Clinical Review

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CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.

Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.

It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.

The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.

In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A_1c, and systolic blood pressure.

Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.

"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.

Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.

The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.

The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m², and were 29-30 years old. They were provided with all the meals.

During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.

However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)

Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).

Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).

Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.

Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

On Twitter @NaseemSMiller

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.

Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.

It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.

The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.

In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A_1c, and systolic blood pressure.

Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.

"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.

Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.

The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.

The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m², and were 29-30 years old. They were provided with all the meals.

During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.

However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)

Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).

Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).

Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.

Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

On Twitter @NaseemSMiller

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.

Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.

It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.

The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.

In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A_1c, and systolic blood pressure.

Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.

"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.

Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.

The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.

The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m², and were 29-30 years old. They were provided with all the meals.

During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.

However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)

Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).

Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).

Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.

Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

On Twitter @NaseemSMiller

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.