calcium channel blocker isradipine were approximately 30% less likely to develop Parkinson’s disease than those who did not. The Cure Parkinson’s Trust brought together international experts in calcium channels and funded research into the brains of healthy controls and patients with Parkinson’s disease. This research helped inform the design of a phase II trial that identified the maximum tolerable dose of isradipine. A phase III trial of isradipine’s efficacy in Parkinson’s disease is ongoing.

To date, the Cure Parkinson’s Trust has evaluated approximately 100 biologic targets relevant to Parkinson’s disease and has funded laboratory screens of more than 100,000 drugs for activity on some of these targets. Researchers have so far compiled detailed dossiers on more than 100 drugs that appear to have strong biochemical evidence for a disease-modifying effect in Parkinson’s disease. These drugs include parkin agonists, parkin interacting substrate (PARIS) inhibitors, mitochondrial and GLP-1 modulators, and various anti-inflammatory and alpha synuclein therapeutic approaches.

An international committee established by the charity regularly assesses these drug dossiers. During annual meetings, committee members prioritize the medicines for proof-of-concept trials. Their decisions are based on the therapies’ safety, efficacy, preclinical data, mechanism of action, and bioavailability. The process ensures that the selected drugs “have strong credentials for their disease-modifying potential in patients with Parkinson’s disease, and that they are also proven to be safe,” said Dr. Wyse.

Since 2012, between four and 10 therapies per year have been prioritized to enter clinical trials. Exenatide is one of these drugs. Six additional clinical trials are under way, and four more trials are in the advanced planning stages. Four of the trials are expected to conclude in 2017, and other trials in this program will launch soon.

Examining Drugs and Combination Therapies

Exenatide is not the only diabetes treatment that the initiative has considered. Among the other drugs in this program are liraglutide and lixisenatide, two injectable medicines for diabetes in the same drug class as exenatide. The liraglutide trial is already under way. In a study scheduled to begin soon, researchers will examine whether lixisenatide has benefits for patients in the early stage of Parkinson’s disease. Participants will begin treatment soon after their initial diagnosis, said Dr. Wyse.

Researchers in 23 UK centers are analyzing whether simvastatin’s anti-inflammatory properties could provide neuroprotection in Parkinson’s disease. The drug is approved to treat high cholesterol. Recruitment for a European trial of deferiprone, an iron chelator, is under way. Investigators are conducting a proof-of-concept trial in Boston, London, Tübingen, Los Angeles, and San Francisco to determine whether EPI-589, which was designed to treat pediatric mitochondrial diseases, may benefit patients with Parkinson’s disease.

Clinical trials for other drugs are in the planning stages. These treatments include N-acetyl cysteine, a therapy for cystic fibrosis and chronic obstructive pulmonary disease; nilotinib, a leukemia treatment; ursodeoxycholic acid, which treats liver disease; and the diabetes drugs alogliptin and MSDC-0160, all of which have strong biochemical rationales for disease-modifying potential in Parkinson’s disease, said Dr. Wyse.

Furthermore, the Cure Parkinson’s Trust plans to investigate the efficacy of various drug combinations. “The effective combinations of disease-modifying therapies are likely to involve two dissimilar biological approaches that work well individually, but complement each other,” said Dr. Wyse. For example, an alpha synuclein antiaggregation therapy might be more effective if it is administered with a mitochondrial therapy that increases energy availability.

“The need for effective disease-modifying therapies for Parkinson’s disease is urgent,” said Dr. Wyse. The Linked Clinical Trials initiative has prompted the initiation of clinical trials for various drugs that otherwise may not have been investigated as disease-modifying therapies for Parkinson’s disease, and many more trials are planned for the future. “It is the funding, not the science, that is slowing down the delivery of these fundamental new therapies for Parkinson’s disease,” Dr. Wyse concluded.

—Erik Greb

Suggested Reading

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123(6):2730-2736.

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4(3):337-344.

Brundin P, Barker RA, Conn PJ, et al. Linked clinical trials--the development of new clinical learning studies in Parkinson’s disease using screening of multiple prospective new treatments. J Parkinsons Dis. 2013;3(3):231-239.

Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831.

Roy A, Pahan K. Prospects of statins in Parkinson disease. Neuroscientist. 2011;17(3):244-255.

PORTLAND, OR—Researchers have completed a double-blinded, placebo-controlled trial examining the potential benefits of a new formulation of exenatide in patients with Parkinson’s disease, according to an overview provided at the Fourth World Parkinson Congress. Results will be published in early 2017. If the findings are similar to those of the early proof-of-concept trial, then “this will be the first-ever demonstration of long-term disease modification and slowing of neurodegeneration in patients with Parkinson’s disease,” said Richard Wyse, MD, Director of Research at the Cure Parkinson’s Trust in London.

Exenatide is a treatment for type 2 diabetes that the Cure Parkinson’s Trust selected for study. As part of the charity’s international PD Linked Clinical Trials initiative, investigators conducted an open-label trial that suggested that 12 months of treatment with exenatide improved motor and nonmotor function in patients with mid-stage Parkinson’s disease. A follow-up study examined the same participants at 12 months after the end of the original study (ie, one year after the active group stopped receiving exenatide). Motor function and cognition were better among patients previously exposed to exenatide, compared with controls. These findings prompted the initiation of the recently completed study.

The Linked Clinical Trials Initiative

The goal of the Linked Clinical Trials initiative is to identify approved treatments for various conditions that may slow, stop, or reverse Parkinson’s disease. The initiative began in 2012 after research indicated that, among people with hypertension, patients who took the calcium channel blocker isradipine were approximately 30% less likely to develop Parkinson’s disease than those who did not. The Cure Parkinson’s Trust brought together international experts in calcium channels and funded research into the brains of healthy controls and patients with Parkinson’s disease. This research helped inform the design of a phase II trial that identified the maximum tolerable dose of isradipine. A phase III trial of isradipine’s efficacy in Parkinson’s disease is ongoing.

To date, the Cure Parkinson’s Trust has evaluated approximately 100 biologic targets relevant to Parkinson’s disease and has funded laboratory screens of more than 100,000 drugs for activity on some of these targets. Researchers have so far compiled detailed dossiers on more than 100 drugs that appear to have strong biochemical evidence for a disease-modifying effect in Parkinson’s disease. These drugs include parkin agonists, parkin interacting substrate (PARIS) inhibitors, mitochondrial and GLP-1 modulators, and various anti-inflammatory and alpha synuclein therapeutic approaches.

An international committee established by the charity regularly assesses these drug dossiers. During annual meetings, committee members prioritize the medicines for proof-of-concept trials. Their decisions are based on the therapies’ safety, efficacy, preclinical data, mechanism of action, and bioavailability. The process ensures that the selected drugs “have strong credentials for their disease-modifying potential in patients with Parkinson’s disease, and that they are also proven to be safe,” said Dr. Wyse.

Since 2012, between four and 10 therapies per year have been prioritized to enter clinical trials. Exenatide is one of these drugs. Six additional clinical trials are under way, and four more trials are in the advanced planning stages. Four of the trials are expected to conclude in 2017, and other trials in this program will launch soon.

Examining Drugs and Combination Therapies

Exenatide is not the only diabetes treatment that the initiative has considered. Among the other drugs in this program are liraglutide and lixisenatide, two injectable medicines for diabetes in the same drug class as exenatide. The liraglutide trial is already under way. In a study scheduled to begin soon, researchers will examine whether lixisenatide has benefits for patients in the early stage of Parkinson’s disease. Participants will begin treatment soon after their initial diagnosis, said Dr. Wyse.

Researchers in 23 UK centers are analyzing whether simvastatin’s anti-inflammatory properties could provide neuroprotection in Parkinson’s disease. The drug is approved to treat high cholesterol. Recruitment for a European trial of deferiprone, an iron chelator, is under way. Investigators are conducting a proof-of-concept trial in Boston, London, Tübingen, Los Angeles, and San Francisco to determine whether EPI-589, which was designed to treat pediatric mitochondrial diseases, may benefit patients with Parkinson’s disease.

Clinical trials for other drugs are in the planning stages. These treatments include N-acetyl cysteine, a therapy for cystic fibrosis and chronic obstructive pulmonary disease; nilotinib, a leukemia treatment; ursodeoxycholic acid, which treats liver disease; and the diabetes drugs alogliptin and MSDC-0160, all of which have strong biochemical rationales for disease-modifying potential in Parkinson’s disease, said Dr. Wyse.

Furthermore, the Cure Parkinson’s Trust plans to investigate the efficacy of various drug combinations. “The effective combinations of disease-modifying therapies are likely to involve two dissimilar biological approaches that work well individually, but complement each other,” said Dr. Wyse. For example, an alpha synuclein antiaggregation therapy might be more effective if it is administered with a mitochondrial therapy that increases energy availability.

“The need for effective disease-modifying therapies for Parkinson’s disease is urgent,” said Dr. Wyse. The Linked Clinical Trials initiative has prompted the initiation of clinical trials for various drugs that otherwise may not have been investigated as disease-modifying therapies for Parkinson’s disease, and many more trials are planned for the future. “It is the funding, not the science, that is slowing down the delivery of these fundamental new therapies for Parkinson’s disease,” Dr. Wyse concluded.

—Erik Greb

Suggested Reading

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123(6):2730-2736.

Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4(3):337-344.

Brundin P, Barker RA, Conn PJ, et al. Linked clinical trials--the development of new clinical learning studies in Parkinson’s disease using screening of multiple prospective new treatments. J Parkinsons Dis. 2013;3(3):231-239.

Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831.

Roy A, Pahan K. Prospects of statins in Parkinson disease. Neuroscientist. 2011;17(3):244-255.

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“IN WHICH CLINICAL SITUATIONS CAN THE USE OF THE 52-MG LEVONORGESTREL-RELEASING IUD (MIRENA) AND THE TCU380A COPPER-IUD (PARAGARD) BE EXTENDED?”

ROBERT L. BARBIERI, MD (SEPTEMBER 2016)

Extended-use IUDs and infection risk

For some time now I have been leaving hormonal intrauterine devices (IUDs) in place for 6 to 7 years, until menses returns. In my practice, long-term use of copper-IUDs has been associated with the presence of actinomycosis in the endometrial cavity, although usually without sepsis.

George Haber, MD
Montreal, Canada
 

Suppressing menses, pain with an IUD

I have a number of patients using the 52-mg levonorgestrel-releasing (LNG) IUD (Mirena) for noncontraceptive reasons, especially for reduction or elimination of menstrual flow and/or pain. Many have permanent sterilization in place (tubal sterilization, partner vasectomy) and I tell them we can leave the IUD in as long as they are satisfied with the results, since we are not concerned with pregnancy. Several have continued IUD use well past the 5-year mark.

Alan Smith, MD
Savannah, Georgia
 

LNG-IUD effective for multiple uses

In our practice, we have used the LNG-IUD Mirena off label for over a decade successfully for men-strual suppression in perimenopausal and postmenopausal women effectively for up to 8 years. We often place this device in the uterus after an endometrial ablation. We also offer it extended use as an alternative for menopausal hormone therapy when a progestin is indicated due to the presence of a uterus. Progestin delivery by this IUD is maximized in the endometrium and minimized in the breast and other systemic sites.

John Lenihan Jr, MD
Tacoma, Washington

Dr. Barbieri responds

I thank Dr. Haber for his observations. He notes that users of IUDs may have Actinomyces organisms identified on cervical cytology. These women should be informed of the finding and examined for evidence of active pelvic infection. If the women are asympto-matic and have a normal physical exam, the IUD does not need to be removed and antibiotic treatment is not recommended. If the woman has evidence of pelvic infection, the IUD should be removed and sent for anaerobic culture.

I appreciate that Drs. Smith and Lenihan shared their clinical pearls with readers. Dr. Smith notes that when an LNG-IUD is used to control bleeding in women who are sterilized, there are few concerns about the duration of its contraceptive efficacy, and adequate control of bleeding is a clinically useful end point demonstrating the IUD’s continued efficacy. If bleeding begins to increase after 5 years, the clinician might choose to remove the old device and replace it with a new one. Dr. Lenihan reports his use of the 52-mg LNG-IUD as the progestin in a regimen of menopausal hormone therapy. Of note, there are multiple reports from Finland that use of an LNG-IUD in premenopausal and menopausal women may be associated with an increased risk of breast cancer.^1,2 Conflicting reports from Finland and Germany did not detect an increased risk of breast cancer in women who used an LNG-IUD.^3,4 Clinicians should be aware that when Mirena is used past its approved 5-year time limit, it is an off-label use of the device.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Cesarean delivery is now the most commonly performed major operation in hospitals across the United States. Approximately 30% of the 4 million deliveries that occur each year are by cesarean. Endometritis and wound infection (superficial and deep surgical site infection) are the most common postoperative complications of cesarean delivery. These 2 infections usually can be treated in a straightforward manner with antibiotics or surgical drainage. In some cases, however, they can lead to serious sequelae, such as pelvic abscess, septic pelvic vein thrombophlebitis, and wound dehiscence/evisceration, thereby prolonging the patient’s hospitalization and significantly increasing medical expenses.

Accordingly, in the past 50 years many investigators have proposed various specific measures to reduce the risk of postcesarean infection. In this article, we critically evaluate 2 of these major interventions: methods of skin preparation and administration of prophylactic antibiotics. In part 2 of this series next month, we will review the evidence regarding preoperative bathing with an antiseptic, preoperative vaginal cleansing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

CASE Cesarean delivery required for nonprogressing labor

A 26-year-old obese primigravid woman, body mass index (BMI) 37 kg m², at 40 weeks’ gestation has been in labor for 20 hours. Her membranes have been ruptured for 16 hours. Her cervix is completely effaced and is 7 cm dilated. The fetal head is at −1 cm station. Her cervical examination findings have not changed in 4 hours despite adequate uterine contractility documented by intrauterine pressure catheter. You are now ready to proceed with cesarean delivery, and you want to do everything possible to prevent the patient from developing a postoperative infection.

What are the best practices for postcesarean infection prevention in this patient?

Skin preparation

Adequate preoperative skin preparation is an important first step in preventing post‑ cesarean infection.

How should you prepare the patient’s skin for surgery?

Two issues to address when preparing the abdominal wall for surgery are hair removal and skin cleansing. More than 40 years ago, Cruse and Foord definitively answered the question about hair removal.¹ In a landmark cohort investigation of more than 23,000 patients having many different types of operative procedures, they demonstrated that shaving the hair on the evening before surgery resulted in a higher rate of wound infection than clipping the hair, removing the hair with a depilatory cream just before surgery, or not removing the hair at all.

Three recent investigations have thoughtfully addressed the issue of skin cleansing. Darouiche and colleagues conducted a prospective, randomized, multicenter trial comparing chlorhexidine-alcohol with povidone-iodine for skin preparation before surgery.² Their investigation included 849 patients having many different types of surgical procedures, only a minority of which were in obstetric and gynecologic patients. They demonstrated fewer superficial wound infections in patients in the chlorhexidine-alcohol group (4.2% vs 8.6%, P = .008). Of even greater importance, patients in the chlorhexidine-alcohol group had fewer deep wound infections (1% vs 3%, P = .005).

Ngai and co-workers recently reported the results of a randomized controlled trial (RCT) in which women undergoing nonurgent cesarean delivery had their skin cleansed with povidone-iodine with alcohol, chlorhexidine with alcohol, or the sequential combination of both solutions.³ The overall rate of surgical site infection was just 4.3%. The 3 groups had comparable infection rates and, accordingly, the authors were unable to conclude that one type of skin preparation was superior to the other.

The most informative recent investigation was by Tuuli and colleagues, who evaluated 1,147 patients having cesarean delivery assigned to undergo skin preparation with either chlorhexidine-alcohol or iodine-alcohol.⁴ Unlike the study by Ngai and co-workers, in this study approximately 40% of the patients in each treatment arm had unscheduled, urgent cesarean deliveries.^3,4 Overall, the rate of infection in the chlorhexidine-alcohol group was 4.0% compared with 7.3% in the iodine-alcohol group (relative risk [RR], 0.55; 95% confidence interval [CI], 0.34–0.90, P = .02).

What the evidence says

Based on the evidence cited above, we advise removing hair at the incision site with clippers or depilatory cream just before the start of surgery. The abdomen should then be cleansed with a chlorhexidine-alcohol solution (Level I Evidence, Level 1A Recommendation; TABLE).

Antibiotic prophylaxis

Questions to consider regarding antibiotic prophylaxis for cesarean delivery include appropriateness of treatment, antibiotic(s) selection, timing of administration, dose, and special circumstances.

Should you give the patient prophylactic antibiotics?

Prophylactic antibiotics are justified for surgical procedures whenever 3 major criteria are met⁵:

1. the surgical site is inevitably contaminated with bacteria
2. in the absence of prophylaxis, the frequency of infection at the operative site is unacceptably high
3. operative site infections have the potential to lead to serious, potentially life-threatening sequelae.

Without a doubt, all 3 of these criteria are fulfilled when considering either urgent or nonurgent cesarean delivery. When cesarean delivery follows a long labor complicated by ruptured membranes, multiple internal vaginal examinations, and internal fetal monitoring, the operative site is inevitably contaminated with hundreds of thousands of pathogenic bacteria. Even when cesarean delivery is scheduled to occur before the onset of labor and ruptured membranes, a high concentration of vaginal organisms is introduced into the uterine and pelvic cavities coincident with making the hysterotomy incision.⁶

In the era before prophylactic antibiotics were used routinely, postoperative infection rates in some highly indigent patient populations approached 85%.⁵ Finally, as noted previously, postcesarean endometritis may progress to pelvic abscess formation, septic pelvic vein thrombophlebitis, and septic shock; wound infections may be complicated by dehiscence and evisceration.

When should you administer antibiotics: Before the surgical incision or after cord clamping?

More than 50 years ago, Burke conducted the classic sequence of basic science experiments that forms the foundation for use of prophylactic antibiotics.⁷ Using a guinea pig model, he showed that prophylactic antibiotics exert their most pronounced effect when they are administered before the surgical incision is made and before bacterial contamination occurs. Prophylaxis that is delayed more than 4 hours after the start of surgery will likely be ineffective.

Interestingly, however, when clinicians first began using prophylactic antibiotics for cesarean delivery, some investigators expressed concern about the possible exposure of the neonate to antibiotics just before delivery—specifically, whether this exposure would increase the frequency of evaluations for suspected sepsis or would promote resistance among organisms that would make neonatal sepsis more difficult to treat.

Gordon and colleagues published an important report in 1979 that showed that preoperative administration of ampicillin did not increase the frequency of immediate or delayed neonatal infections.⁸ However, delaying the administration of ampicillin until after the umbilical cord was clamped was just as effective in preventing post‑cesarean endometritis. Subsequently, Cunningham and co-workers showed that preoperative administration of prophylactic antibiotics significantly increased the frequency of sepsis workups in exposed neonates compared with infants with no preoperative antibiotic exposure (28% vs 15%; P<.025).⁹ Based on these 2 reports, obstetricians adopted a policy of delaying antibiotic administration until after the infant’s umbilical cord was clamped.

In 2007, Sullivan and colleagues challenged this long-standing practice.¹⁰ In a carefully designed prospective, randomized, double-blind trial, they showed that patients who received preoperative cefazolin had a significant reduction in the frequency of endometritis compared with women who received the same antibiotic after cord clamping (1% vs 5%; RR, 0.2; 95% CI, 0.2–0.94). The rate of wound infection was lower in the preoperative antibiotic group (3% vs 5%), but this difference did not reach statistical significance. The total infection-related morbidity was significantly reduced in women who received antibiotics preoperatively (4.0% vs 11.5%; RR, 0.4; 95% CI, 0.18–0.87). Additionally, there was no increase in the frequency of proven or suspected neonatal infection in the infants exposed to antibiotics before delivery.

Subsequent to the publication by Sullivan and colleagues, other reports have confirmed that administration of antibiotics prior to surgery is superior to administration after clamping of the umbilical cord.^10–12 Thus, we have come full circle back to Burke’s principle established more than a half century ago.⁷

Which antibiotic(s) should you administer for prophylaxis, and how many doses?

In an earlier review, one of us (PD) examined the evidence regarding choice of antibiotics and number of doses, concluding that a single dose of a first-generation cephalosporin, such as cefazolin, was the preferred regimen.⁵ The single dose was comparable in effectiveness to 2- or 3-dose regimens and to single- or multiple-dose regimens of broader-spectrum agents. For more than 20 years now, the standard of care for antibiotic prophylaxis has been a single 1- to 2-g dose of cefazolin.

Several recent reports, however, have raised the question of whether the prophylactic effect could be enhanced if the spectrum of activity of the antibiotic regimen was broadened to include an agent effective against Ureaplasma species.

Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection; they showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis.¹³ In a follow-up report from the same institution, Tita and co-workers demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.¹⁴ In both of these investigations, the antibiotics were administered after cord clamping.

In a subsequent report, Ward and Duff¹⁵ showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a very low rate of both endometritis and wound infection in a population similar to that studied by Tita et al.^13,14

Very recently, Tita and associates published the results of the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial conducted at 14 US hospitals.¹⁶ This study included 2,013 women undergoing cesarean delivery during labor or after membrane rupture who were randomly assigned to receive intravenous azithromycin 500 mg (n = 1,019) or placebo (n = 994). All women also received standard antibiotic prophylaxis with cefazolin. The primary outcome (a composite of endometritis, wound infection, or other infection within 6 weeks) was significantly lower in the azithromycin group than in the placebo group (6.1% vs 12.0%, P<.001). In addition, there were significant differences between the treatment groups in the rates of endometritis (3.8% in the azithromycin group vs 6.1% in the placebo group, P = .02) as well as in the rates of wound infection (2.4% vs 6.6%, respectively, P<.001). Of additional note, there were no differences between the 2 groups in the composite neonatal outcome of death and serious neonatal complications (14.3% vs 13.6%, P = .63).The investigators concluded that extended-spectrum prophylaxis with adjunctive azithromycin safely reduces infection rates without raising the risk of neonatal adverse outcomes.

What the evidence says

We conclude that all patients, even those having a scheduled cesarean before the onset of labor or ruptured membranes, should receive prophylactic antibiotics in a single dose administered preoperatively rather than after cord clamping (Level I Evidence, Level 1A Recommendation; TABLE). In high-risk populations (eg, women in labor with ruptured membranes who are having an urgent cesarean), for whom the baseline risk of infection is high, administer the combination of cefazolin plus azithromycin in lieu of cefazolin alone (Level I Evidence, Level 1A Recommendation; TABLE).

If the patient has a history of an immediate hypersensitivity reaction to beta-lactam antibiotics, we recommend the combination of clindamycin (900 mg) plus gentamicin (1.5 mg/kg) as a single infusion prior to surgery. We base this recommendation on the need to provide reasonable coverage against a broad range of pathogens. Clindamycin covers gram-positive aerobes, such as staphylococci species and group B streptococci, and anaerobes; gentamicin covers aerobic gram-negative bacilli. A single agent, such as clindamycin or metronidazole, does not provide the broad-based coverage necessary for effective prophylaxis (Level III Evidence, Level 1C Recommendation; TABLE).

If the patient is overweight or obese, should you modify the antibiotic dose?

The prevalence of obesity in the United States continues to increase. One-third of all US reproductive-aged women are obese, and 6% of women are extremely obese.¹⁷ Obesity increases the risk of postcesarean infection 3- to 5- fold.¹⁸ Because both pregnancy and obesity increase the total volume of a drug’s distribution, achieving adequate antibiotic tissue concentrations may be hindered by a dilutional effect. Furthermore, pharmacokinetic studies consistently have shown that the tissue concentration of an antibiotic—which, ideally, should be above the minimum inhibitory concentration (MIC) for common bacteria—determines the susceptibility of those tissues to infection, regardless of whether the serum concentration of the antibiotic is in the therapeutic range.¹⁹

These concerns have led to several recent investigations evaluating different doses of cefazolin for obese patients. Pevzner and colleagues conducted a prospective cohort study of 29 women having a scheduled cesarean delivery.²⁰ The patients were divided into 3 groups: lean (BMI <30 kg m²), obese (BMI 30.0–39.9 kg m²), and extremely obese (BMI >40 kg m²). All women received a 2-g dose of cefazolin 30 to 60 minutes before surgery. Cefazolin concentrations in adipose tissue obtained at the time of skin incision were inversely proportional to maternal BMI (r, −0.67; P<.001). All specimens demonstrated a therapeutic concentration (>1 µg/g) of cefazolin for gram-positive cocci, but 20% of the obese women and 33% of the extremely obese women did not achieve the MIC (>4 µg/g) for gram-negative bacilli (P = .29 and P = .14, respectively). At the time of skin closure, 20% of obese women and 44% of extremely obese women did not have tissue concentrations that exceeded the MIC for gram-negative bacteria.

Swank and associates conducted a prospective cohort study that included 28 women.¹⁸ They demonstrated that, after a 2-g dose of cefazolin, only 20% of the obese women (BMI 30–40 kg m²) and 0% of the extremely obese women (BMI >40 kg m²) achieved an adipose tissue concentration that exceeded the MIC for gram-negative rods (8 µg/mL). However, 100% and 71.4%, respectively, achieved such a tissue concentration after a 3-g dose. When the women were stratified by actual weight, there was a statistically significant difference between those who weighed less than 120 kg and those who weighed more than 120 kg. Seventy-nine percent of the former had a tissue concentration of cefazolin greater than 8 µg/mL compared with 0% of the women who weighed more than 120 kg. Based on these observations, the authors recommended a 3-g dose of cefazolin for women who weigh more than 120 kg.

In a double-blind RCT with 26 obese women (BMI ≥30 kg m²), Young and colleagues demonstrated that, at the time of hysterotomy and fascial closure, significantly higher concentrations of cefazolin were found in the adipose tissue of obese women who received a 3-g dose of antibiotic compared with those who received a 2-g dose.²¹ However, all concentrations of cefazolin were consistently above the MIC of cefazolin for gram-positive cocci (1 µg/g) and gram-negative bacilli (4 µg/g). Further, Maggio and co-workers conducted a double-blind RCT comparing a 2-g dose of cefazolin versus a 3-g dose in 57 obese women (BMI ≥30 kg m²).²² They found no statistically significant difference in the percentage of women who had tissue concentrations of cefazolin greater than the MIC for gram-positive cocci (8 µg/g). All samples were above the MIC of cefazolin for gram-negative bacilli (2 µg/g). Based on these data, these investigators did not recommend increasing the dose of cefazolin from 2 g to 3 g in obese patients.^21,22

The studies discussed above are difficult to compare for 3 reasons. First, each study used a different MIC of cefazolin for both gram-positive and gram-negative bacteria. Second, the authors sampled different maternal tissues or serum at varying times during the cesarean delivery. Third, the studies did not specifically investigate, or were not powered sufficiently to address, the more important clinical outcome of surgical site infection. In a recent historical cohort study, Ward and Duff were unable to show that increasing the dose of cefazolin to 2 g in all women with a BMI <30 kg m² and to 3 g in all women with a BMI >30 kg m² reduced the rate of endometritis and wound infection below the level already achieved with combined prophylaxis with cefazolin (1 g) plus azithromycin (500 mg).¹⁵

Sutton and colleagues recently assessed the pharmacokinetics of azithromycin when used as prophylaxis for cesarean delivery.²³ They studied 30 women who had a scheduled cesarean delivery and who received a 500-mg intravenous dose of azithromycin that was initiated 15, 30, or 60 minutes before the surgical incision and then infused over 1 hour. They obtained maternal plasma samples multiple times during the first 8 hours after surgery. They also obtained samples of amniotic fluid, placenta, myometrium, adipose tissue, and umbilical cord blood intraoperatively. The median concentration of azithromycin in adipose tissue was 102 ng/g, which is below the MIC₅₀ for Ureaplasma species (250 ng/mL). The median concentration in myometrial tissue was 402 ng/g. The concentration in maternal plasma consistently exceeded the MIC₅₀ for Ureaplasma species.

What the evidence says

All women, regardless of weight, who will undergo cesarean delivery should receive a 2-g dose of cefazolin (Level II Evidence, Level 1B Recommendation; TABLE).If azithromycin is used in combination with cefazolin, an intravenous dose of 500 mg appears to provide adequate concentrations in serum and myometrium, but probably not in adipose tissue. More information is needed before we can make a firm recommendation about weight-based dosing of azithromycin.

CASE Resolved

For the 26-year-old obese laboring patient about to undergo cesarean delivery, reasonable steps for prevention of infection include removing the hair at the incision site with clippers or depilatory cream immediately prior to the start of surgery; cleansing the abdomen with a chlorhexidine-alcohol solution; and administering cefazolin (2 g) plus azithromycin (500 mg) preoperatively.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Cesarean delivery is now the most commonly performed major operation in hospitals across the United States. Approximately 30% of the 4 million deliveries that occur each year are by cesarean. Endometritis and wound infection (superficial and deep surgical site infection) are the most common postoperative complications of cesarean delivery. These 2 infections usually can be treated in a straightforward manner with antibiotics or surgical drainage. In some cases, however, they can lead to serious sequelae, such as pelvic abscess, septic pelvic vein thrombophlebitis, and wound dehiscence/evisceration, thereby prolonging the patient’s hospitalization and significantly increasing medical expenses.

Accordingly, in the past 50 years many investigators have proposed various specific measures to reduce the risk of postcesarean infection. In this article, we critically evaluate 2 of these major interventions: methods of skin preparation and administration of prophylactic antibiotics. In part 2 of this series next month, we will review the evidence regarding preoperative bathing with an antiseptic, preoperative vaginal cleansing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

CASE Cesarean delivery required for nonprogressing labor

A 26-year-old obese primigravid woman, body mass index (BMI) 37 kg m², at 40 weeks’ gestation has been in labor for 20 hours. Her membranes have been ruptured for 16 hours. Her cervix is completely effaced and is 7 cm dilated. The fetal head is at −1 cm station. Her cervical examination findings have not changed in 4 hours despite adequate uterine contractility documented by intrauterine pressure catheter. You are now ready to proceed with cesarean delivery, and you want to do everything possible to prevent the patient from developing a postoperative infection.

What are the best practices for postcesarean infection prevention in this patient?

Skin preparation

Adequate preoperative skin preparation is an important first step in preventing post‑ cesarean infection.

How should you prepare the patient’s skin for surgery?

Two issues to address when preparing the abdominal wall for surgery are hair removal and skin cleansing. More than 40 years ago, Cruse and Foord definitively answered the question about hair removal.¹ In a landmark cohort investigation of more than 23,000 patients having many different types of operative procedures, they demonstrated that shaving the hair on the evening before surgery resulted in a higher rate of wound infection than clipping the hair, removing the hair with a depilatory cream just before surgery, or not removing the hair at all.

Three recent investigations have thoughtfully addressed the issue of skin cleansing. Darouiche and colleagues conducted a prospective, randomized, multicenter trial comparing chlorhexidine-alcohol with povidone-iodine for skin preparation before surgery.² Their investigation included 849 patients having many different types of surgical procedures, only a minority of which were in obstetric and gynecologic patients. They demonstrated fewer superficial wound infections in patients in the chlorhexidine-alcohol group (4.2% vs 8.6%, P = .008). Of even greater importance, patients in the chlorhexidine-alcohol group had fewer deep wound infections (1% vs 3%, P = .005).

Ngai and co-workers recently reported the results of a randomized controlled trial (RCT) in which women undergoing nonurgent cesarean delivery had their skin cleansed with povidone-iodine with alcohol, chlorhexidine with alcohol, or the sequential combination of both solutions.³ The overall rate of surgical site infection was just 4.3%. The 3 groups had comparable infection rates and, accordingly, the authors were unable to conclude that one type of skin preparation was superior to the other.

The most informative recent investigation was by Tuuli and colleagues, who evaluated 1,147 patients having cesarean delivery assigned to undergo skin preparation with either chlorhexidine-alcohol or iodine-alcohol.⁴ Unlike the study by Ngai and co-workers, in this study approximately 40% of the patients in each treatment arm had unscheduled, urgent cesarean deliveries.^3,4 Overall, the rate of infection in the chlorhexidine-alcohol group was 4.0% compared with 7.3% in the iodine-alcohol group (relative risk [RR], 0.55; 95% confidence interval [CI], 0.34–0.90, P = .02).

What the evidence says

Based on the evidence cited above, we advise removing hair at the incision site with clippers or depilatory cream just before the start of surgery. The abdomen should then be cleansed with a chlorhexidine-alcohol solution (Level I Evidence, Level 1A Recommendation; TABLE).

Antibiotic prophylaxis

Questions to consider regarding antibiotic prophylaxis for cesarean delivery include appropriateness of treatment, antibiotic(s) selection, timing of administration, dose, and special circumstances.

Should you give the patient prophylactic antibiotics?

Prophylactic antibiotics are justified for surgical procedures whenever 3 major criteria are met⁵:

1. the surgical site is inevitably contaminated with bacteria
2. in the absence of prophylaxis, the frequency of infection at the operative site is unacceptably high
3. operative site infections have the potential to lead to serious, potentially life-threatening sequelae.

Without a doubt, all 3 of these criteria are fulfilled when considering either urgent or nonurgent cesarean delivery. When cesarean delivery follows a long labor complicated by ruptured membranes, multiple internal vaginal examinations, and internal fetal monitoring, the operative site is inevitably contaminated with hundreds of thousands of pathogenic bacteria. Even when cesarean delivery is scheduled to occur before the onset of labor and ruptured membranes, a high concentration of vaginal organisms is introduced into the uterine and pelvic cavities coincident with making the hysterotomy incision.⁶

In the era before prophylactic antibiotics were used routinely, postoperative infection rates in some highly indigent patient populations approached 85%.⁵ Finally, as noted previously, postcesarean endometritis may progress to pelvic abscess formation, septic pelvic vein thrombophlebitis, and septic shock; wound infections may be complicated by dehiscence and evisceration.

When should you administer antibiotics: Before the surgical incision or after cord clamping?

More than 50 years ago, Burke conducted the classic sequence of basic science experiments that forms the foundation for use of prophylactic antibiotics.⁷ Using a guinea pig model, he showed that prophylactic antibiotics exert their most pronounced effect when they are administered before the surgical incision is made and before bacterial contamination occurs. Prophylaxis that is delayed more than 4 hours after the start of surgery will likely be ineffective.

Interestingly, however, when clinicians first began using prophylactic antibiotics for cesarean delivery, some investigators expressed concern about the possible exposure of the neonate to antibiotics just before delivery—specifically, whether this exposure would increase the frequency of evaluations for suspected sepsis or would promote resistance among organisms that would make neonatal sepsis more difficult to treat.

Gordon and colleagues published an important report in 1979 that showed that preoperative administration of ampicillin did not increase the frequency of immediate or delayed neonatal infections.⁸ However, delaying the administration of ampicillin until after the umbilical cord was clamped was just as effective in preventing post‑cesarean endometritis. Subsequently, Cunningham and co-workers showed that preoperative administration of prophylactic antibiotics significantly increased the frequency of sepsis workups in exposed neonates compared with infants with no preoperative antibiotic exposure (28% vs 15%; P<.025).⁹ Based on these 2 reports, obstetricians adopted a policy of delaying antibiotic administration until after the infant’s umbilical cord was clamped.

In 2007, Sullivan and colleagues challenged this long-standing practice.¹⁰ In a carefully designed prospective, randomized, double-blind trial, they showed that patients who received preoperative cefazolin had a significant reduction in the frequency of endometritis compared with women who received the same antibiotic after cord clamping (1% vs 5%; RR, 0.2; 95% CI, 0.2–0.94). The rate of wound infection was lower in the preoperative antibiotic group (3% vs 5%), but this difference did not reach statistical significance. The total infection-related morbidity was significantly reduced in women who received antibiotics preoperatively (4.0% vs 11.5%; RR, 0.4; 95% CI, 0.18–0.87). Additionally, there was no increase in the frequency of proven or suspected neonatal infection in the infants exposed to antibiotics before delivery.

Subsequent to the publication by Sullivan and colleagues, other reports have confirmed that administration of antibiotics prior to surgery is superior to administration after clamping of the umbilical cord.^10–12 Thus, we have come full circle back to Burke’s principle established more than a half century ago.⁷

Which antibiotic(s) should you administer for prophylaxis, and how many doses?

In an earlier review, one of us (PD) examined the evidence regarding choice of antibiotics and number of doses, concluding that a single dose of a first-generation cephalosporin, such as cefazolin, was the preferred regimen.⁵ The single dose was comparable in effectiveness to 2- or 3-dose regimens and to single- or multiple-dose regimens of broader-spectrum agents. For more than 20 years now, the standard of care for antibiotic prophylaxis has been a single 1- to 2-g dose of cefazolin.

Several recent reports, however, have raised the question of whether the prophylactic effect could be enhanced if the spectrum of activity of the antibiotic regimen was broadened to include an agent effective against Ureaplasma species.

Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection; they showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis.¹³ In a follow-up report from the same institution, Tita and co-workers demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.¹⁴ In both of these investigations, the antibiotics were administered after cord clamping.

In a subsequent report, Ward and Duff¹⁵ showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a very low rate of both endometritis and wound infection in a population similar to that studied by Tita et al.^13,14

Very recently, Tita and associates published the results of the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial conducted at 14 US hospitals.¹⁶ This study included 2,013 women undergoing cesarean delivery during labor or after membrane rupture who were randomly assigned to receive intravenous azithromycin 500 mg (n = 1,019) or placebo (n = 994). All women also received standard antibiotic prophylaxis with cefazolin. The primary outcome (a composite of endometritis, wound infection, or other infection within 6 weeks) was significantly lower in the azithromycin group than in the placebo group (6.1% vs 12.0%, P<.001). In addition, there were significant differences between the treatment groups in the rates of endometritis (3.8% in the azithromycin group vs 6.1% in the placebo group, P = .02) as well as in the rates of wound infection (2.4% vs 6.6%, respectively, P<.001). Of additional note, there were no differences between the 2 groups in the composite neonatal outcome of death and serious neonatal complications (14.3% vs 13.6%, P = .63).The investigators concluded that extended-spectrum prophylaxis with adjunctive azithromycin safely reduces infection rates without raising the risk of neonatal adverse outcomes.

What the evidence says

We conclude that all patients, even those having a scheduled cesarean before the onset of labor or ruptured membranes, should receive prophylactic antibiotics in a single dose administered preoperatively rather than after cord clamping (Level I Evidence, Level 1A Recommendation; TABLE). In high-risk populations (eg, women in labor with ruptured membranes who are having an urgent cesarean), for whom the baseline risk of infection is high, administer the combination of cefazolin plus azithromycin in lieu of cefazolin alone (Level I Evidence, Level 1A Recommendation; TABLE).

If the patient has a history of an immediate hypersensitivity reaction to beta-lactam antibiotics, we recommend the combination of clindamycin (900 mg) plus gentamicin (1.5 mg/kg) as a single infusion prior to surgery. We base this recommendation on the need to provide reasonable coverage against a broad range of pathogens. Clindamycin covers gram-positive aerobes, such as staphylococci species and group B streptococci, and anaerobes; gentamicin covers aerobic gram-negative bacilli. A single agent, such as clindamycin or metronidazole, does not provide the broad-based coverage necessary for effective prophylaxis (Level III Evidence, Level 1C Recommendation; TABLE).

If the patient is overweight or obese, should you modify the antibiotic dose?

The prevalence of obesity in the United States continues to increase. One-third of all US reproductive-aged women are obese, and 6% of women are extremely obese.¹⁷ Obesity increases the risk of postcesarean infection 3- to 5- fold.¹⁸ Because both pregnancy and obesity increase the total volume of a drug’s distribution, achieving adequate antibiotic tissue concentrations may be hindered by a dilutional effect. Furthermore, pharmacokinetic studies consistently have shown that the tissue concentration of an antibiotic—which, ideally, should be above the minimum inhibitory concentration (MIC) for common bacteria—determines the susceptibility of those tissues to infection, regardless of whether the serum concentration of the antibiotic is in the therapeutic range.¹⁹

These concerns have led to several recent investigations evaluating different doses of cefazolin for obese patients. Pevzner and colleagues conducted a prospective cohort study of 29 women having a scheduled cesarean delivery.²⁰ The patients were divided into 3 groups: lean (BMI <30 kg m²), obese (BMI 30.0–39.9 kg m²), and extremely obese (BMI >40 kg m²). All women received a 2-g dose of cefazolin 30 to 60 minutes before surgery. Cefazolin concentrations in adipose tissue obtained at the time of skin incision were inversely proportional to maternal BMI (r, −0.67; P<.001). All specimens demonstrated a therapeutic concentration (>1 µg/g) of cefazolin for gram-positive cocci, but 20% of the obese women and 33% of the extremely obese women did not achieve the MIC (>4 µg/g) for gram-negative bacilli (P = .29 and P = .14, respectively). At the time of skin closure, 20% of obese women and 44% of extremely obese women did not have tissue concentrations that exceeded the MIC for gram-negative bacteria.

Swank and associates conducted a prospective cohort study that included 28 women.¹⁸ They demonstrated that, after a 2-g dose of cefazolin, only 20% of the obese women (BMI 30–40 kg m²) and 0% of the extremely obese women (BMI >40 kg m²) achieved an adipose tissue concentration that exceeded the MIC for gram-negative rods (8 µg/mL). However, 100% and 71.4%, respectively, achieved such a tissue concentration after a 3-g dose. When the women were stratified by actual weight, there was a statistically significant difference between those who weighed less than 120 kg and those who weighed more than 120 kg. Seventy-nine percent of the former had a tissue concentration of cefazolin greater than 8 µg/mL compared with 0% of the women who weighed more than 120 kg. Based on these observations, the authors recommended a 3-g dose of cefazolin for women who weigh more than 120 kg.

In a double-blind RCT with 26 obese women (BMI ≥30 kg m²), Young and colleagues demonstrated that, at the time of hysterotomy and fascial closure, significantly higher concentrations of cefazolin were found in the adipose tissue of obese women who received a 3-g dose of antibiotic compared with those who received a 2-g dose.²¹ However, all concentrations of cefazolin were consistently above the MIC of cefazolin for gram-positive cocci (1 µg/g) and gram-negative bacilli (4 µg/g). Further, Maggio and co-workers conducted a double-blind RCT comparing a 2-g dose of cefazolin versus a 3-g dose in 57 obese women (BMI ≥30 kg m²).²² They found no statistically significant difference in the percentage of women who had tissue concentrations of cefazolin greater than the MIC for gram-positive cocci (8 µg/g). All samples were above the MIC of cefazolin for gram-negative bacilli (2 µg/g). Based on these data, these investigators did not recommend increasing the dose of cefazolin from 2 g to 3 g in obese patients.^21,22

The studies discussed above are difficult to compare for 3 reasons. First, each study used a different MIC of cefazolin for both gram-positive and gram-negative bacteria. Second, the authors sampled different maternal tissues or serum at varying times during the cesarean delivery. Third, the studies did not specifically investigate, or were not powered sufficiently to address, the more important clinical outcome of surgical site infection. In a recent historical cohort study, Ward and Duff were unable to show that increasing the dose of cefazolin to 2 g in all women with a BMI <30 kg m² and to 3 g in all women with a BMI >30 kg m² reduced the rate of endometritis and wound infection below the level already achieved with combined prophylaxis with cefazolin (1 g) plus azithromycin (500 mg).¹⁵

Sutton and colleagues recently assessed the pharmacokinetics of azithromycin when used as prophylaxis for cesarean delivery.²³ They studied 30 women who had a scheduled cesarean delivery and who received a 500-mg intravenous dose of azithromycin that was initiated 15, 30, or 60 minutes before the surgical incision and then infused over 1 hour. They obtained maternal plasma samples multiple times during the first 8 hours after surgery. They also obtained samples of amniotic fluid, placenta, myometrium, adipose tissue, and umbilical cord blood intraoperatively. The median concentration of azithromycin in adipose tissue was 102 ng/g, which is below the MIC₅₀ for Ureaplasma species (250 ng/mL). The median concentration in myometrial tissue was 402 ng/g. The concentration in maternal plasma consistently exceeded the MIC₅₀ for Ureaplasma species.

What the evidence says

All women, regardless of weight, who will undergo cesarean delivery should receive a 2-g dose of cefazolin (Level II Evidence, Level 1B Recommendation; TABLE).If azithromycin is used in combination with cefazolin, an intravenous dose of 500 mg appears to provide adequate concentrations in serum and myometrium, but probably not in adipose tissue. More information is needed before we can make a firm recommendation about weight-based dosing of azithromycin.

CASE Resolved

For the 26-year-old obese laboring patient about to undergo cesarean delivery, reasonable steps for prevention of infection include removing the hair at the incision site with clippers or depilatory cream immediately prior to the start of surgery; cleansing the abdomen with a chlorhexidine-alcohol solution; and administering cefazolin (2 g) plus azithromycin (500 mg) preoperatively.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Cesarean delivery is now the most commonly performed major operation in hospitals across the United States. Approximately 30% of the 4 million deliveries that occur each year are by cesarean. Endometritis and wound infection (superficial and deep surgical site infection) are the most common postoperative complications of cesarean delivery. These 2 infections usually can be treated in a straightforward manner with antibiotics or surgical drainage. In some cases, however, they can lead to serious sequelae, such as pelvic abscess, septic pelvic vein thrombophlebitis, and wound dehiscence/evisceration, thereby prolonging the patient’s hospitalization and significantly increasing medical expenses.

Accordingly, in the past 50 years many investigators have proposed various specific measures to reduce the risk of postcesarean infection. In this article, we critically evaluate 2 of these major interventions: methods of skin preparation and administration of prophylactic antibiotics. In part 2 of this series next month, we will review the evidence regarding preoperative bathing with an antiseptic, preoperative vaginal cleansing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

CASE Cesarean delivery required for nonprogressing labor

A 26-year-old obese primigravid woman, body mass index (BMI) 37 kg m², at 40 weeks’ gestation has been in labor for 20 hours. Her membranes have been ruptured for 16 hours. Her cervix is completely effaced and is 7 cm dilated. The fetal head is at −1 cm station. Her cervical examination findings have not changed in 4 hours despite adequate uterine contractility documented by intrauterine pressure catheter. You are now ready to proceed with cesarean delivery, and you want to do everything possible to prevent the patient from developing a postoperative infection.

What are the best practices for postcesarean infection prevention in this patient?

Skin preparation

Adequate preoperative skin preparation is an important first step in preventing post‑ cesarean infection.

How should you prepare the patient’s skin for surgery?

Two issues to address when preparing the abdominal wall for surgery are hair removal and skin cleansing. More than 40 years ago, Cruse and Foord definitively answered the question about hair removal.¹ In a landmark cohort investigation of more than 23,000 patients having many different types of operative procedures, they demonstrated that shaving the hair on the evening before surgery resulted in a higher rate of wound infection than clipping the hair, removing the hair with a depilatory cream just before surgery, or not removing the hair at all.

Three recent investigations have thoughtfully addressed the issue of skin cleansing. Darouiche and colleagues conducted a prospective, randomized, multicenter trial comparing chlorhexidine-alcohol with povidone-iodine for skin preparation before surgery.² Their investigation included 849 patients having many different types of surgical procedures, only a minority of which were in obstetric and gynecologic patients. They demonstrated fewer superficial wound infections in patients in the chlorhexidine-alcohol group (4.2% vs 8.6%, P = .008). Of even greater importance, patients in the chlorhexidine-alcohol group had fewer deep wound infections (1% vs 3%, P = .005).

Ngai and co-workers recently reported the results of a randomized controlled trial (RCT) in which women undergoing nonurgent cesarean delivery had their skin cleansed with povidone-iodine with alcohol, chlorhexidine with alcohol, or the sequential combination of both solutions.³ The overall rate of surgical site infection was just 4.3%. The 3 groups had comparable infection rates and, accordingly, the authors were unable to conclude that one type of skin preparation was superior to the other.

The most informative recent investigation was by Tuuli and colleagues, who evaluated 1,147 patients having cesarean delivery assigned to undergo skin preparation with either chlorhexidine-alcohol or iodine-alcohol.⁴ Unlike the study by Ngai and co-workers, in this study approximately 40% of the patients in each treatment arm had unscheduled, urgent cesarean deliveries.^3,4 Overall, the rate of infection in the chlorhexidine-alcohol group was 4.0% compared with 7.3% in the iodine-alcohol group (relative risk [RR], 0.55; 95% confidence interval [CI], 0.34–0.90, P = .02).

What the evidence says

Based on the evidence cited above, we advise removing hair at the incision site with clippers or depilatory cream just before the start of surgery. The abdomen should then be cleansed with a chlorhexidine-alcohol solution (Level I Evidence, Level 1A Recommendation; TABLE).

Antibiotic prophylaxis

Questions to consider regarding antibiotic prophylaxis for cesarean delivery include appropriateness of treatment, antibiotic(s) selection, timing of administration, dose, and special circumstances.

Should you give the patient prophylactic antibiotics?

Prophylactic antibiotics are justified for surgical procedures whenever 3 major criteria are met⁵:

1. the surgical site is inevitably contaminated with bacteria
2. in the absence of prophylaxis, the frequency of infection at the operative site is unacceptably high
3. operative site infections have the potential to lead to serious, potentially life-threatening sequelae.

Without a doubt, all 3 of these criteria are fulfilled when considering either urgent or nonurgent cesarean delivery. When cesarean delivery follows a long labor complicated by ruptured membranes, multiple internal vaginal examinations, and internal fetal monitoring, the operative site is inevitably contaminated with hundreds of thousands of pathogenic bacteria. Even when cesarean delivery is scheduled to occur before the onset of labor and ruptured membranes, a high concentration of vaginal organisms is introduced into the uterine and pelvic cavities coincident with making the hysterotomy incision.⁶

In the era before prophylactic antibiotics were used routinely, postoperative infection rates in some highly indigent patient populations approached 85%.⁵ Finally, as noted previously, postcesarean endometritis may progress to pelvic abscess formation, septic pelvic vein thrombophlebitis, and septic shock; wound infections may be complicated by dehiscence and evisceration.

When should you administer antibiotics: Before the surgical incision or after cord clamping?

More than 50 years ago, Burke conducted the classic sequence of basic science experiments that forms the foundation for use of prophylactic antibiotics.⁷ Using a guinea pig model, he showed that prophylactic antibiotics exert their most pronounced effect when they are administered before the surgical incision is made and before bacterial contamination occurs. Prophylaxis that is delayed more than 4 hours after the start of surgery will likely be ineffective.

Interestingly, however, when clinicians first began using prophylactic antibiotics for cesarean delivery, some investigators expressed concern about the possible exposure of the neonate to antibiotics just before delivery—specifically, whether this exposure would increase the frequency of evaluations for suspected sepsis or would promote resistance among organisms that would make neonatal sepsis more difficult to treat.

Gordon and colleagues published an important report in 1979 that showed that preoperative administration of ampicillin did not increase the frequency of immediate or delayed neonatal infections.⁸ However, delaying the administration of ampicillin until after the umbilical cord was clamped was just as effective in preventing post‑cesarean endometritis. Subsequently, Cunningham and co-workers showed that preoperative administration of prophylactic antibiotics significantly increased the frequency of sepsis workups in exposed neonates compared with infants with no preoperative antibiotic exposure (28% vs 15%; P<.025).⁹ Based on these 2 reports, obstetricians adopted a policy of delaying antibiotic administration until after the infant’s umbilical cord was clamped.

In 2007, Sullivan and colleagues challenged this long-standing practice.¹⁰ In a carefully designed prospective, randomized, double-blind trial, they showed that patients who received preoperative cefazolin had a significant reduction in the frequency of endometritis compared with women who received the same antibiotic after cord clamping (1% vs 5%; RR, 0.2; 95% CI, 0.2–0.94). The rate of wound infection was lower in the preoperative antibiotic group (3% vs 5%), but this difference did not reach statistical significance. The total infection-related morbidity was significantly reduced in women who received antibiotics preoperatively (4.0% vs 11.5%; RR, 0.4; 95% CI, 0.18–0.87). Additionally, there was no increase in the frequency of proven or suspected neonatal infection in the infants exposed to antibiotics before delivery.

Subsequent to the publication by Sullivan and colleagues, other reports have confirmed that administration of antibiotics prior to surgery is superior to administration after clamping of the umbilical cord.^10–12 Thus, we have come full circle back to Burke’s principle established more than a half century ago.⁷

Which antibiotic(s) should you administer for prophylaxis, and how many doses?

In an earlier review, one of us (PD) examined the evidence regarding choice of antibiotics and number of doses, concluding that a single dose of a first-generation cephalosporin, such as cefazolin, was the preferred regimen.⁵ The single dose was comparable in effectiveness to 2- or 3-dose regimens and to single- or multiple-dose regimens of broader-spectrum agents. For more than 20 years now, the standard of care for antibiotic prophylaxis has been a single 1- to 2-g dose of cefazolin.

Several recent reports, however, have raised the question of whether the prophylactic effect could be enhanced if the spectrum of activity of the antibiotic regimen was broadened to include an agent effective against Ureaplasma species.

Tita and colleagues evaluated an indigent patient population with an inherently high rate of postoperative infection; they showed that adding azithromycin 500 mg to cefazolin significantly reduced the rate of postcesarean endometritis.¹³ In a follow-up report from the same institution, Tita and co-workers demonstrated that adding azithromycin also significantly reduced the frequency of wound infection.¹⁴ In both of these investigations, the antibiotics were administered after cord clamping.

In a subsequent report, Ward and Duff¹⁵ showed that the combination of azithromycin plus cefazolin administered preoperatively resulted in a very low rate of both endometritis and wound infection in a population similar to that studied by Tita et al.^13,14

Very recently, Tita and associates published the results of the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial conducted at 14 US hospitals.¹⁶ This study included 2,013 women undergoing cesarean delivery during labor or after membrane rupture who were randomly assigned to receive intravenous azithromycin 500 mg (n = 1,019) or placebo (n = 994). All women also received standard antibiotic prophylaxis with cefazolin. The primary outcome (a composite of endometritis, wound infection, or other infection within 6 weeks) was significantly lower in the azithromycin group than in the placebo group (6.1% vs 12.0%, P<.001). In addition, there were significant differences between the treatment groups in the rates of endometritis (3.8% in the azithromycin group vs 6.1% in the placebo group, P = .02) as well as in the rates of wound infection (2.4% vs 6.6%, respectively, P<.001). Of additional note, there were no differences between the 2 groups in the composite neonatal outcome of death and serious neonatal complications (14.3% vs 13.6%, P = .63).The investigators concluded that extended-spectrum prophylaxis with adjunctive azithromycin safely reduces infection rates without raising the risk of neonatal adverse outcomes.

What the evidence says

We conclude that all patients, even those having a scheduled cesarean before the onset of labor or ruptured membranes, should receive prophylactic antibiotics in a single dose administered preoperatively rather than after cord clamping (Level I Evidence, Level 1A Recommendation; TABLE). In high-risk populations (eg, women in labor with ruptured membranes who are having an urgent cesarean), for whom the baseline risk of infection is high, administer the combination of cefazolin plus azithromycin in lieu of cefazolin alone (Level I Evidence, Level 1A Recommendation; TABLE).

If the patient has a history of an immediate hypersensitivity reaction to beta-lactam antibiotics, we recommend the combination of clindamycin (900 mg) plus gentamicin (1.5 mg/kg) as a single infusion prior to surgery. We base this recommendation on the need to provide reasonable coverage against a broad range of pathogens. Clindamycin covers gram-positive aerobes, such as staphylococci species and group B streptococci, and anaerobes; gentamicin covers aerobic gram-negative bacilli. A single agent, such as clindamycin or metronidazole, does not provide the broad-based coverage necessary for effective prophylaxis (Level III Evidence, Level 1C Recommendation; TABLE).

If the patient is overweight or obese, should you modify the antibiotic dose?

The prevalence of obesity in the United States continues to increase. One-third of all US reproductive-aged women are obese, and 6% of women are extremely obese.¹⁷ Obesity increases the risk of postcesarean infection 3- to 5- fold.¹⁸ Because both pregnancy and obesity increase the total volume of a drug’s distribution, achieving adequate antibiotic tissue concentrations may be hindered by a dilutional effect. Furthermore, pharmacokinetic studies consistently have shown that the tissue concentration of an antibiotic—which, ideally, should be above the minimum inhibitory concentration (MIC) for common bacteria—determines the susceptibility of those tissues to infection, regardless of whether the serum concentration of the antibiotic is in the therapeutic range.¹⁹

These concerns have led to several recent investigations evaluating different doses of cefazolin for obese patients. Pevzner and colleagues conducted a prospective cohort study of 29 women having a scheduled cesarean delivery.²⁰ The patients were divided into 3 groups: lean (BMI <30 kg m²), obese (BMI 30.0–39.9 kg m²), and extremely obese (BMI >40 kg m²). All women received a 2-g dose of cefazolin 30 to 60 minutes before surgery. Cefazolin concentrations in adipose tissue obtained at the time of skin incision were inversely proportional to maternal BMI (r, −0.67; P<.001). All specimens demonstrated a therapeutic concentration (>1 µg/g) of cefazolin for gram-positive cocci, but 20% of the obese women and 33% of the extremely obese women did not achieve the MIC (>4 µg/g) for gram-negative bacilli (P = .29 and P = .14, respectively). At the time of skin closure, 20% of obese women and 44% of extremely obese women did not have tissue concentrations that exceeded the MIC for gram-negative bacteria.

Swank and associates conducted a prospective cohort study that included 28 women.¹⁸ They demonstrated that, after a 2-g dose of cefazolin, only 20% of the obese women (BMI 30–40 kg m²) and 0% of the extremely obese women (BMI >40 kg m²) achieved an adipose tissue concentration that exceeded the MIC for gram-negative rods (8 µg/mL). However, 100% and 71.4%, respectively, achieved such a tissue concentration after a 3-g dose. When the women were stratified by actual weight, there was a statistically significant difference between those who weighed less than 120 kg and those who weighed more than 120 kg. Seventy-nine percent of the former had a tissue concentration of cefazolin greater than 8 µg/mL compared with 0% of the women who weighed more than 120 kg. Based on these observations, the authors recommended a 3-g dose of cefazolin for women who weigh more than 120 kg.

In a double-blind RCT with 26 obese women (BMI ≥30 kg m²), Young and colleagues demonstrated that, at the time of hysterotomy and fascial closure, significantly higher concentrations of cefazolin were found in the adipose tissue of obese women who received a 3-g dose of antibiotic compared with those who received a 2-g dose.²¹ However, all concentrations of cefazolin were consistently above the MIC of cefazolin for gram-positive cocci (1 µg/g) and gram-negative bacilli (4 µg/g). Further, Maggio and co-workers conducted a double-blind RCT comparing a 2-g dose of cefazolin versus a 3-g dose in 57 obese women (BMI ≥30 kg m²).²² They found no statistically significant difference in the percentage of women who had tissue concentrations of cefazolin greater than the MIC for gram-positive cocci (8 µg/g). All samples were above the MIC of cefazolin for gram-negative bacilli (2 µg/g). Based on these data, these investigators did not recommend increasing the dose of cefazolin from 2 g to 3 g in obese patients.^21,22

The studies discussed above are difficult to compare for 3 reasons. First, each study used a different MIC of cefazolin for both gram-positive and gram-negative bacteria. Second, the authors sampled different maternal tissues or serum at varying times during the cesarean delivery. Third, the studies did not specifically investigate, or were not powered sufficiently to address, the more important clinical outcome of surgical site infection. In a recent historical cohort study, Ward and Duff were unable to show that increasing the dose of cefazolin to 2 g in all women with a BMI <30 kg m² and to 3 g in all women with a BMI >30 kg m² reduced the rate of endometritis and wound infection below the level already achieved with combined prophylaxis with cefazolin (1 g) plus azithromycin (500 mg).¹⁵

Sutton and colleagues recently assessed the pharmacokinetics of azithromycin when used as prophylaxis for cesarean delivery.²³ They studied 30 women who had a scheduled cesarean delivery and who received a 500-mg intravenous dose of azithromycin that was initiated 15, 30, or 60 minutes before the surgical incision and then infused over 1 hour. They obtained maternal plasma samples multiple times during the first 8 hours after surgery. They also obtained samples of amniotic fluid, placenta, myometrium, adipose tissue, and umbilical cord blood intraoperatively. The median concentration of azithromycin in adipose tissue was 102 ng/g, which is below the MIC₅₀ for Ureaplasma species (250 ng/mL). The median concentration in myometrial tissue was 402 ng/g. The concentration in maternal plasma consistently exceeded the MIC₅₀ for Ureaplasma species.

What the evidence says

All women, regardless of weight, who will undergo cesarean delivery should receive a 2-g dose of cefazolin (Level II Evidence, Level 1B Recommendation; TABLE).If azithromycin is used in combination with cefazolin, an intravenous dose of 500 mg appears to provide adequate concentrations in serum and myometrium, but probably not in adipose tissue. More information is needed before we can make a firm recommendation about weight-based dosing of azithromycin.

CASE Resolved

For the 26-year-old obese laboring patient about to undergo cesarean delivery, reasonable steps for prevention of infection include removing the hair at the incision site with clippers or depilatory cream immediately prior to the start of surgery; cleansing the abdomen with a chlorhexidine-alcohol solution; and administering cefazolin (2 g) plus azithromycin (500 mg) preoperatively.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Are you in search of materials that can reinforce what you’ve told patients about how to get a good night’s sleep? Then download this handout, which includes 8 tips that cover the wake-promoting agents to avoid, the proper environment in which to go to sleep, and the dos and don’ts of before-bedtime activities. It also discusses when patients should seek professional help for a possible sleep disorder. This PDF from Neurology Reviews is available at: http://www.mdedge.com/neurologyreviews/article/115138/sleep-medicine/tips-sleep-hygiene/pdf.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Can the public health threat posed by the hepatitis C virus (HCV) be eliminated by 2030? Researchers in Italy say it can be done. Important elements of success will include the use of oral direct-acting antivirals and a global commitment to prevention. Earlier this year, the World Health Organization (WHO) announced plans to wipe out HCV worldwide by 2030 using the time between now and 2021 to reduce the number of annual new infections by 70%, and to slash the fatality rate by 60%. Find out what success in meeting the WHO challenge will hinge on by going to Family Practice News: http://www.mdedge.com/familypracticenews/article/114780/gastroenterology/direct-acting-antivirals-one-several-keys-hcv.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled pilot studies. But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend upon the skills and experience of the individual specialists who deliver the care. To learn more about these 2 studies, go to Family Practice News: http://www.mdedge.com/familypracticenews/article/115737/cardiology/palliative-care-boosts-heart-failure-patient-outcomes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Early age at menopause was associated with the incidence of type 2 diabetes, independent of obesity and a host of other potentially confounding factors, according to a prospect cohort study. “This association is independent of potential intermediate risk factors: obesity, insulin, glucose, inflammation, but also  estradiol and other endogenous sex hormone levels,” said Taulant Muka, MD, PhD, a postdoctoral fellow at Erasmus Medical College, Rotterdam, the Netherlands. Among the 3210 participants in the study, 319 incident cases were identified over the median 10.9-year follow-up period, with a relative risk for incident diabetes of 2.29 for women undergoing menopause before age 40, and 1.49 for those experiencing menopause between the ages of 40 and 44. Read more at Family Practice News: http://www.mdedge.com/familypracticenews/article/115648/diabetes/early-menopause-risk-factor-type-2-diabetes.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.

Patients with chronic obstructive pulmonary disease (COPD) who also suffer from depression are less likely to take their COPD maintenance medications, according to a review of Medicare claims by researchers at the University of Maryland, Baltimore. Researchers found that patients with newly diagnosed depression were about 7% less likely to have good adherence to their medications. For more on this research, see the article in CHEST Physician, available at http://www.mdedge.com/chestphysician/article/115659/depression/depression-drops-copd-medication-adherence.