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Practice Pearls for Titrating Antiglycemics
Over 100 Unnecessary Psychiatric Admissions
A Model for Mental Health Care
Sexual dysfunction: The challenge of treatment
Case reports of patients helped by therapy,
Say you see 100 adult patients this week. How many have a sexual dysfunction? 10? 20? Would you believe 43? In a National Health and Social Life Survey1 of 1,749 women and 1,410 men aged 18 to 59 years, 43% of women and 31% of men reported sexual dysfunction. Rates that high make sexual dysfunction an important public health concern—one that is highly associated with impaired well-being and negative experiences in sexual relationships.
Similar findings marked a study2 of general practice patients in Britain: 41% of 979 women and 34% of 789 men reported sexual dysfunction. Although 52% wanted professional help, only 10% had received it.
As primary care providers, Ob/Gyns must identify common problems, treat those within our expertise, and refer the others. In all likelihood, we are the first physicians women see about a sexual problem. For these reasons—and because dysfunction is so common—it is appropriate that we screen for and address female sexual dysfunction.
This article presents a medical model of management and tells how to take a sexual history, formulate a differential diagnosis, manage common sexual problems, and identify indications for referral.
The medical model
According to the medical model, a patient presents with a problem, which is investigated by history and physical examination. A differential diagnosis is formulated, and appropriate laboratory tests or other evaluations are conducted. The patient’s problem is compared to a normal physiologic process to determine pathophysiology. Diagnosis and therapy follow.
The medical model for sexual dysfunction is the same as that for any disease, such as asthma, in which normal breathing is interrupted. In the sexual response cycle, physiologic changes can be measured and specifically described, as Masters and Johnson explained in 1966 in Human Sexual Response (FIGURE 1). Any barriers that interrupt this progression “block” the normal response cycle, resulting in sexual dysfunction. We aim to identify and remove or get around any barriers.
FIGURE 1 Use the sexual response cycle in dialogue with the patient
Most patients with sexual dysfunction can identify the phase in the Masters and Johnson sexual response cycle where normal progression is interrupted. Using a sketch of this cycle helps patients understand and articulate their problem.
The sexual response cycle
Desire initiates the cycle, followed by the excitement phase, during which breathing rate and pulse increase, blood flow shifts away from muscles and into the skin and pelvic organs, and there is an associated expansion, lengthening, and lubrication of the vagina. A plateau follows, during which there is no further increase in signs such as increased pulse rate. Orgasm is the first point in the response cycle that is different in men and women. Men have an obligatory resolution phase and return to baseline state; women can return to the plateau state and then have another orgasm. The resolution phase lengthens in duration in both sexes with increasing age.
The sexual response cycle is innate, like any physiologic process. It cannot be taught or learned, and is not under voluntary control. It is critical that patients understand that the sexual response cycle is a natural function that everyone has—just as everyone has innate capacity to breathe. Patients do not learn it, any more than they have to learn respiration.
Sexual behavior, however, is learned, and sexual dysfunctions are exhibited by behavior. Sex therapy is a learning process, the aim of which is to change the behavior. Sexual dysfunctions have both cognitive and physical components; although response is physiologic, it can be altered by emotion, as can respiration.
The relationship is the patient. Sexual dysfunction occurs within a relationship, and the relationship needs and stands to benefit from therapy.
Reassuring anxious, angry patients
Approach is critical, and must reflect an understanding that sexual dysfunction is real. Many patients have been told that the problem is “all in their head” or that they are deliberately acting dysfunctionally.
Confrontation and support are useful communication tools. Confrontation means identifying behaviors and beliefs and how beliefs influence behaviors. Support means conveying to the patient that you understand that she is in distress and that it couldn’t have happened any other way for her.
A “therapeutic mirror” technique can show the patient her beliefs, attitudes, and behaviors. The therapist repeats the the patient’s beliefs and behaviors until the patient states that they are an accurate reflection, or tells the therapist what is inaccurate.
Assure the patient that anxiety is to be expected, and that her probelm is common and treatable. These patients believe they have thought of everything, and nothing has worked. Just reassuring them may help.
Anger must also be acknowledged—and these patients are angry. Their anger may be directed at their partner, a former physician, or you. You may elicit a surprising outburst of pent-up anger when you ask what seems to be a neutral question.
The patient always has an internal theory and everything you say is filtered through this theory. If there is a dichotomy, it must be addressed before you can proceed successfully. Usually, you can simply ask, “What do you think is the cause?” Often she will tell you. If she is uncertain, you might say, “I realize you don’t really know. What do you think it might be? What are you afraid it might be?”
You have to ask
Many patients do not express the fact that their chief complaint is sexual dysfunction. (See How to take a sexual history,).
In many cases, sexual dysfunction may be suggested in the investigation of another complaint such as infertility, pelvic pain with no particular pattern, malaise, or depression. With these complaints, it is important to pursue a sexual history. Determine any associated or causal condition and look for associated dysfunction.
The sexual history is like a history for any disease, in that you begin with the present illness. The differential diagnosis begins with a determination of where in the cycle the dysfunction occurs.
- One way to start is to describe the normal human sexual response. I find it best to sketch out the response cycle (FIGURE 1 ) on a piece of paper and ask, “Is this what happens to you?” Most patients understand and can tell where in the cycle the interruption occurs.
- 3 questions in a review of systems disclose nearly all sexual dysfunction:
- “How often do you have intercourse?” The only “right” answer is “as often as I want to.” If the patient is not having intercourse, is it by choice or involuntary?
- “Do you have pain with intercourse?”
- “How often do you have orgasm?” Most answer “hardly ever” or “most of the time.”
- Allegories like these are useful:
- Elements and example questions
Physical examination
Ageneral physical examination with pelvic examination should always be performed. If the patient complains of pain, the site of pain should be determined. A wet prep is useful to exclude vaginitis. A patient may have dyspareunia from vaginitis even if there are no obvious physical signs.
The most common dysfunctions: Desire phase disorders
Female sexual arousal disorder is either low libido or inhibited sexual desire. In both cases the patient is likely to report that she has no desire. But if you ask what happens when her partner wants to have intercourse, a patient with low libido describes low interest behavior, and a patient with inhibited desire describes aversion behavior.
Patients with low libido sometimes report that their orgasms are less intense, or that they do not become excited. Women on estrogen replacement after oophorectomy may have low libido related to decreased androgen.
Depression is by far the most common cause. Other contributors: chronic disease, hypoestrogenic states, hyperprolactinemia, and breastfeeding.
Inhibited sexual desire, which is a result of pain or other dysfunction, is far more common than low libido. Careful history usually reveals aversion behavior. They avoid going to bed at the same time as their partner, or develop other behaviors that preclude intercourse.
Women with inhibited desire have a conditioned negative response. In studies, these patients exhibit normal objective measures of vaginal vasocongestion in response to sexual stimuli, but self-reported subjective measures of arousal do not correlate.
They report that they simply have no desire, but the cause of their avoidance is negative conditioning. Here’s where the therapist supports, but also confronts their belief system, and attempts to help them understand that they have a normal desire for intercourse. The therapist may ask the patient to consider whether she ever has sexual dreams, reads romance novels, or fantasizes, to show that these phenomena demonstrate normal desire.
The role of testosterone in inhibited sexual desire
Measuring serum testosterone isn’t helpful. It is my belief that inhibited desire is most often related to other factors. Counseling should be the first-line therapy. Drug therapy without counseling is less likely to be effective than therapy that includes counseling.
Normal serum testosterone levels are 20 to 80 ng/dL in reproductive-age women, who produce 0.2 to 0.3 mg/day of testosterone. Levels increase 10% to 20% at midcycle. Testosterone falls 40% to 60% at natural menopause and by similar amounts with use of oral contraceptive pills, and by 80% with surgical menopause.
Testosterone levels have little correlation with sexual desire in cycling women or women on oral contraceptives.3 Most studies have found no correlation between testosterone levels and sexual function in perimenopausal or naturally menopausal women.4,5 Other studies have failed to show a difference in testosterone levels between women with arousal disorders and normal controls.6
Testosterone therapy may be effective in surgically menopausal women with low libido. Shifrin and colleagues7 randomized 75 surgically menopausal women being treated with conjugated equine estrogens to placebo or transdermal testosterone, 150 or 300 μg per day, in a crossover trial. They reported, “Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm. At the higher dose, the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased 2 to 3 times from base line.”
Testosterone is not yet approved for female sexual dysfunction, but a transdermal testosterone is being proposed for women with hypoactive sexual desire disorder who have had bilateral oophorectomy.
Excitement phase disorders
These disorders are caused by pain with intercourse. What the patient says about the site of pain and when she began experiencing pain help form the differential diagnosis.
Dyspareunia can be due to physiological causes such as obstetric laceration, endometriosis, pelvic inflammatory disease, vaginitis, vulvar disease, and vestibulitis. Interstitial cystitis and inflammatory bowel disease can cause dyspareunia, as can a simple fungal infection. Ask how long the pain continues after intercourse. If internal pain continues for hours, it is highly suggestive of intra-abdominal pathology.
Any cause of pain can begin a self-perpetuating conditioned response cycle that leads to inhibited desire. Anything that causes pain elicits aversion behavior, even without the stimulus. With conditioned response comes failure of excitement, which is where the sexual response cycle is interrupted.
When pain interrupts the sexual response cycle, the patient may still have intercourse, but without excitement, lubrication, and vaginal expansion—and with consequent further pain. Further attempts at intercourse then cause more pain, leading to the cycle of dyspareunia. Pain may be introital, vaginal, or deep. The pain may be reproduced on exam.
Treatment is twofold. Identify and correct source of pain first. Then the patient must learn that intercourse is not painful but pleasurable. Sensate focus exercises are often useful.
Vaginismus, an involuntary spasm of muscles around the outer third of the vagina, may make penetration impossible. Vaginismus can be caused by pain, severe negative parental attitudes about sex, or extreme religious orthodoxy. These patients may be hyper-feminine. They often have bizarre mental images of their genitals. They usually have a partner who supports the dysfunction.
Treatment involves dilators, but the purpose is not to dilate the vagina. It is to learn to have something in the vagina and to confront fears and feelings rregarding penetration. Treatment must involve the partner.
Plateau and orgasmic dysfunctions
Delayed or absent orgasm is common. It may be primary or secondary, global, situational, or random. Etiologies include performance anxiety, fear of loss of control, and boredom. Patients with orgasmic dysfunction often develop “spectator” behavior. When they reach plateau they begin to wonder if they will have orgasm. They begin to watch to see what is happening rather than participating. As a result, they lose excitement and do not have orgasm. They become increasingly anxious about whether they will achieve orgasm. Anxiety interferes with the sexual response cycle, and orgasm does not occur.
Treatment involves sensate focus. By learning to focus on the sensations that occur, the patient learns not to focus on anxiety or assume the spectator frame of mind.
When the patient reports “no desire” but describes aversion behavior, inhibited desire is typically a conditioned response to the experience of pain during intercourse. Pain—from any cause—during sexual intercourse, can begin a conditioned response that requires recognition, treatment, and, often, counseling to eliminate.
How can the Ob/Gyn help? Therapy model: P LI SS IT
Permission giving. Many sexual problems can be solved by permission-giving. A patient might be bored and wish to try new positions; permission may be all that is required.
LImited information. A patient might have orgasm with masturbation but not penetration. Explaining to the patient that 50% of women do not have orgasm with penetration alone and that it is OK to combine manual stimulation with penetration may be all that is needed.
Specific Suggestions. A patient on decongestants may note decreased lubrication. Use of a lubricant might help. A patient with the “busy mother syndrome” may need specific instruction to make time for a relationship.
Intensive Therapy. Patients with childhood sexual abuse probably require intensive therapy. Vaginismus may require intensive therapy.
- 47 yo woman married to a physician for 23 years. No intercourse for 20 years, and no communication outside the bedroom about their sexual relationship. She is very angry. Her last gynecologist said she should get a good divorce attorney.
- 50 yo woman complains of no desire and lack of lubrication. Married for 20 years. She has insulin-dependent diabetes. Her last gynecologist told her to use KY jelly. She became very angry saying KY jelly was “too clinical.”
- 30 yo woman referred for severe dyspareunia and pelvic pain. Prior workup including IVP, ultrasound, and laparoscopy found no organic cause. She describes severe inhibited sexual desire and had not attempted intercourse in 4 months.
- 34 yo married woman complains of anorgasmia since starting fluoxetine (Prozac) 2 years ago. She had orgasm prior to that. After changing to bupropion (Wellbutrin), her anorgasmia continued.
Summary
Many gynecologists are concerned about lack of time or skills to deal with sexual problems. However, it often takes less time to deal with the problem than to ignore it. If a problem is uncovered during a scheduled brief visit, the patient can be given a follow-up appointment to ensure adequate time.
Dr. Carey is a member of the Female Sexual Dysfunction CME Steering Committee, sponsored by the University of Medicine and Dentistry of New Jersey, through a grant from Proctor and Gamble.
1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281:537-544.
2. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract. 1998;15:519-524.
3. Bancroft J, Sherwin BB, Alexander GM, Davidson DW, Walker A. Oral contraceptives, androgens, and the sexuality of young women: II. The role of androgens. Arch Sex Behav. 1991;20:121-135.
4. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones and the menopausal transition. Maturitas. 1997;26:83-93.
5. Kirchengast S, Hartmann B, Gruber D, Huber J. Decreased sexual interest and its relationship to body build in postmenopausal women. Maturitas. 1996;23:63-71.
6. Schreiner-Engel P, Schiavi RC, White D, Ghizzani A. Low sexual desire in women: the role of reproductive hormones. Horm Behav. 1989;23:221-234.
7. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.
Case reports of patients helped by therapy,
Say you see 100 adult patients this week. How many have a sexual dysfunction? 10? 20? Would you believe 43? In a National Health and Social Life Survey1 of 1,749 women and 1,410 men aged 18 to 59 years, 43% of women and 31% of men reported sexual dysfunction. Rates that high make sexual dysfunction an important public health concern—one that is highly associated with impaired well-being and negative experiences in sexual relationships.
Similar findings marked a study2 of general practice patients in Britain: 41% of 979 women and 34% of 789 men reported sexual dysfunction. Although 52% wanted professional help, only 10% had received it.
As primary care providers, Ob/Gyns must identify common problems, treat those within our expertise, and refer the others. In all likelihood, we are the first physicians women see about a sexual problem. For these reasons—and because dysfunction is so common—it is appropriate that we screen for and address female sexual dysfunction.
This article presents a medical model of management and tells how to take a sexual history, formulate a differential diagnosis, manage common sexual problems, and identify indications for referral.
The medical model
According to the medical model, a patient presents with a problem, which is investigated by history and physical examination. A differential diagnosis is formulated, and appropriate laboratory tests or other evaluations are conducted. The patient’s problem is compared to a normal physiologic process to determine pathophysiology. Diagnosis and therapy follow.
The medical model for sexual dysfunction is the same as that for any disease, such as asthma, in which normal breathing is interrupted. In the sexual response cycle, physiologic changes can be measured and specifically described, as Masters and Johnson explained in 1966 in Human Sexual Response (FIGURE 1). Any barriers that interrupt this progression “block” the normal response cycle, resulting in sexual dysfunction. We aim to identify and remove or get around any barriers.
FIGURE 1 Use the sexual response cycle in dialogue with the patient
Most patients with sexual dysfunction can identify the phase in the Masters and Johnson sexual response cycle where normal progression is interrupted. Using a sketch of this cycle helps patients understand and articulate their problem.
The sexual response cycle
Desire initiates the cycle, followed by the excitement phase, during which breathing rate and pulse increase, blood flow shifts away from muscles and into the skin and pelvic organs, and there is an associated expansion, lengthening, and lubrication of the vagina. A plateau follows, during which there is no further increase in signs such as increased pulse rate. Orgasm is the first point in the response cycle that is different in men and women. Men have an obligatory resolution phase and return to baseline state; women can return to the plateau state and then have another orgasm. The resolution phase lengthens in duration in both sexes with increasing age.
The sexual response cycle is innate, like any physiologic process. It cannot be taught or learned, and is not under voluntary control. It is critical that patients understand that the sexual response cycle is a natural function that everyone has—just as everyone has innate capacity to breathe. Patients do not learn it, any more than they have to learn respiration.
Sexual behavior, however, is learned, and sexual dysfunctions are exhibited by behavior. Sex therapy is a learning process, the aim of which is to change the behavior. Sexual dysfunctions have both cognitive and physical components; although response is physiologic, it can be altered by emotion, as can respiration.
The relationship is the patient. Sexual dysfunction occurs within a relationship, and the relationship needs and stands to benefit from therapy.
Reassuring anxious, angry patients
Approach is critical, and must reflect an understanding that sexual dysfunction is real. Many patients have been told that the problem is “all in their head” or that they are deliberately acting dysfunctionally.
Confrontation and support are useful communication tools. Confrontation means identifying behaviors and beliefs and how beliefs influence behaviors. Support means conveying to the patient that you understand that she is in distress and that it couldn’t have happened any other way for her.
A “therapeutic mirror” technique can show the patient her beliefs, attitudes, and behaviors. The therapist repeats the the patient’s beliefs and behaviors until the patient states that they are an accurate reflection, or tells the therapist what is inaccurate.
Assure the patient that anxiety is to be expected, and that her probelm is common and treatable. These patients believe they have thought of everything, and nothing has worked. Just reassuring them may help.
Anger must also be acknowledged—and these patients are angry. Their anger may be directed at their partner, a former physician, or you. You may elicit a surprising outburst of pent-up anger when you ask what seems to be a neutral question.
The patient always has an internal theory and everything you say is filtered through this theory. If there is a dichotomy, it must be addressed before you can proceed successfully. Usually, you can simply ask, “What do you think is the cause?” Often she will tell you. If she is uncertain, you might say, “I realize you don’t really know. What do you think it might be? What are you afraid it might be?”
You have to ask
Many patients do not express the fact that their chief complaint is sexual dysfunction. (See How to take a sexual history,).
In many cases, sexual dysfunction may be suggested in the investigation of another complaint such as infertility, pelvic pain with no particular pattern, malaise, or depression. With these complaints, it is important to pursue a sexual history. Determine any associated or causal condition and look for associated dysfunction.
The sexual history is like a history for any disease, in that you begin with the present illness. The differential diagnosis begins with a determination of where in the cycle the dysfunction occurs.
- One way to start is to describe the normal human sexual response. I find it best to sketch out the response cycle (FIGURE 1 ) on a piece of paper and ask, “Is this what happens to you?” Most patients understand and can tell where in the cycle the interruption occurs.
- 3 questions in a review of systems disclose nearly all sexual dysfunction:
- “How often do you have intercourse?” The only “right” answer is “as often as I want to.” If the patient is not having intercourse, is it by choice or involuntary?
- “Do you have pain with intercourse?”
- “How often do you have orgasm?” Most answer “hardly ever” or “most of the time.”
- Allegories like these are useful:
- Elements and example questions
Physical examination
Ageneral physical examination with pelvic examination should always be performed. If the patient complains of pain, the site of pain should be determined. A wet prep is useful to exclude vaginitis. A patient may have dyspareunia from vaginitis even if there are no obvious physical signs.
The most common dysfunctions: Desire phase disorders
Female sexual arousal disorder is either low libido or inhibited sexual desire. In both cases the patient is likely to report that she has no desire. But if you ask what happens when her partner wants to have intercourse, a patient with low libido describes low interest behavior, and a patient with inhibited desire describes aversion behavior.
Patients with low libido sometimes report that their orgasms are less intense, or that they do not become excited. Women on estrogen replacement after oophorectomy may have low libido related to decreased androgen.
Depression is by far the most common cause. Other contributors: chronic disease, hypoestrogenic states, hyperprolactinemia, and breastfeeding.
Inhibited sexual desire, which is a result of pain or other dysfunction, is far more common than low libido. Careful history usually reveals aversion behavior. They avoid going to bed at the same time as their partner, or develop other behaviors that preclude intercourse.
Women with inhibited desire have a conditioned negative response. In studies, these patients exhibit normal objective measures of vaginal vasocongestion in response to sexual stimuli, but self-reported subjective measures of arousal do not correlate.
They report that they simply have no desire, but the cause of their avoidance is negative conditioning. Here’s where the therapist supports, but also confronts their belief system, and attempts to help them understand that they have a normal desire for intercourse. The therapist may ask the patient to consider whether she ever has sexual dreams, reads romance novels, or fantasizes, to show that these phenomena demonstrate normal desire.
The role of testosterone in inhibited sexual desire
Measuring serum testosterone isn’t helpful. It is my belief that inhibited desire is most often related to other factors. Counseling should be the first-line therapy. Drug therapy without counseling is less likely to be effective than therapy that includes counseling.
Normal serum testosterone levels are 20 to 80 ng/dL in reproductive-age women, who produce 0.2 to 0.3 mg/day of testosterone. Levels increase 10% to 20% at midcycle. Testosterone falls 40% to 60% at natural menopause and by similar amounts with use of oral contraceptive pills, and by 80% with surgical menopause.
Testosterone levels have little correlation with sexual desire in cycling women or women on oral contraceptives.3 Most studies have found no correlation between testosterone levels and sexual function in perimenopausal or naturally menopausal women.4,5 Other studies have failed to show a difference in testosterone levels between women with arousal disorders and normal controls.6
Testosterone therapy may be effective in surgically menopausal women with low libido. Shifrin and colleagues7 randomized 75 surgically menopausal women being treated with conjugated equine estrogens to placebo or transdermal testosterone, 150 or 300 μg per day, in a crossover trial. They reported, “Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm. At the higher dose, the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased 2 to 3 times from base line.”
Testosterone is not yet approved for female sexual dysfunction, but a transdermal testosterone is being proposed for women with hypoactive sexual desire disorder who have had bilateral oophorectomy.
Excitement phase disorders
These disorders are caused by pain with intercourse. What the patient says about the site of pain and when she began experiencing pain help form the differential diagnosis.
Dyspareunia can be due to physiological causes such as obstetric laceration, endometriosis, pelvic inflammatory disease, vaginitis, vulvar disease, and vestibulitis. Interstitial cystitis and inflammatory bowel disease can cause dyspareunia, as can a simple fungal infection. Ask how long the pain continues after intercourse. If internal pain continues for hours, it is highly suggestive of intra-abdominal pathology.
Any cause of pain can begin a self-perpetuating conditioned response cycle that leads to inhibited desire. Anything that causes pain elicits aversion behavior, even without the stimulus. With conditioned response comes failure of excitement, which is where the sexual response cycle is interrupted.
When pain interrupts the sexual response cycle, the patient may still have intercourse, but without excitement, lubrication, and vaginal expansion—and with consequent further pain. Further attempts at intercourse then cause more pain, leading to the cycle of dyspareunia. Pain may be introital, vaginal, or deep. The pain may be reproduced on exam.
Treatment is twofold. Identify and correct source of pain first. Then the patient must learn that intercourse is not painful but pleasurable. Sensate focus exercises are often useful.
Vaginismus, an involuntary spasm of muscles around the outer third of the vagina, may make penetration impossible. Vaginismus can be caused by pain, severe negative parental attitudes about sex, or extreme religious orthodoxy. These patients may be hyper-feminine. They often have bizarre mental images of their genitals. They usually have a partner who supports the dysfunction.
Treatment involves dilators, but the purpose is not to dilate the vagina. It is to learn to have something in the vagina and to confront fears and feelings rregarding penetration. Treatment must involve the partner.
Plateau and orgasmic dysfunctions
Delayed or absent orgasm is common. It may be primary or secondary, global, situational, or random. Etiologies include performance anxiety, fear of loss of control, and boredom. Patients with orgasmic dysfunction often develop “spectator” behavior. When they reach plateau they begin to wonder if they will have orgasm. They begin to watch to see what is happening rather than participating. As a result, they lose excitement and do not have orgasm. They become increasingly anxious about whether they will achieve orgasm. Anxiety interferes with the sexual response cycle, and orgasm does not occur.
Treatment involves sensate focus. By learning to focus on the sensations that occur, the patient learns not to focus on anxiety or assume the spectator frame of mind.
When the patient reports “no desire” but describes aversion behavior, inhibited desire is typically a conditioned response to the experience of pain during intercourse. Pain—from any cause—during sexual intercourse, can begin a conditioned response that requires recognition, treatment, and, often, counseling to eliminate.
How can the Ob/Gyn help? Therapy model: P LI SS IT
Permission giving. Many sexual problems can be solved by permission-giving. A patient might be bored and wish to try new positions; permission may be all that is required.
LImited information. A patient might have orgasm with masturbation but not penetration. Explaining to the patient that 50% of women do not have orgasm with penetration alone and that it is OK to combine manual stimulation with penetration may be all that is needed.
Specific Suggestions. A patient on decongestants may note decreased lubrication. Use of a lubricant might help. A patient with the “busy mother syndrome” may need specific instruction to make time for a relationship.
Intensive Therapy. Patients with childhood sexual abuse probably require intensive therapy. Vaginismus may require intensive therapy.
- 47 yo woman married to a physician for 23 years. No intercourse for 20 years, and no communication outside the bedroom about their sexual relationship. She is very angry. Her last gynecologist said she should get a good divorce attorney.
- 50 yo woman complains of no desire and lack of lubrication. Married for 20 years. She has insulin-dependent diabetes. Her last gynecologist told her to use KY jelly. She became very angry saying KY jelly was “too clinical.”
- 30 yo woman referred for severe dyspareunia and pelvic pain. Prior workup including IVP, ultrasound, and laparoscopy found no organic cause. She describes severe inhibited sexual desire and had not attempted intercourse in 4 months.
- 34 yo married woman complains of anorgasmia since starting fluoxetine (Prozac) 2 years ago. She had orgasm prior to that. After changing to bupropion (Wellbutrin), her anorgasmia continued.
Summary
Many gynecologists are concerned about lack of time or skills to deal with sexual problems. However, it often takes less time to deal with the problem than to ignore it. If a problem is uncovered during a scheduled brief visit, the patient can be given a follow-up appointment to ensure adequate time.
Dr. Carey is a member of the Female Sexual Dysfunction CME Steering Committee, sponsored by the University of Medicine and Dentistry of New Jersey, through a grant from Proctor and Gamble.
Case reports of patients helped by therapy,
Say you see 100 adult patients this week. How many have a sexual dysfunction? 10? 20? Would you believe 43? In a National Health and Social Life Survey1 of 1,749 women and 1,410 men aged 18 to 59 years, 43% of women and 31% of men reported sexual dysfunction. Rates that high make sexual dysfunction an important public health concern—one that is highly associated with impaired well-being and negative experiences in sexual relationships.
Similar findings marked a study2 of general practice patients in Britain: 41% of 979 women and 34% of 789 men reported sexual dysfunction. Although 52% wanted professional help, only 10% had received it.
As primary care providers, Ob/Gyns must identify common problems, treat those within our expertise, and refer the others. In all likelihood, we are the first physicians women see about a sexual problem. For these reasons—and because dysfunction is so common—it is appropriate that we screen for and address female sexual dysfunction.
This article presents a medical model of management and tells how to take a sexual history, formulate a differential diagnosis, manage common sexual problems, and identify indications for referral.
The medical model
According to the medical model, a patient presents with a problem, which is investigated by history and physical examination. A differential diagnosis is formulated, and appropriate laboratory tests or other evaluations are conducted. The patient’s problem is compared to a normal physiologic process to determine pathophysiology. Diagnosis and therapy follow.
The medical model for sexual dysfunction is the same as that for any disease, such as asthma, in which normal breathing is interrupted. In the sexual response cycle, physiologic changes can be measured and specifically described, as Masters and Johnson explained in 1966 in Human Sexual Response (FIGURE 1). Any barriers that interrupt this progression “block” the normal response cycle, resulting in sexual dysfunction. We aim to identify and remove or get around any barriers.
FIGURE 1 Use the sexual response cycle in dialogue with the patient
Most patients with sexual dysfunction can identify the phase in the Masters and Johnson sexual response cycle where normal progression is interrupted. Using a sketch of this cycle helps patients understand and articulate their problem.
The sexual response cycle
Desire initiates the cycle, followed by the excitement phase, during which breathing rate and pulse increase, blood flow shifts away from muscles and into the skin and pelvic organs, and there is an associated expansion, lengthening, and lubrication of the vagina. A plateau follows, during which there is no further increase in signs such as increased pulse rate. Orgasm is the first point in the response cycle that is different in men and women. Men have an obligatory resolution phase and return to baseline state; women can return to the plateau state and then have another orgasm. The resolution phase lengthens in duration in both sexes with increasing age.
The sexual response cycle is innate, like any physiologic process. It cannot be taught or learned, and is not under voluntary control. It is critical that patients understand that the sexual response cycle is a natural function that everyone has—just as everyone has innate capacity to breathe. Patients do not learn it, any more than they have to learn respiration.
Sexual behavior, however, is learned, and sexual dysfunctions are exhibited by behavior. Sex therapy is a learning process, the aim of which is to change the behavior. Sexual dysfunctions have both cognitive and physical components; although response is physiologic, it can be altered by emotion, as can respiration.
The relationship is the patient. Sexual dysfunction occurs within a relationship, and the relationship needs and stands to benefit from therapy.
Reassuring anxious, angry patients
Approach is critical, and must reflect an understanding that sexual dysfunction is real. Many patients have been told that the problem is “all in their head” or that they are deliberately acting dysfunctionally.
Confrontation and support are useful communication tools. Confrontation means identifying behaviors and beliefs and how beliefs influence behaviors. Support means conveying to the patient that you understand that she is in distress and that it couldn’t have happened any other way for her.
A “therapeutic mirror” technique can show the patient her beliefs, attitudes, and behaviors. The therapist repeats the the patient’s beliefs and behaviors until the patient states that they are an accurate reflection, or tells the therapist what is inaccurate.
Assure the patient that anxiety is to be expected, and that her probelm is common and treatable. These patients believe they have thought of everything, and nothing has worked. Just reassuring them may help.
Anger must also be acknowledged—and these patients are angry. Their anger may be directed at their partner, a former physician, or you. You may elicit a surprising outburst of pent-up anger when you ask what seems to be a neutral question.
The patient always has an internal theory and everything you say is filtered through this theory. If there is a dichotomy, it must be addressed before you can proceed successfully. Usually, you can simply ask, “What do you think is the cause?” Often she will tell you. If she is uncertain, you might say, “I realize you don’t really know. What do you think it might be? What are you afraid it might be?”
You have to ask
Many patients do not express the fact that their chief complaint is sexual dysfunction. (See How to take a sexual history,).
In many cases, sexual dysfunction may be suggested in the investigation of another complaint such as infertility, pelvic pain with no particular pattern, malaise, or depression. With these complaints, it is important to pursue a sexual history. Determine any associated or causal condition and look for associated dysfunction.
The sexual history is like a history for any disease, in that you begin with the present illness. The differential diagnosis begins with a determination of where in the cycle the dysfunction occurs.
- One way to start is to describe the normal human sexual response. I find it best to sketch out the response cycle (FIGURE 1 ) on a piece of paper and ask, “Is this what happens to you?” Most patients understand and can tell where in the cycle the interruption occurs.
- 3 questions in a review of systems disclose nearly all sexual dysfunction:
- “How often do you have intercourse?” The only “right” answer is “as often as I want to.” If the patient is not having intercourse, is it by choice or involuntary?
- “Do you have pain with intercourse?”
- “How often do you have orgasm?” Most answer “hardly ever” or “most of the time.”
- Allegories like these are useful:
- Elements and example questions
Physical examination
Ageneral physical examination with pelvic examination should always be performed. If the patient complains of pain, the site of pain should be determined. A wet prep is useful to exclude vaginitis. A patient may have dyspareunia from vaginitis even if there are no obvious physical signs.
The most common dysfunctions: Desire phase disorders
Female sexual arousal disorder is either low libido or inhibited sexual desire. In both cases the patient is likely to report that she has no desire. But if you ask what happens when her partner wants to have intercourse, a patient with low libido describes low interest behavior, and a patient with inhibited desire describes aversion behavior.
Patients with low libido sometimes report that their orgasms are less intense, or that they do not become excited. Women on estrogen replacement after oophorectomy may have low libido related to decreased androgen.
Depression is by far the most common cause. Other contributors: chronic disease, hypoestrogenic states, hyperprolactinemia, and breastfeeding.
Inhibited sexual desire, which is a result of pain or other dysfunction, is far more common than low libido. Careful history usually reveals aversion behavior. They avoid going to bed at the same time as their partner, or develop other behaviors that preclude intercourse.
Women with inhibited desire have a conditioned negative response. In studies, these patients exhibit normal objective measures of vaginal vasocongestion in response to sexual stimuli, but self-reported subjective measures of arousal do not correlate.
They report that they simply have no desire, but the cause of their avoidance is negative conditioning. Here’s where the therapist supports, but also confronts their belief system, and attempts to help them understand that they have a normal desire for intercourse. The therapist may ask the patient to consider whether she ever has sexual dreams, reads romance novels, or fantasizes, to show that these phenomena demonstrate normal desire.
The role of testosterone in inhibited sexual desire
Measuring serum testosterone isn’t helpful. It is my belief that inhibited desire is most often related to other factors. Counseling should be the first-line therapy. Drug therapy without counseling is less likely to be effective than therapy that includes counseling.
Normal serum testosterone levels are 20 to 80 ng/dL in reproductive-age women, who produce 0.2 to 0.3 mg/day of testosterone. Levels increase 10% to 20% at midcycle. Testosterone falls 40% to 60% at natural menopause and by similar amounts with use of oral contraceptive pills, and by 80% with surgical menopause.
Testosterone levels have little correlation with sexual desire in cycling women or women on oral contraceptives.3 Most studies have found no correlation between testosterone levels and sexual function in perimenopausal or naturally menopausal women.4,5 Other studies have failed to show a difference in testosterone levels between women with arousal disorders and normal controls.6
Testosterone therapy may be effective in surgically menopausal women with low libido. Shifrin and colleagues7 randomized 75 surgically menopausal women being treated with conjugated equine estrogens to placebo or transdermal testosterone, 150 or 300 μg per day, in a crossover trial. They reported, “Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm. At the higher dose, the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased 2 to 3 times from base line.”
Testosterone is not yet approved for female sexual dysfunction, but a transdermal testosterone is being proposed for women with hypoactive sexual desire disorder who have had bilateral oophorectomy.
Excitement phase disorders
These disorders are caused by pain with intercourse. What the patient says about the site of pain and when she began experiencing pain help form the differential diagnosis.
Dyspareunia can be due to physiological causes such as obstetric laceration, endometriosis, pelvic inflammatory disease, vaginitis, vulvar disease, and vestibulitis. Interstitial cystitis and inflammatory bowel disease can cause dyspareunia, as can a simple fungal infection. Ask how long the pain continues after intercourse. If internal pain continues for hours, it is highly suggestive of intra-abdominal pathology.
Any cause of pain can begin a self-perpetuating conditioned response cycle that leads to inhibited desire. Anything that causes pain elicits aversion behavior, even without the stimulus. With conditioned response comes failure of excitement, which is where the sexual response cycle is interrupted.
When pain interrupts the sexual response cycle, the patient may still have intercourse, but without excitement, lubrication, and vaginal expansion—and with consequent further pain. Further attempts at intercourse then cause more pain, leading to the cycle of dyspareunia. Pain may be introital, vaginal, or deep. The pain may be reproduced on exam.
Treatment is twofold. Identify and correct source of pain first. Then the patient must learn that intercourse is not painful but pleasurable. Sensate focus exercises are often useful.
Vaginismus, an involuntary spasm of muscles around the outer third of the vagina, may make penetration impossible. Vaginismus can be caused by pain, severe negative parental attitudes about sex, or extreme religious orthodoxy. These patients may be hyper-feminine. They often have bizarre mental images of their genitals. They usually have a partner who supports the dysfunction.
Treatment involves dilators, but the purpose is not to dilate the vagina. It is to learn to have something in the vagina and to confront fears and feelings rregarding penetration. Treatment must involve the partner.
Plateau and orgasmic dysfunctions
Delayed or absent orgasm is common. It may be primary or secondary, global, situational, or random. Etiologies include performance anxiety, fear of loss of control, and boredom. Patients with orgasmic dysfunction often develop “spectator” behavior. When they reach plateau they begin to wonder if they will have orgasm. They begin to watch to see what is happening rather than participating. As a result, they lose excitement and do not have orgasm. They become increasingly anxious about whether they will achieve orgasm. Anxiety interferes with the sexual response cycle, and orgasm does not occur.
Treatment involves sensate focus. By learning to focus on the sensations that occur, the patient learns not to focus on anxiety or assume the spectator frame of mind.
When the patient reports “no desire” but describes aversion behavior, inhibited desire is typically a conditioned response to the experience of pain during intercourse. Pain—from any cause—during sexual intercourse, can begin a conditioned response that requires recognition, treatment, and, often, counseling to eliminate.
How can the Ob/Gyn help? Therapy model: P LI SS IT
Permission giving. Many sexual problems can be solved by permission-giving. A patient might be bored and wish to try new positions; permission may be all that is required.
LImited information. A patient might have orgasm with masturbation but not penetration. Explaining to the patient that 50% of women do not have orgasm with penetration alone and that it is OK to combine manual stimulation with penetration may be all that is needed.
Specific Suggestions. A patient on decongestants may note decreased lubrication. Use of a lubricant might help. A patient with the “busy mother syndrome” may need specific instruction to make time for a relationship.
Intensive Therapy. Patients with childhood sexual abuse probably require intensive therapy. Vaginismus may require intensive therapy.
- 47 yo woman married to a physician for 23 years. No intercourse for 20 years, and no communication outside the bedroom about their sexual relationship. She is very angry. Her last gynecologist said she should get a good divorce attorney.
- 50 yo woman complains of no desire and lack of lubrication. Married for 20 years. She has insulin-dependent diabetes. Her last gynecologist told her to use KY jelly. She became very angry saying KY jelly was “too clinical.”
- 30 yo woman referred for severe dyspareunia and pelvic pain. Prior workup including IVP, ultrasound, and laparoscopy found no organic cause. She describes severe inhibited sexual desire and had not attempted intercourse in 4 months.
- 34 yo married woman complains of anorgasmia since starting fluoxetine (Prozac) 2 years ago. She had orgasm prior to that. After changing to bupropion (Wellbutrin), her anorgasmia continued.
Summary
Many gynecologists are concerned about lack of time or skills to deal with sexual problems. However, it often takes less time to deal with the problem than to ignore it. If a problem is uncovered during a scheduled brief visit, the patient can be given a follow-up appointment to ensure adequate time.
Dr. Carey is a member of the Female Sexual Dysfunction CME Steering Committee, sponsored by the University of Medicine and Dentistry of New Jersey, through a grant from Proctor and Gamble.
1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281:537-544.
2. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract. 1998;15:519-524.
3. Bancroft J, Sherwin BB, Alexander GM, Davidson DW, Walker A. Oral contraceptives, androgens, and the sexuality of young women: II. The role of androgens. Arch Sex Behav. 1991;20:121-135.
4. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones and the menopausal transition. Maturitas. 1997;26:83-93.
5. Kirchengast S, Hartmann B, Gruber D, Huber J. Decreased sexual interest and its relationship to body build in postmenopausal women. Maturitas. 1996;23:63-71.
6. Schreiner-Engel P, Schiavi RC, White D, Ghizzani A. Low sexual desire in women: the role of reproductive hormones. Horm Behav. 1989;23:221-234.
7. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.
1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281:537-544.
2. Dunn KM, Croft PR, Hackett GI. Sexual problems: a study of the prevalence and need for health care in the general population. Fam Pract. 1998;15:519-524.
3. Bancroft J, Sherwin BB, Alexander GM, Davidson DW, Walker A. Oral contraceptives, androgens, and the sexuality of young women: II. The role of androgens. Arch Sex Behav. 1991;20:121-135.
4. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones and the menopausal transition. Maturitas. 1997;26:83-93.
5. Kirchengast S, Hartmann B, Gruber D, Huber J. Decreased sexual interest and its relationship to body build in postmenopausal women. Maturitas. 1996;23:63-71.
6. Schreiner-Engel P, Schiavi RC, White D, Ghizzani A. Low sexual desire in women: the role of reproductive hormones. Horm Behav. 1989;23:221-234.
7. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.
Estradiol gel: A new option in hormone replacement therapy
- Percutaneous estradiol gel can be prescribed at low doses.
- Relief of menopausal symptoms can begin as early as 2 weeks after starting treatment.
- Treatment with estradiol gel maintains or increases bone mineral density.
- No large randomized, controlled trials have explored the effect of estradiol gel on coronary artery disease. It appears to have metabolic effects similar to those of oral estradiol.
- Because percutaneous estradiol stimulates the endometrium, women with an intact uterus should also take a progestogen.
Although the Women’s Health Initiative1 discouraged many menopausal women from using oral estrogen, it failed to address the risks of treatment with other dosages or forms of estrogen and progestin.
Nor has any other trial of similar size and complexity taken up the issue. However, numerous smaller studies have been published.
This article summarizes findings on percutaneous delivery of estradiol gel (EstroGel), the most recently FDA-approved estrogen option for treatment of menopausal symptoms.
It describes the overall safety of estradiol gel, as well as its effectson:
- menopausal symptoms,
- bone,
- metabolism, and
- endometrium.
(In this article, “percutaneous delivery” refers to estradiol gel applied to the skin, and “transdermal estradiol” indicates delivery via a transdermal reservoir or matrix system, otherwise known as “the patch.” I have used an arbitrary definition to distinguish the gel from other methods of delivering estradiol across the skin. For example, Estrasorb is a liposomal formulation that is applied to the skin of the thigh. Although it is a percutaneous estradiol similar to the gel, this article focuses only on the latter option.)
Easy to apply, few skin reactions
Percutaneous estradiol gel formulations have been available for almost 30 years in Europe, where they are utilized by a majority of women on hormone therapy. In the United States, the hydroalcoholic gel is packaged in a pump that delivers 64 standardized 1.25-g doses, which contain 0.75 mg of 17ß-estradiol. Once it is applied, the gel is absorbed into an intradermal reservoir (FIGURE) and dries in 2 to 5 minutes, leaving no residue.
Patient selection. Estradiol gel is well-suited for patients who are concerned about the risks of oral estrogen (as portrayed in the mainstream press following the Women’s Health Initiative) and want to avoid that route of administration, as well as women who dislike or have difficulty swallowing pills. Percutaneous administration also is appropriate for physically active women who may have adhesion problems or skin irritation with the transdermal patch, or those who have had reactions to local adhesives in the past. The patient should be motivated to apply the gel on a daily basis.
Indications are moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy, although topical vaginal products should also be considered for the latter indication.
Contraindications are undiagnosed abnormal vaginal bleeding; history of breast cancer, other estrogen-dependent malignancy, stroke, heart attack, or liver disease or dysfunction; active thrombophlebitis or thromboembolic disorders (or a history of these); and known or suspected pregnancy.
Common side effects include headache, breast pain, irregular vaginal bleeding or spotting, stomach cramps or bloating, nausea and vomiting, and hair loss.
- Skin reactions are infrequent, but should be taken into account when discussing per-cutaneous or transdermal delivery of any drug. However, estradiol gel appears to cause fewer skin reactions than the patch. In a study over more than 5 years, 0 of 157 women treated with percutaneous estradiol reported skin irritation.2 Other comparisons found similar outcomes.3,4
Onset of action is rapid, as it is with the transdermal patch.5 Dose variability is minimized when the gel is applied at the same time every day to a large area of skin, preferably the arm, although all application sites appear to produce similar results: abdomen, shoulders, arms, and inner thigh.6 The gel should not be applied to the breast or vagina.
Diminished effect with skin washing. In 1 trial, site washing 1/2 hour after application significantly decreased bioavailability and time to reach peak plasma concentrations.7 For this reason, the gel should be not applied before a bath, shower, or sauna.
Dosing options. The initial dose is 1.25 mg of gel, which is 1 pump of the bottle. The gel is collected in the palm of 1 hand and applied to the skin of the opposite arm from the wrist to the shoulder. The dose can be titrated by adding a second pump of the gel and applying it to the opposite arm. The dose can be lowered by using less than a full depression of the pump.
Stable, physiologic estrogen levels
Estradiol gel produces relatively stable serum estradiol levels, and therapeutic estradiol levels similar to those seen with other formulations, routes of administration, and dosages.
Percutaneous administration produces serum estrone to estradiol ratios close to 1, in contrast to higher ratios (5:1) with oral administration.8-11 The lower ratio approximates levels during the menstrual cycle of premenopausal women. (TABLE 1 gives estradiol and estrone levels from different studies following administration of estradiol as a gel, oral formulation, and transdermal patch.)
The percutaneous route also allows for delivery directly to the systemic circulation, avoiding gastrointestinal and first-pass hepatic metabolism and elimination. In contrast, oral micronized estradiol causes large fluctuations in serum estradiol and estrone levels due to absorption and metabolism.8
More stable serum levels than with the patch. One study12 comparing percutaneous and transdermal estradiol found similar interindividual variability but less stable serum levels in women using the transdermal system. A separate study13 also reported greater fluctuation of serum estradiol levels in women using a transdermal system than in those using the gel.
TABLE 1
Serum estradiol and estrone levels for various routes of estradiol
| AUTHOR | THERAPY | ESTRADIOL LEVEL (PG/ML) | ESTRONE LEVEL (PG/ML) |
|---|---|---|---|
| Scott et al8 | E2gel 3 mg/day | 102.9±39.9 | 120.0±50.5 |
| E2gel 1.5 mg/day | 68.1±27.4 | 90.6±45.7 | |
| Transdermal estradiol 50 μg/day | 41.1±13.5 | 45.0±15.9 | |
| Oral micronized estradiol 2 mg/day | 114.0±65.2 | 575.2±279.9 | |
| Palacios et al10 | E2gel 1.5 mg/day | 75.7±1.0 | 58.5±2.9 |
| Oral conjugated estrogen 0.625 mg/day | 39.6±4.6 | 126.0±7.6 | |
| Basdevant et al11 | E2gel 3 mg/day | 221.0±35.0 | 146.0±19.0 |
| Oral micronized estradiol 2 mg/day | 121.0±27.0 | 811.0±370.0 | |
| Archer15 | E2gel 0.75 mg/day | 33.5* | 49.0* |
| E2gel 1.5 mg/day | 65.0* | 58.0* | |
| Placebo | 5.0* | 23.0* | |
| *Median value | |||
| E2gel = percutaneous estradiol gel | |||
Studies compared relief of menopausal symptoms
Estradiol gel effectively relieved meno-pausal symptoms in randomized, double-blind studies, open label comparisons, and observational trials in postmenopausal women, with and without the addition of various progestins.
Symptom relief in comparison with baseline values is statistically significant as early as 2 weeks after initiating treatment. Relief of up to 2 years’ duration has been reported.3,14
Several studies have compared symptom relief achieved with estradiol gel, oral estrogen, transdermal delivery systems, and placebo3,9,14-18; findings are summarized in TABLE 2.
Same efficacy when progestogen is added. The following studies, and other studies,14 demonstrated that estradiol gel relieves menopausal symptoms whether it is administered alone or in combination with a progestogen, with efficacy similar to other estrogen formulations:
Climacteric symptoms decreased to the same extent when estradiol gel was combined with a levonorgestrel-releasing intrauterine device, oral micronized progesterone, or vaginal micronized progesterone.19
A study20 that added lynestrenol decreased the frequency of hot flushes and night sweats more than in women using estradiol gel alone. However, negative mood symptoms were more pronounced in the progestin-treated group.
Estradiol gel 1 mg/day in combination with monthly or quarterly oral medroxyprog-esterone acetate reduced the severity of hot flushes, sweating, and vaginal dryness, according to a 12-month trial.21
Symptoms decreased the same whether a levonorgestrel-releasing IUD or oral or vaginal progesterone was added.
Bone mineral density maintained or increased
Several randomized, controlled trials have documented the effects of estradiol gel on bone mineral density (BMD) and various markers of bone metabolism. In these studies, BMD remained steady22,23 or increased10,24,25 following treatment, and estradiol gel remained effective for up to 4 years.25 Estradiol gel maintained or increased BMD with or without addition of progestins.22,23,26
These investigations involved measurement of BMD at the lumbar spine, forearms, or hip, as well as biologic markers of bone turnover such as urinary hydroxyproline/creatinine ratio, serum alkaline phosphatase, and serum osteocalcin.
Serum estradiol and skeletal uptake of a bone-seeking agent also were determined. Estradiol gel regimens ranged from 0.75 mg/day to 3 mg/day, and populations included both surgical and natural menopausal subjects in several countries.
Effects comparable to oral estrogen. Compared with oral conjugated estrogen, which increased BMD at the lumbar spine by 4.3% (±3.2%), estradiol gel produced increases of 5.6% (±2.9%) at 24 months and 4.7% (±3.2%) at 36 months.10
The case. A 52-year-old woman with no menses for 8 months presents for management complaining of disabling hot flushes. Although she is moderately obese, with a body mass index of 29, she is normotensive without any other significant medical history except for hysterectomy at age 44 for excessive bleeding.
Counseling. During her 20s, the patient tried to use oral contraceptives on 3 separate occasions, but was unable to continue them because of nausea. Although she is interested in estrogen therapy for her vasomotor symptoms, she is concerned about the possibility of experiencing nausea again. You explain that one of the benefits of percutaneous estradiol is that it avoids the gastrointestinal tract.
Physical findings. Her physical examination is within normal limits, and gynecologic examination confirms no uterus and finds no palpable adnexal masses.
Outcome. After weighing the pros and cons, she elects to use estradiol gel. At her 3-month follow-up, she reports effective relief and good compliance.
Minimum level of protection achieved. Following a comparison of oral and percutaneous estradiol, Reginster et al27 suggested that a minimum estradiol level of 60 pg/mL is necessary to prevent postmenopausal bone loss. Mean serum estradiol levels in women receiving 1.5 mg/day estradiol gel were 75.7 pg/mL and 78.4 pg/mL at 24 and 36 months, respectively, in a study by Palacios et al,10 and 85.8 pg/mL in a study by Devogelaer and colleagues.24 In these trials, BMD increased, and it remained steady in other investigations.28,29
More recent trials suggest that lower serum estradiol levels secondary to smaller estrogen doses have the capacity to maintain BMD.30,31 A 1.9% mean increase of BMD at the lumbar spine was reported in women with a mean serum concentration of 17 pg/mL in a 2-year study30 of a transdermal estradiol delivery system. The percutaneous route does not appear to limit these beneficial effects.
How are metabolic factors affected?
In general, oral estrogens produce beneficial changes in lipid metabolism, particularly higher levels of high-density lipoprotein (HDL) cholesterol. However, they also elevate triglyceride and glucose levels. How this plays out clinically is unclear. Both the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study (HERS) found no cardioprotective effects of oral estrogen despite increases in HDL and decreases in low-density lipoprotein (LDL) levels.1,32
Oral versus percutaneous estradiol. No long-term studies of this magnitude have investigated the effect of percutaneous estradiol on coronary artery disease, although numerous clinical trials have shown that the route of estrogen delivery affects many of the metabolic variables used to estimate the risk of negative cardiac outcomes. It remains to be determined whether percutaneous estradiol affects these metabolic factors in ways that influence morbidity and mortality.
In 1 trial,33 oral conjugated estrogen led to the following significant changes in lipids:
- increase in very low density lipoprotein (VLDL) cholesterol,
- decrease in LDL cholesterol (but not the LDL apoprotein B),
- increase in HDL and apoprotein A1, and
- significant increase in HDL2 cholesterol.
In a separate study,9 oral conjugated estrogen had a 2.5-fold increase in serum angiotensin, and percutaneous estradiol gel, no effect.
Same effects when progestin is added. Beneficial effects were not diminished when oral micronized progesterone was added to percutaneous estradiol.34 Estradiol gel significantly reduced total serum cholesterol and LDL cholesterol in the first year of treatment, compared with placebo.
Coagulation effects. Percutaneous estradiol has fewer negative effects on coagulation factors than its oral counterpart. One study35 investigating combination therapy with micronized progesterone compared the effects of percutaneous estradiol and oral estradiol valerate. The group receiving percutaneous estradiol gel/micronized progesterone had no significant changes in plasminogen activator inhibitor, tissue-type plasminogen concentration, and global fibrinolytic capacity. The other group had a significant decrease in mean tissue-type plasminogen concentration and plasminogen activator inhibitor activity and a significant rise in global fibrinolytic capacity.
The oral estradiol—but not the percutaneous formulation—significantly increased the mean value of prothrombin activation peptide and decreased mean antithrombin activity compared with no treatment.
Poor glycemic control may increase the risk of cardiovascular disease, but oral and percutaneous estradiol appear to have similar glycemic effects. A comparative trial36 of oral estradiol valerate 2 mg/day and percutaneous estradiol 1 mg/day found no differences in glycosylated hemoglobin A1c levels (declined in both groups) or in fasting and 2-hour post-prandial blood glucose levels (constant in both groups) or insulin sensitivity.
Treatment duration may also influence how percutaneous estradiol affects metabolic factors. An open-label longitudinal prospective study37 of 30 women receiving estradiol gel 1.5 mg/day for 6 months found a significant decrease in lipoprotein (a), apoprotein A-I, apoprotein B, HDL cholesterol, and HDL3 cholesterol. At 1 year, however, these changes were not significant.
No association with venous thromboembolism. Transdermal estradiol administered as a patch or percutaneous gel had no effect on the risk of venous thromboembolism in a multicenter case-control investigation.38
In contrast, a recent retrospective study found a risk of venous thromboembolism that was at least 4 times greater with oral estrogen than with transdermal estradiol.38
Use a progestogen to prevent endometrial hyperplasia
Like other forms of estrogen, percutaneous estradiol stimulates the endometrium. For this reason, women who have an intact uterus should use a progestogen in an adequate dose to prevent hyperplastic changes.39 Although numerous regimens appear to be effective, the optimal route, dose, and duration of progestin in women using percutaneous estrogen remain to be determined.
Percutaneous estradiol versus other routes of administration. Endometrial thickness and amenorrhea rates over 6 months were not statistically different among 54 women treated with estradiol gel 1.5 mg/day, transdermal estradiol 50 μg/day, or oral estradiol valerate 2 mg/day—all in combination with nomegestrol acetate 2.5 mg/day.40 The overall rates of no bleeding or spotting over 6 cycles of treatment were 78% in the percutaneous estradiol group, 48% in the transdermal group, and 60% in the oral group.
Although the percutaneous estradiol group had a lower overall incidence of no bleeding or spotting than the other groups, the difference was not significant. Nor were there significant differences in the variation of endometrial thickness from baseline: A mean increase of 1.5 mm (±0.4 mm) was reported in the percutaneous group, compared with 1.5 mm (±0.7 mm) and 1.7 mm (±0.6 mm) in the transdermal and oral estrogen groups, respectively.
Estrogenic and progestogenic effects were similar for transdermal and percutaneous estradiol (with dydrogesterone 10 mg/day for days 1 to 12) after a baseline atropic endometrium was identified.3
Estradiol gel produces stable, physiologic serum estradiol levels and has a serum estrone to estradiol ratio close to 1.
The most effective progestogen dosage and duration are unknown, although many regimens have been studied:
- Percutaneous estradiol 1.5 mg/day for the first 24 days of the month in combination with nomegestrol acetate 5 mg/day for days 11 to 24: Over 6 months, researchers found a secretory pattern in the majority of women and no evidence of hyperplasia.18
- Percutaneous estradiol 3 mg/day for 3 of every 4 weeks in combination with nomegestrol acetate 5 mg/day for 10 days: No reduction in estrogenic endometrial effects.41,42
- Estradiol gel 3 mg/day for 3 of every 4 weeks in combination with 200 mg or 300 mg oral micronized progesterone for the last 10 days of treatment: Dose was too low or treatment too short to produce a complete secretory transformation of the endometrium.43 However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial44 found no increased occurrence of hyperplasia in women using micronized progesterone 200 mg for 12 days of each cycle for more than 3 years in combination with oral conjugated estrogen 0.625 mg.
- Percutaneous estradiol 1.5 mg/day combined with micronized progesterone 100 mg daily (orally or vaginally) for the first 25 days of the month: Fully inhibited mitoses and induced amenorrhea in most of the women studied, with amenorrhea rates of 93.3% at 3 months and 91.6% at 6 months.45
- Estradiol gel 1.5 mg/day with 100 mg vaginal micronized progesterone for 21 days per cycle: Stable endometrial thickness and no endometrial hyperplasia over 12 months.46 However, breakthrough bleeding was reported in up to 30% of subjects, principally in the second 3 months of treatment.
- Percutaneous estradiol 1 mg/day for 3 months with oral medroxyprogesterone acetate 20 mg/day for the last 14 days, followed by a 7-day free interval: No reports of endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 2 mg/day for 21 days with 10 mg oral medroxyprogesterone acetate for the last 14 days, followed by a 7-day free interval: No endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 1 mg/day with medroxyprogesterone acetate 10 mg on days 1-12 every month or every 3 months: Endometrial hyperplasia was found in 1 woman (0.3%) in the group receiving the progestogen every 3 months. Endometrial histology did not differ between women taking medroxyprogesterone monthly and those taking it every 3 months.21
- Estradiol gel 3 mg/day with oral micronized progesterone 200 mg for 12 days of each cycle: Regular withdrawal bleeding in 70% of women.34
- Percutaneous estradiol 1.5 mg/day in combination with a levonorgestrel-releasing intrauterine device: 80% of women were amenorrheic at 1 year, with a mean endometrial thickness 3 mm; at 5 years, 100% of women had epithelial atrophy.47
- Estradiol gel 1.5 mg for 21 days with 200 mg oral progesterone for 14 days (126 women); 3 mg percutaneous estradiol for 21 days with 300 mg oral progesterone for 10 days (23 women); 1.5 mg estradiol gel with 300 mg oral progesterone (3 women); or 3 mg estradiol gel for 28 days with 200 mg progesterone for 14 days (5 women): No evidence of hyperplasia after 5 years of treatment.2
1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
2. Moyer DL, de Lignieres B, Driguez P, et al. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993;59:992-997.
3. Hirvonen E, Cacciatore B, Wahlström T, et al. Effects of transdermal oestrogen therapy in postmenopausal women: a comparative study of an oestradiol gel and an oestradiol delivering patch. BJOG. 1997;104(Suppl 16):26-31.
4. Travassos de Figueiredo Alves S, et al. Comparison of gel and patch estradiol replacement in Brazil, a tropical country. Maturitas. 2000;36:69-74.
5. Henzl MR, Loomba PK. Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. J Reprod Med. 2003;48:525-540.
6. Holst J, et al. Serum estrogen levels after topic application of estradiol-17 beta on two different cutaneous areas. Acta Obstet Gynecol Scand. 1987;662:151-152.
7. Jarvinen A, Granander M, Nykanen S, Laine T, Geurts P, Viitanen A. Steady-state pharmacokinetics of oestradiol gel in post-menopausal women: effects of application area and washing. Br J Obstet Gynaecol. 1997;104(Suppl 16):14-18.
8. Scott RT, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991;77:758-764.
9. Dupont A, Dupont P, Cusan M, et al. Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women. Maturitas. 1991;13:297-311.
10. Palacios S, Menéndez C, Jurado AR, Vargas JC. Effects of percutaneous oestradiol versus oral oestrogens on bone density. Maturitas. 1995;20:209-213.
11. Basdevant A, de Lignieres B, Simon P, et al. Hepatic lipase activity during oral and parenteral 17ß-estradiol replacement therapy: high-density lipoprotein increase may not be antiatherogenic. Fertil Steril. 1991;55:1112-1117.
12. Simon JA, et al. Are there significant differences between patch and gel cutaneous estradiol therapy? In: Genazzani AR, Petraglia F, Volpe A, Facchinetti F, eds. Recent Research on Gynecological Endocrinology. Casterton Hall, Carnforth, Lancashire, UK: Parthenon Publishing, Casterton Hall; 1998;317-324.
13. Paoletti AM, et al. Comparison of pharmacokinetic profiles of 17ß-estradiol gel 0.6mg/g (Gelestra) with a transdermal delivery system (Estraderm TTS 50) in postmenopausal women at steady state. Maturitas. 2001;40:203-209.
14. Jensen PB, Jensen J, Riis BJ, et al. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas. 1987;9:207-215.
15. Archer DF. for the EstroGel Study Group. Percutaneous 17ß-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
16. Kornafel KL, March CM. Estradiol gel in the treatment of menopausal symptoms: a placebo-controlled double-blind case study of efficacy and safety. South Med J. 1992;85:270-273.
17. Hirvonen E, Lamberg-Allardt C, Lankinen KS, Geurts P, Wilén-Rosenqvist G. Transdermal oestradiol gel in the treatment of the climacterium: a comparison with oral therapy. BJOG. 1997;104(Suppl 16):19-25.
18. Foidart JM, Béliard A, Hedon B, et al. Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium. BJOG. 1997;104:305-310.
19. Suvanto-Luukkonen E, Sundström H, Penttinen J, et al. Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy. Maturitas. 1997;26:211-17.
20. Holst J, et al. Progestogen addition during oestrogen replacement therapy—effects on vasomotor symptoms and mood. Maturitas. 1989;11:13-20.
21. Hirvonen E, et al. Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding. Climacteric. 2000;3:262-270.
22. Ng HT, Chang SP, Yang TS, Cho MP, Wei TC. Estradiol administered in a percutaneous gel for the prevention of postmenopausal bone loss. Asia-Oceania J Obstet Gynaecol. 1993;19(2):115-119.
23. Riis B, Thomsen K, et al. Does calcium supplementation prevent postmenopausal bone loss? A double blind, controlled clinical study. N Engl J Med. 1987;316:173-177.
24. Devogelaer JP, Lecart C, Dupret P, De Nayer P, Nagant De Deuxchaisnes C. Long-term effects of percutaneous estradiol on bone loss and bone metabolism in post-menopausal hysterectomized women. Maturitas. 1998;28:243-249.
25. Wimalawansa SJ. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four year randomized study. Am J Med. 1995;99:36-42.
26. Sun A, Lin S, Yu W, et al. Percutaneous estrogen in prevention of early post-menopausal bone loss in Chinese women. Chin Med J. 2002;115:1790-1795.
27. Reginster JY, Sarlet N, Deroisy R, et al. Minimum levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int. 1992;51:340-343.
28. Cicinelli E, Cantatore FP, Galantino P, et al. Effects of continuous percutaneous estradiol administration on skeletal turnover in postmenopausal women: a 1-year prospective controlled study. Eur J Obstet Gynecol Reprod Biol. 1996;69(2):109-113.
29. Riis B, et al. The effect of percutaneous estradiol and natural progesterone on post-menopausal bone loss. Am J Obstet Gynecol. 1987;156:61-65.
30. Notelvitz M, John VA, Good WR. Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, post-menopausal women. Menopause. 2002;9:343-353.
31. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17ß-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003;290:1042-1048.
32. Hully S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.
33. Moorjani S, Dupont A, Labrie F, et al. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with Utrogestan in menopausal women. J Clin Endocrinol Metab. 1991;73:373-379.
34. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gyencol. 1987;156:66-71.
35. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17:3071-3078.
36. Karjalainen A, Paassilta M, Heikkinen J, et al. Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism. Clin Endocrin. 2001;54:165-173.
37. Haines CJ, Chung TKH, Masarei JRL, Tomlinson B, Lau JTF. The effect of per-cutaneous oestrogen replacement therapy on Lp(a) and other lipoproteins. Maturitas. 1995;22:219-225.
38. Scarabin PY, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432.
39. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
40. Blanc B, Cravello L, Micheletti MC, et al. Continuous hormone replacement therapy for menopause combining nomegestrol acetate and gel, patch, or oral estrogen: a comparison of amenorrhea rates. Clin Therap. 1998;20(5):901-912.
41. Holst J. Percutaneous estrogen therapy. Endometrial response and metabolic effects. Acta Obstet Gynecol Scand Suppl. 1983;115:1-30
42. Holst J, Cajander S, von Schoultz B. Cellular morphometric analysis of the post-menopausal endometrium during treatment with percutaneous estradiol-17ß with and without oral gestagen. Acta Obstet Gynecol Scand. 1983;62:267-270.
43. Holst J, Cajander S, von Schoultz B. Endometrial response in post-menopausal women during treatment with percutaneous 17ß-oestradiol opposed by oral progesterone. Maturitas. 1986;8:201-207.
44. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370-375.
45. Gillet JY, Andre G, Faguer B, et al. Induction of amenorrhea during hormone replacement therapy: optimized micronized progesterone dose. A multicenter study. Maturitas. 1994;19:103-115.
46. Vilodre LC, et al. Endometrial response to a cyclic regimen of percutaneous 17ß-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension. Gynecol Endocrinol. 2003;17:323-328.
47. Suvanto-Luukkonen E, Kauppila A. The levonorgestrel intrauterine system in menopausal hormone replacement therapy: five-year experience. Fertil Steril. 1999;72:161-163.
- Percutaneous estradiol gel can be prescribed at low doses.
- Relief of menopausal symptoms can begin as early as 2 weeks after starting treatment.
- Treatment with estradiol gel maintains or increases bone mineral density.
- No large randomized, controlled trials have explored the effect of estradiol gel on coronary artery disease. It appears to have metabolic effects similar to those of oral estradiol.
- Because percutaneous estradiol stimulates the endometrium, women with an intact uterus should also take a progestogen.
Although the Women’s Health Initiative1 discouraged many menopausal women from using oral estrogen, it failed to address the risks of treatment with other dosages or forms of estrogen and progestin.
Nor has any other trial of similar size and complexity taken up the issue. However, numerous smaller studies have been published.
This article summarizes findings on percutaneous delivery of estradiol gel (EstroGel), the most recently FDA-approved estrogen option for treatment of menopausal symptoms.
It describes the overall safety of estradiol gel, as well as its effectson:
- menopausal symptoms,
- bone,
- metabolism, and
- endometrium.
(In this article, “percutaneous delivery” refers to estradiol gel applied to the skin, and “transdermal estradiol” indicates delivery via a transdermal reservoir or matrix system, otherwise known as “the patch.” I have used an arbitrary definition to distinguish the gel from other methods of delivering estradiol across the skin. For example, Estrasorb is a liposomal formulation that is applied to the skin of the thigh. Although it is a percutaneous estradiol similar to the gel, this article focuses only on the latter option.)
Easy to apply, few skin reactions
Percutaneous estradiol gel formulations have been available for almost 30 years in Europe, where they are utilized by a majority of women on hormone therapy. In the United States, the hydroalcoholic gel is packaged in a pump that delivers 64 standardized 1.25-g doses, which contain 0.75 mg of 17ß-estradiol. Once it is applied, the gel is absorbed into an intradermal reservoir (FIGURE) and dries in 2 to 5 minutes, leaving no residue.
Patient selection. Estradiol gel is well-suited for patients who are concerned about the risks of oral estrogen (as portrayed in the mainstream press following the Women’s Health Initiative) and want to avoid that route of administration, as well as women who dislike or have difficulty swallowing pills. Percutaneous administration also is appropriate for physically active women who may have adhesion problems or skin irritation with the transdermal patch, or those who have had reactions to local adhesives in the past. The patient should be motivated to apply the gel on a daily basis.
Indications are moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy, although topical vaginal products should also be considered for the latter indication.
Contraindications are undiagnosed abnormal vaginal bleeding; history of breast cancer, other estrogen-dependent malignancy, stroke, heart attack, or liver disease or dysfunction; active thrombophlebitis or thromboembolic disorders (or a history of these); and known or suspected pregnancy.
Common side effects include headache, breast pain, irregular vaginal bleeding or spotting, stomach cramps or bloating, nausea and vomiting, and hair loss.
- Skin reactions are infrequent, but should be taken into account when discussing per-cutaneous or transdermal delivery of any drug. However, estradiol gel appears to cause fewer skin reactions than the patch. In a study over more than 5 years, 0 of 157 women treated with percutaneous estradiol reported skin irritation.2 Other comparisons found similar outcomes.3,4
Onset of action is rapid, as it is with the transdermal patch.5 Dose variability is minimized when the gel is applied at the same time every day to a large area of skin, preferably the arm, although all application sites appear to produce similar results: abdomen, shoulders, arms, and inner thigh.6 The gel should not be applied to the breast or vagina.
Diminished effect with skin washing. In 1 trial, site washing 1/2 hour after application significantly decreased bioavailability and time to reach peak plasma concentrations.7 For this reason, the gel should be not applied before a bath, shower, or sauna.
Dosing options. The initial dose is 1.25 mg of gel, which is 1 pump of the bottle. The gel is collected in the palm of 1 hand and applied to the skin of the opposite arm from the wrist to the shoulder. The dose can be titrated by adding a second pump of the gel and applying it to the opposite arm. The dose can be lowered by using less than a full depression of the pump.
Stable, physiologic estrogen levels
Estradiol gel produces relatively stable serum estradiol levels, and therapeutic estradiol levels similar to those seen with other formulations, routes of administration, and dosages.
Percutaneous administration produces serum estrone to estradiol ratios close to 1, in contrast to higher ratios (5:1) with oral administration.8-11 The lower ratio approximates levels during the menstrual cycle of premenopausal women. (TABLE 1 gives estradiol and estrone levels from different studies following administration of estradiol as a gel, oral formulation, and transdermal patch.)
The percutaneous route also allows for delivery directly to the systemic circulation, avoiding gastrointestinal and first-pass hepatic metabolism and elimination. In contrast, oral micronized estradiol causes large fluctuations in serum estradiol and estrone levels due to absorption and metabolism.8
More stable serum levels than with the patch. One study12 comparing percutaneous and transdermal estradiol found similar interindividual variability but less stable serum levels in women using the transdermal system. A separate study13 also reported greater fluctuation of serum estradiol levels in women using a transdermal system than in those using the gel.
TABLE 1
Serum estradiol and estrone levels for various routes of estradiol
| AUTHOR | THERAPY | ESTRADIOL LEVEL (PG/ML) | ESTRONE LEVEL (PG/ML) |
|---|---|---|---|
| Scott et al8 | E2gel 3 mg/day | 102.9±39.9 | 120.0±50.5 |
| E2gel 1.5 mg/day | 68.1±27.4 | 90.6±45.7 | |
| Transdermal estradiol 50 μg/day | 41.1±13.5 | 45.0±15.9 | |
| Oral micronized estradiol 2 mg/day | 114.0±65.2 | 575.2±279.9 | |
| Palacios et al10 | E2gel 1.5 mg/day | 75.7±1.0 | 58.5±2.9 |
| Oral conjugated estrogen 0.625 mg/day | 39.6±4.6 | 126.0±7.6 | |
| Basdevant et al11 | E2gel 3 mg/day | 221.0±35.0 | 146.0±19.0 |
| Oral micronized estradiol 2 mg/day | 121.0±27.0 | 811.0±370.0 | |
| Archer15 | E2gel 0.75 mg/day | 33.5* | 49.0* |
| E2gel 1.5 mg/day | 65.0* | 58.0* | |
| Placebo | 5.0* | 23.0* | |
| *Median value | |||
| E2gel = percutaneous estradiol gel | |||
Studies compared relief of menopausal symptoms
Estradiol gel effectively relieved meno-pausal symptoms in randomized, double-blind studies, open label comparisons, and observational trials in postmenopausal women, with and without the addition of various progestins.
Symptom relief in comparison with baseline values is statistically significant as early as 2 weeks after initiating treatment. Relief of up to 2 years’ duration has been reported.3,14
Several studies have compared symptom relief achieved with estradiol gel, oral estrogen, transdermal delivery systems, and placebo3,9,14-18; findings are summarized in TABLE 2.
Same efficacy when progestogen is added. The following studies, and other studies,14 demonstrated that estradiol gel relieves menopausal symptoms whether it is administered alone or in combination with a progestogen, with efficacy similar to other estrogen formulations:
Climacteric symptoms decreased to the same extent when estradiol gel was combined with a levonorgestrel-releasing intrauterine device, oral micronized progesterone, or vaginal micronized progesterone.19
A study20 that added lynestrenol decreased the frequency of hot flushes and night sweats more than in women using estradiol gel alone. However, negative mood symptoms were more pronounced in the progestin-treated group.
Estradiol gel 1 mg/day in combination with monthly or quarterly oral medroxyprog-esterone acetate reduced the severity of hot flushes, sweating, and vaginal dryness, according to a 12-month trial.21
Symptoms decreased the same whether a levonorgestrel-releasing IUD or oral or vaginal progesterone was added.
Bone mineral density maintained or increased
Several randomized, controlled trials have documented the effects of estradiol gel on bone mineral density (BMD) and various markers of bone metabolism. In these studies, BMD remained steady22,23 or increased10,24,25 following treatment, and estradiol gel remained effective for up to 4 years.25 Estradiol gel maintained or increased BMD with or without addition of progestins.22,23,26
These investigations involved measurement of BMD at the lumbar spine, forearms, or hip, as well as biologic markers of bone turnover such as urinary hydroxyproline/creatinine ratio, serum alkaline phosphatase, and serum osteocalcin.
Serum estradiol and skeletal uptake of a bone-seeking agent also were determined. Estradiol gel regimens ranged from 0.75 mg/day to 3 mg/day, and populations included both surgical and natural menopausal subjects in several countries.
Effects comparable to oral estrogen. Compared with oral conjugated estrogen, which increased BMD at the lumbar spine by 4.3% (±3.2%), estradiol gel produced increases of 5.6% (±2.9%) at 24 months and 4.7% (±3.2%) at 36 months.10
The case. A 52-year-old woman with no menses for 8 months presents for management complaining of disabling hot flushes. Although she is moderately obese, with a body mass index of 29, she is normotensive without any other significant medical history except for hysterectomy at age 44 for excessive bleeding.
Counseling. During her 20s, the patient tried to use oral contraceptives on 3 separate occasions, but was unable to continue them because of nausea. Although she is interested in estrogen therapy for her vasomotor symptoms, she is concerned about the possibility of experiencing nausea again. You explain that one of the benefits of percutaneous estradiol is that it avoids the gastrointestinal tract.
Physical findings. Her physical examination is within normal limits, and gynecologic examination confirms no uterus and finds no palpable adnexal masses.
Outcome. After weighing the pros and cons, she elects to use estradiol gel. At her 3-month follow-up, she reports effective relief and good compliance.
Minimum level of protection achieved. Following a comparison of oral and percutaneous estradiol, Reginster et al27 suggested that a minimum estradiol level of 60 pg/mL is necessary to prevent postmenopausal bone loss. Mean serum estradiol levels in women receiving 1.5 mg/day estradiol gel were 75.7 pg/mL and 78.4 pg/mL at 24 and 36 months, respectively, in a study by Palacios et al,10 and 85.8 pg/mL in a study by Devogelaer and colleagues.24 In these trials, BMD increased, and it remained steady in other investigations.28,29
More recent trials suggest that lower serum estradiol levels secondary to smaller estrogen doses have the capacity to maintain BMD.30,31 A 1.9% mean increase of BMD at the lumbar spine was reported in women with a mean serum concentration of 17 pg/mL in a 2-year study30 of a transdermal estradiol delivery system. The percutaneous route does not appear to limit these beneficial effects.
How are metabolic factors affected?
In general, oral estrogens produce beneficial changes in lipid metabolism, particularly higher levels of high-density lipoprotein (HDL) cholesterol. However, they also elevate triglyceride and glucose levels. How this plays out clinically is unclear. Both the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study (HERS) found no cardioprotective effects of oral estrogen despite increases in HDL and decreases in low-density lipoprotein (LDL) levels.1,32
Oral versus percutaneous estradiol. No long-term studies of this magnitude have investigated the effect of percutaneous estradiol on coronary artery disease, although numerous clinical trials have shown that the route of estrogen delivery affects many of the metabolic variables used to estimate the risk of negative cardiac outcomes. It remains to be determined whether percutaneous estradiol affects these metabolic factors in ways that influence morbidity and mortality.
In 1 trial,33 oral conjugated estrogen led to the following significant changes in lipids:
- increase in very low density lipoprotein (VLDL) cholesterol,
- decrease in LDL cholesterol (but not the LDL apoprotein B),
- increase in HDL and apoprotein A1, and
- significant increase in HDL2 cholesterol.
In a separate study,9 oral conjugated estrogen had a 2.5-fold increase in serum angiotensin, and percutaneous estradiol gel, no effect.
Same effects when progestin is added. Beneficial effects were not diminished when oral micronized progesterone was added to percutaneous estradiol.34 Estradiol gel significantly reduced total serum cholesterol and LDL cholesterol in the first year of treatment, compared with placebo.
Coagulation effects. Percutaneous estradiol has fewer negative effects on coagulation factors than its oral counterpart. One study35 investigating combination therapy with micronized progesterone compared the effects of percutaneous estradiol and oral estradiol valerate. The group receiving percutaneous estradiol gel/micronized progesterone had no significant changes in plasminogen activator inhibitor, tissue-type plasminogen concentration, and global fibrinolytic capacity. The other group had a significant decrease in mean tissue-type plasminogen concentration and plasminogen activator inhibitor activity and a significant rise in global fibrinolytic capacity.
The oral estradiol—but not the percutaneous formulation—significantly increased the mean value of prothrombin activation peptide and decreased mean antithrombin activity compared with no treatment.
Poor glycemic control may increase the risk of cardiovascular disease, but oral and percutaneous estradiol appear to have similar glycemic effects. A comparative trial36 of oral estradiol valerate 2 mg/day and percutaneous estradiol 1 mg/day found no differences in glycosylated hemoglobin A1c levels (declined in both groups) or in fasting and 2-hour post-prandial blood glucose levels (constant in both groups) or insulin sensitivity.
Treatment duration may also influence how percutaneous estradiol affects metabolic factors. An open-label longitudinal prospective study37 of 30 women receiving estradiol gel 1.5 mg/day for 6 months found a significant decrease in lipoprotein (a), apoprotein A-I, apoprotein B, HDL cholesterol, and HDL3 cholesterol. At 1 year, however, these changes were not significant.
No association with venous thromboembolism. Transdermal estradiol administered as a patch or percutaneous gel had no effect on the risk of venous thromboembolism in a multicenter case-control investigation.38
In contrast, a recent retrospective study found a risk of venous thromboembolism that was at least 4 times greater with oral estrogen than with transdermal estradiol.38
Use a progestogen to prevent endometrial hyperplasia
Like other forms of estrogen, percutaneous estradiol stimulates the endometrium. For this reason, women who have an intact uterus should use a progestogen in an adequate dose to prevent hyperplastic changes.39 Although numerous regimens appear to be effective, the optimal route, dose, and duration of progestin in women using percutaneous estrogen remain to be determined.
Percutaneous estradiol versus other routes of administration. Endometrial thickness and amenorrhea rates over 6 months were not statistically different among 54 women treated with estradiol gel 1.5 mg/day, transdermal estradiol 50 μg/day, or oral estradiol valerate 2 mg/day—all in combination with nomegestrol acetate 2.5 mg/day.40 The overall rates of no bleeding or spotting over 6 cycles of treatment were 78% in the percutaneous estradiol group, 48% in the transdermal group, and 60% in the oral group.
Although the percutaneous estradiol group had a lower overall incidence of no bleeding or spotting than the other groups, the difference was not significant. Nor were there significant differences in the variation of endometrial thickness from baseline: A mean increase of 1.5 mm (±0.4 mm) was reported in the percutaneous group, compared with 1.5 mm (±0.7 mm) and 1.7 mm (±0.6 mm) in the transdermal and oral estrogen groups, respectively.
Estrogenic and progestogenic effects were similar for transdermal and percutaneous estradiol (with dydrogesterone 10 mg/day for days 1 to 12) after a baseline atropic endometrium was identified.3
Estradiol gel produces stable, physiologic serum estradiol levels and has a serum estrone to estradiol ratio close to 1.
The most effective progestogen dosage and duration are unknown, although many regimens have been studied:
- Percutaneous estradiol 1.5 mg/day for the first 24 days of the month in combination with nomegestrol acetate 5 mg/day for days 11 to 24: Over 6 months, researchers found a secretory pattern in the majority of women and no evidence of hyperplasia.18
- Percutaneous estradiol 3 mg/day for 3 of every 4 weeks in combination with nomegestrol acetate 5 mg/day for 10 days: No reduction in estrogenic endometrial effects.41,42
- Estradiol gel 3 mg/day for 3 of every 4 weeks in combination with 200 mg or 300 mg oral micronized progesterone for the last 10 days of treatment: Dose was too low or treatment too short to produce a complete secretory transformation of the endometrium.43 However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial44 found no increased occurrence of hyperplasia in women using micronized progesterone 200 mg for 12 days of each cycle for more than 3 years in combination with oral conjugated estrogen 0.625 mg.
- Percutaneous estradiol 1.5 mg/day combined with micronized progesterone 100 mg daily (orally or vaginally) for the first 25 days of the month: Fully inhibited mitoses and induced amenorrhea in most of the women studied, with amenorrhea rates of 93.3% at 3 months and 91.6% at 6 months.45
- Estradiol gel 1.5 mg/day with 100 mg vaginal micronized progesterone for 21 days per cycle: Stable endometrial thickness and no endometrial hyperplasia over 12 months.46 However, breakthrough bleeding was reported in up to 30% of subjects, principally in the second 3 months of treatment.
- Percutaneous estradiol 1 mg/day for 3 months with oral medroxyprogesterone acetate 20 mg/day for the last 14 days, followed by a 7-day free interval: No reports of endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 2 mg/day for 21 days with 10 mg oral medroxyprogesterone acetate for the last 14 days, followed by a 7-day free interval: No endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 1 mg/day with medroxyprogesterone acetate 10 mg on days 1-12 every month or every 3 months: Endometrial hyperplasia was found in 1 woman (0.3%) in the group receiving the progestogen every 3 months. Endometrial histology did not differ between women taking medroxyprogesterone monthly and those taking it every 3 months.21
- Estradiol gel 3 mg/day with oral micronized progesterone 200 mg for 12 days of each cycle: Regular withdrawal bleeding in 70% of women.34
- Percutaneous estradiol 1.5 mg/day in combination with a levonorgestrel-releasing intrauterine device: 80% of women were amenorrheic at 1 year, with a mean endometrial thickness 3 mm; at 5 years, 100% of women had epithelial atrophy.47
- Estradiol gel 1.5 mg for 21 days with 200 mg oral progesterone for 14 days (126 women); 3 mg percutaneous estradiol for 21 days with 300 mg oral progesterone for 10 days (23 women); 1.5 mg estradiol gel with 300 mg oral progesterone (3 women); or 3 mg estradiol gel for 28 days with 200 mg progesterone for 14 days (5 women): No evidence of hyperplasia after 5 years of treatment.2
- Percutaneous estradiol gel can be prescribed at low doses.
- Relief of menopausal symptoms can begin as early as 2 weeks after starting treatment.
- Treatment with estradiol gel maintains or increases bone mineral density.
- No large randomized, controlled trials have explored the effect of estradiol gel on coronary artery disease. It appears to have metabolic effects similar to those of oral estradiol.
- Because percutaneous estradiol stimulates the endometrium, women with an intact uterus should also take a progestogen.
Although the Women’s Health Initiative1 discouraged many menopausal women from using oral estrogen, it failed to address the risks of treatment with other dosages or forms of estrogen and progestin.
Nor has any other trial of similar size and complexity taken up the issue. However, numerous smaller studies have been published.
This article summarizes findings on percutaneous delivery of estradiol gel (EstroGel), the most recently FDA-approved estrogen option for treatment of menopausal symptoms.
It describes the overall safety of estradiol gel, as well as its effectson:
- menopausal symptoms,
- bone,
- metabolism, and
- endometrium.
(In this article, “percutaneous delivery” refers to estradiol gel applied to the skin, and “transdermal estradiol” indicates delivery via a transdermal reservoir or matrix system, otherwise known as “the patch.” I have used an arbitrary definition to distinguish the gel from other methods of delivering estradiol across the skin. For example, Estrasorb is a liposomal formulation that is applied to the skin of the thigh. Although it is a percutaneous estradiol similar to the gel, this article focuses only on the latter option.)
Easy to apply, few skin reactions
Percutaneous estradiol gel formulations have been available for almost 30 years in Europe, where they are utilized by a majority of women on hormone therapy. In the United States, the hydroalcoholic gel is packaged in a pump that delivers 64 standardized 1.25-g doses, which contain 0.75 mg of 17ß-estradiol. Once it is applied, the gel is absorbed into an intradermal reservoir (FIGURE) and dries in 2 to 5 minutes, leaving no residue.
Patient selection. Estradiol gel is well-suited for patients who are concerned about the risks of oral estrogen (as portrayed in the mainstream press following the Women’s Health Initiative) and want to avoid that route of administration, as well as women who dislike or have difficulty swallowing pills. Percutaneous administration also is appropriate for physically active women who may have adhesion problems or skin irritation with the transdermal patch, or those who have had reactions to local adhesives in the past. The patient should be motivated to apply the gel on a daily basis.
Indications are moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy, although topical vaginal products should also be considered for the latter indication.
Contraindications are undiagnosed abnormal vaginal bleeding; history of breast cancer, other estrogen-dependent malignancy, stroke, heart attack, or liver disease or dysfunction; active thrombophlebitis or thromboembolic disorders (or a history of these); and known or suspected pregnancy.
Common side effects include headache, breast pain, irregular vaginal bleeding or spotting, stomach cramps or bloating, nausea and vomiting, and hair loss.
- Skin reactions are infrequent, but should be taken into account when discussing per-cutaneous or transdermal delivery of any drug. However, estradiol gel appears to cause fewer skin reactions than the patch. In a study over more than 5 years, 0 of 157 women treated with percutaneous estradiol reported skin irritation.2 Other comparisons found similar outcomes.3,4
Onset of action is rapid, as it is with the transdermal patch.5 Dose variability is minimized when the gel is applied at the same time every day to a large area of skin, preferably the arm, although all application sites appear to produce similar results: abdomen, shoulders, arms, and inner thigh.6 The gel should not be applied to the breast or vagina.
Diminished effect with skin washing. In 1 trial, site washing 1/2 hour after application significantly decreased bioavailability and time to reach peak plasma concentrations.7 For this reason, the gel should be not applied before a bath, shower, or sauna.
Dosing options. The initial dose is 1.25 mg of gel, which is 1 pump of the bottle. The gel is collected in the palm of 1 hand and applied to the skin of the opposite arm from the wrist to the shoulder. The dose can be titrated by adding a second pump of the gel and applying it to the opposite arm. The dose can be lowered by using less than a full depression of the pump.
Stable, physiologic estrogen levels
Estradiol gel produces relatively stable serum estradiol levels, and therapeutic estradiol levels similar to those seen with other formulations, routes of administration, and dosages.
Percutaneous administration produces serum estrone to estradiol ratios close to 1, in contrast to higher ratios (5:1) with oral administration.8-11 The lower ratio approximates levels during the menstrual cycle of premenopausal women. (TABLE 1 gives estradiol and estrone levels from different studies following administration of estradiol as a gel, oral formulation, and transdermal patch.)
The percutaneous route also allows for delivery directly to the systemic circulation, avoiding gastrointestinal and first-pass hepatic metabolism and elimination. In contrast, oral micronized estradiol causes large fluctuations in serum estradiol and estrone levels due to absorption and metabolism.8
More stable serum levels than with the patch. One study12 comparing percutaneous and transdermal estradiol found similar interindividual variability but less stable serum levels in women using the transdermal system. A separate study13 also reported greater fluctuation of serum estradiol levels in women using a transdermal system than in those using the gel.
TABLE 1
Serum estradiol and estrone levels for various routes of estradiol
| AUTHOR | THERAPY | ESTRADIOL LEVEL (PG/ML) | ESTRONE LEVEL (PG/ML) |
|---|---|---|---|
| Scott et al8 | E2gel 3 mg/day | 102.9±39.9 | 120.0±50.5 |
| E2gel 1.5 mg/day | 68.1±27.4 | 90.6±45.7 | |
| Transdermal estradiol 50 μg/day | 41.1±13.5 | 45.0±15.9 | |
| Oral micronized estradiol 2 mg/day | 114.0±65.2 | 575.2±279.9 | |
| Palacios et al10 | E2gel 1.5 mg/day | 75.7±1.0 | 58.5±2.9 |
| Oral conjugated estrogen 0.625 mg/day | 39.6±4.6 | 126.0±7.6 | |
| Basdevant et al11 | E2gel 3 mg/day | 221.0±35.0 | 146.0±19.0 |
| Oral micronized estradiol 2 mg/day | 121.0±27.0 | 811.0±370.0 | |
| Archer15 | E2gel 0.75 mg/day | 33.5* | 49.0* |
| E2gel 1.5 mg/day | 65.0* | 58.0* | |
| Placebo | 5.0* | 23.0* | |
| *Median value | |||
| E2gel = percutaneous estradiol gel | |||
Studies compared relief of menopausal symptoms
Estradiol gel effectively relieved meno-pausal symptoms in randomized, double-blind studies, open label comparisons, and observational trials in postmenopausal women, with and without the addition of various progestins.
Symptom relief in comparison with baseline values is statistically significant as early as 2 weeks after initiating treatment. Relief of up to 2 years’ duration has been reported.3,14
Several studies have compared symptom relief achieved with estradiol gel, oral estrogen, transdermal delivery systems, and placebo3,9,14-18; findings are summarized in TABLE 2.
Same efficacy when progestogen is added. The following studies, and other studies,14 demonstrated that estradiol gel relieves menopausal symptoms whether it is administered alone or in combination with a progestogen, with efficacy similar to other estrogen formulations:
Climacteric symptoms decreased to the same extent when estradiol gel was combined with a levonorgestrel-releasing intrauterine device, oral micronized progesterone, or vaginal micronized progesterone.19
A study20 that added lynestrenol decreased the frequency of hot flushes and night sweats more than in women using estradiol gel alone. However, negative mood symptoms were more pronounced in the progestin-treated group.
Estradiol gel 1 mg/day in combination with monthly or quarterly oral medroxyprog-esterone acetate reduced the severity of hot flushes, sweating, and vaginal dryness, according to a 12-month trial.21
Symptoms decreased the same whether a levonorgestrel-releasing IUD or oral or vaginal progesterone was added.
Bone mineral density maintained or increased
Several randomized, controlled trials have documented the effects of estradiol gel on bone mineral density (BMD) and various markers of bone metabolism. In these studies, BMD remained steady22,23 or increased10,24,25 following treatment, and estradiol gel remained effective for up to 4 years.25 Estradiol gel maintained or increased BMD with or without addition of progestins.22,23,26
These investigations involved measurement of BMD at the lumbar spine, forearms, or hip, as well as biologic markers of bone turnover such as urinary hydroxyproline/creatinine ratio, serum alkaline phosphatase, and serum osteocalcin.
Serum estradiol and skeletal uptake of a bone-seeking agent also were determined. Estradiol gel regimens ranged from 0.75 mg/day to 3 mg/day, and populations included both surgical and natural menopausal subjects in several countries.
Effects comparable to oral estrogen. Compared with oral conjugated estrogen, which increased BMD at the lumbar spine by 4.3% (±3.2%), estradiol gel produced increases of 5.6% (±2.9%) at 24 months and 4.7% (±3.2%) at 36 months.10
The case. A 52-year-old woman with no menses for 8 months presents for management complaining of disabling hot flushes. Although she is moderately obese, with a body mass index of 29, she is normotensive without any other significant medical history except for hysterectomy at age 44 for excessive bleeding.
Counseling. During her 20s, the patient tried to use oral contraceptives on 3 separate occasions, but was unable to continue them because of nausea. Although she is interested in estrogen therapy for her vasomotor symptoms, she is concerned about the possibility of experiencing nausea again. You explain that one of the benefits of percutaneous estradiol is that it avoids the gastrointestinal tract.
Physical findings. Her physical examination is within normal limits, and gynecologic examination confirms no uterus and finds no palpable adnexal masses.
Outcome. After weighing the pros and cons, she elects to use estradiol gel. At her 3-month follow-up, she reports effective relief and good compliance.
Minimum level of protection achieved. Following a comparison of oral and percutaneous estradiol, Reginster et al27 suggested that a minimum estradiol level of 60 pg/mL is necessary to prevent postmenopausal bone loss. Mean serum estradiol levels in women receiving 1.5 mg/day estradiol gel were 75.7 pg/mL and 78.4 pg/mL at 24 and 36 months, respectively, in a study by Palacios et al,10 and 85.8 pg/mL in a study by Devogelaer and colleagues.24 In these trials, BMD increased, and it remained steady in other investigations.28,29
More recent trials suggest that lower serum estradiol levels secondary to smaller estrogen doses have the capacity to maintain BMD.30,31 A 1.9% mean increase of BMD at the lumbar spine was reported in women with a mean serum concentration of 17 pg/mL in a 2-year study30 of a transdermal estradiol delivery system. The percutaneous route does not appear to limit these beneficial effects.
How are metabolic factors affected?
In general, oral estrogens produce beneficial changes in lipid metabolism, particularly higher levels of high-density lipoprotein (HDL) cholesterol. However, they also elevate triglyceride and glucose levels. How this plays out clinically is unclear. Both the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study (HERS) found no cardioprotective effects of oral estrogen despite increases in HDL and decreases in low-density lipoprotein (LDL) levels.1,32
Oral versus percutaneous estradiol. No long-term studies of this magnitude have investigated the effect of percutaneous estradiol on coronary artery disease, although numerous clinical trials have shown that the route of estrogen delivery affects many of the metabolic variables used to estimate the risk of negative cardiac outcomes. It remains to be determined whether percutaneous estradiol affects these metabolic factors in ways that influence morbidity and mortality.
In 1 trial,33 oral conjugated estrogen led to the following significant changes in lipids:
- increase in very low density lipoprotein (VLDL) cholesterol,
- decrease in LDL cholesterol (but not the LDL apoprotein B),
- increase in HDL and apoprotein A1, and
- significant increase in HDL2 cholesterol.
In a separate study,9 oral conjugated estrogen had a 2.5-fold increase in serum angiotensin, and percutaneous estradiol gel, no effect.
Same effects when progestin is added. Beneficial effects were not diminished when oral micronized progesterone was added to percutaneous estradiol.34 Estradiol gel significantly reduced total serum cholesterol and LDL cholesterol in the first year of treatment, compared with placebo.
Coagulation effects. Percutaneous estradiol has fewer negative effects on coagulation factors than its oral counterpart. One study35 investigating combination therapy with micronized progesterone compared the effects of percutaneous estradiol and oral estradiol valerate. The group receiving percutaneous estradiol gel/micronized progesterone had no significant changes in plasminogen activator inhibitor, tissue-type plasminogen concentration, and global fibrinolytic capacity. The other group had a significant decrease in mean tissue-type plasminogen concentration and plasminogen activator inhibitor activity and a significant rise in global fibrinolytic capacity.
The oral estradiol—but not the percutaneous formulation—significantly increased the mean value of prothrombin activation peptide and decreased mean antithrombin activity compared with no treatment.
Poor glycemic control may increase the risk of cardiovascular disease, but oral and percutaneous estradiol appear to have similar glycemic effects. A comparative trial36 of oral estradiol valerate 2 mg/day and percutaneous estradiol 1 mg/day found no differences in glycosylated hemoglobin A1c levels (declined in both groups) or in fasting and 2-hour post-prandial blood glucose levels (constant in both groups) or insulin sensitivity.
Treatment duration may also influence how percutaneous estradiol affects metabolic factors. An open-label longitudinal prospective study37 of 30 women receiving estradiol gel 1.5 mg/day for 6 months found a significant decrease in lipoprotein (a), apoprotein A-I, apoprotein B, HDL cholesterol, and HDL3 cholesterol. At 1 year, however, these changes were not significant.
No association with venous thromboembolism. Transdermal estradiol administered as a patch or percutaneous gel had no effect on the risk of venous thromboembolism in a multicenter case-control investigation.38
In contrast, a recent retrospective study found a risk of venous thromboembolism that was at least 4 times greater with oral estrogen than with transdermal estradiol.38
Use a progestogen to prevent endometrial hyperplasia
Like other forms of estrogen, percutaneous estradiol stimulates the endometrium. For this reason, women who have an intact uterus should use a progestogen in an adequate dose to prevent hyperplastic changes.39 Although numerous regimens appear to be effective, the optimal route, dose, and duration of progestin in women using percutaneous estrogen remain to be determined.
Percutaneous estradiol versus other routes of administration. Endometrial thickness and amenorrhea rates over 6 months were not statistically different among 54 women treated with estradiol gel 1.5 mg/day, transdermal estradiol 50 μg/day, or oral estradiol valerate 2 mg/day—all in combination with nomegestrol acetate 2.5 mg/day.40 The overall rates of no bleeding or spotting over 6 cycles of treatment were 78% in the percutaneous estradiol group, 48% in the transdermal group, and 60% in the oral group.
Although the percutaneous estradiol group had a lower overall incidence of no bleeding or spotting than the other groups, the difference was not significant. Nor were there significant differences in the variation of endometrial thickness from baseline: A mean increase of 1.5 mm (±0.4 mm) was reported in the percutaneous group, compared with 1.5 mm (±0.7 mm) and 1.7 mm (±0.6 mm) in the transdermal and oral estrogen groups, respectively.
Estrogenic and progestogenic effects were similar for transdermal and percutaneous estradiol (with dydrogesterone 10 mg/day for days 1 to 12) after a baseline atropic endometrium was identified.3
Estradiol gel produces stable, physiologic serum estradiol levels and has a serum estrone to estradiol ratio close to 1.
The most effective progestogen dosage and duration are unknown, although many regimens have been studied:
- Percutaneous estradiol 1.5 mg/day for the first 24 days of the month in combination with nomegestrol acetate 5 mg/day for days 11 to 24: Over 6 months, researchers found a secretory pattern in the majority of women and no evidence of hyperplasia.18
- Percutaneous estradiol 3 mg/day for 3 of every 4 weeks in combination with nomegestrol acetate 5 mg/day for 10 days: No reduction in estrogenic endometrial effects.41,42
- Estradiol gel 3 mg/day for 3 of every 4 weeks in combination with 200 mg or 300 mg oral micronized progesterone for the last 10 days of treatment: Dose was too low or treatment too short to produce a complete secretory transformation of the endometrium.43 However, the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial44 found no increased occurrence of hyperplasia in women using micronized progesterone 200 mg for 12 days of each cycle for more than 3 years in combination with oral conjugated estrogen 0.625 mg.
- Percutaneous estradiol 1.5 mg/day combined with micronized progesterone 100 mg daily (orally or vaginally) for the first 25 days of the month: Fully inhibited mitoses and induced amenorrhea in most of the women studied, with amenorrhea rates of 93.3% at 3 months and 91.6% at 6 months.45
- Estradiol gel 1.5 mg/day with 100 mg vaginal micronized progesterone for 21 days per cycle: Stable endometrial thickness and no endometrial hyperplasia over 12 months.46 However, breakthrough bleeding was reported in up to 30% of subjects, principally in the second 3 months of treatment.
- Percutaneous estradiol 1 mg/day for 3 months with oral medroxyprogesterone acetate 20 mg/day for the last 14 days, followed by a 7-day free interval: No reports of endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 2 mg/day for 21 days with 10 mg oral medroxyprogesterone acetate for the last 14 days, followed by a 7-day free interval: No endometrial hyperplasia or suspect changes at 12 and 24 months.17
- Estradiol gel 1 mg/day with medroxyprogesterone acetate 10 mg on days 1-12 every month or every 3 months: Endometrial hyperplasia was found in 1 woman (0.3%) in the group receiving the progestogen every 3 months. Endometrial histology did not differ between women taking medroxyprogesterone monthly and those taking it every 3 months.21
- Estradiol gel 3 mg/day with oral micronized progesterone 200 mg for 12 days of each cycle: Regular withdrawal bleeding in 70% of women.34
- Percutaneous estradiol 1.5 mg/day in combination with a levonorgestrel-releasing intrauterine device: 80% of women were amenorrheic at 1 year, with a mean endometrial thickness 3 mm; at 5 years, 100% of women had epithelial atrophy.47
- Estradiol gel 1.5 mg for 21 days with 200 mg oral progesterone for 14 days (126 women); 3 mg percutaneous estradiol for 21 days with 300 mg oral progesterone for 10 days (23 women); 1.5 mg estradiol gel with 300 mg oral progesterone (3 women); or 3 mg estradiol gel for 28 days with 200 mg progesterone for 14 days (5 women): No evidence of hyperplasia after 5 years of treatment.2
1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
2. Moyer DL, de Lignieres B, Driguez P, et al. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993;59:992-997.
3. Hirvonen E, Cacciatore B, Wahlström T, et al. Effects of transdermal oestrogen therapy in postmenopausal women: a comparative study of an oestradiol gel and an oestradiol delivering patch. BJOG. 1997;104(Suppl 16):26-31.
4. Travassos de Figueiredo Alves S, et al. Comparison of gel and patch estradiol replacement in Brazil, a tropical country. Maturitas. 2000;36:69-74.
5. Henzl MR, Loomba PK. Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. J Reprod Med. 2003;48:525-540.
6. Holst J, et al. Serum estrogen levels after topic application of estradiol-17 beta on two different cutaneous areas. Acta Obstet Gynecol Scand. 1987;662:151-152.
7. Jarvinen A, Granander M, Nykanen S, Laine T, Geurts P, Viitanen A. Steady-state pharmacokinetics of oestradiol gel in post-menopausal women: effects of application area and washing. Br J Obstet Gynaecol. 1997;104(Suppl 16):14-18.
8. Scott RT, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991;77:758-764.
9. Dupont A, Dupont P, Cusan M, et al. Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women. Maturitas. 1991;13:297-311.
10. Palacios S, Menéndez C, Jurado AR, Vargas JC. Effects of percutaneous oestradiol versus oral oestrogens on bone density. Maturitas. 1995;20:209-213.
11. Basdevant A, de Lignieres B, Simon P, et al. Hepatic lipase activity during oral and parenteral 17ß-estradiol replacement therapy: high-density lipoprotein increase may not be antiatherogenic. Fertil Steril. 1991;55:1112-1117.
12. Simon JA, et al. Are there significant differences between patch and gel cutaneous estradiol therapy? In: Genazzani AR, Petraglia F, Volpe A, Facchinetti F, eds. Recent Research on Gynecological Endocrinology. Casterton Hall, Carnforth, Lancashire, UK: Parthenon Publishing, Casterton Hall; 1998;317-324.
13. Paoletti AM, et al. Comparison of pharmacokinetic profiles of 17ß-estradiol gel 0.6mg/g (Gelestra) with a transdermal delivery system (Estraderm TTS 50) in postmenopausal women at steady state. Maturitas. 2001;40:203-209.
14. Jensen PB, Jensen J, Riis BJ, et al. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas. 1987;9:207-215.
15. Archer DF. for the EstroGel Study Group. Percutaneous 17ß-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
16. Kornafel KL, March CM. Estradiol gel in the treatment of menopausal symptoms: a placebo-controlled double-blind case study of efficacy and safety. South Med J. 1992;85:270-273.
17. Hirvonen E, Lamberg-Allardt C, Lankinen KS, Geurts P, Wilén-Rosenqvist G. Transdermal oestradiol gel in the treatment of the climacterium: a comparison with oral therapy. BJOG. 1997;104(Suppl 16):19-25.
18. Foidart JM, Béliard A, Hedon B, et al. Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium. BJOG. 1997;104:305-310.
19. Suvanto-Luukkonen E, Sundström H, Penttinen J, et al. Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy. Maturitas. 1997;26:211-17.
20. Holst J, et al. Progestogen addition during oestrogen replacement therapy—effects on vasomotor symptoms and mood. Maturitas. 1989;11:13-20.
21. Hirvonen E, et al. Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding. Climacteric. 2000;3:262-270.
22. Ng HT, Chang SP, Yang TS, Cho MP, Wei TC. Estradiol administered in a percutaneous gel for the prevention of postmenopausal bone loss. Asia-Oceania J Obstet Gynaecol. 1993;19(2):115-119.
23. Riis B, Thomsen K, et al. Does calcium supplementation prevent postmenopausal bone loss? A double blind, controlled clinical study. N Engl J Med. 1987;316:173-177.
24. Devogelaer JP, Lecart C, Dupret P, De Nayer P, Nagant De Deuxchaisnes C. Long-term effects of percutaneous estradiol on bone loss and bone metabolism in post-menopausal hysterectomized women. Maturitas. 1998;28:243-249.
25. Wimalawansa SJ. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four year randomized study. Am J Med. 1995;99:36-42.
26. Sun A, Lin S, Yu W, et al. Percutaneous estrogen in prevention of early post-menopausal bone loss in Chinese women. Chin Med J. 2002;115:1790-1795.
27. Reginster JY, Sarlet N, Deroisy R, et al. Minimum levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int. 1992;51:340-343.
28. Cicinelli E, Cantatore FP, Galantino P, et al. Effects of continuous percutaneous estradiol administration on skeletal turnover in postmenopausal women: a 1-year prospective controlled study. Eur J Obstet Gynecol Reprod Biol. 1996;69(2):109-113.
29. Riis B, et al. The effect of percutaneous estradiol and natural progesterone on post-menopausal bone loss. Am J Obstet Gynecol. 1987;156:61-65.
30. Notelvitz M, John VA, Good WR. Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, post-menopausal women. Menopause. 2002;9:343-353.
31. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17ß-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003;290:1042-1048.
32. Hully S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.
33. Moorjani S, Dupont A, Labrie F, et al. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with Utrogestan in menopausal women. J Clin Endocrinol Metab. 1991;73:373-379.
34. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gyencol. 1987;156:66-71.
35. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17:3071-3078.
36. Karjalainen A, Paassilta M, Heikkinen J, et al. Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism. Clin Endocrin. 2001;54:165-173.
37. Haines CJ, Chung TKH, Masarei JRL, Tomlinson B, Lau JTF. The effect of per-cutaneous oestrogen replacement therapy on Lp(a) and other lipoproteins. Maturitas. 1995;22:219-225.
38. Scarabin PY, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432.
39. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
40. Blanc B, Cravello L, Micheletti MC, et al. Continuous hormone replacement therapy for menopause combining nomegestrol acetate and gel, patch, or oral estrogen: a comparison of amenorrhea rates. Clin Therap. 1998;20(5):901-912.
41. Holst J. Percutaneous estrogen therapy. Endometrial response and metabolic effects. Acta Obstet Gynecol Scand Suppl. 1983;115:1-30
42. Holst J, Cajander S, von Schoultz B. Cellular morphometric analysis of the post-menopausal endometrium during treatment with percutaneous estradiol-17ß with and without oral gestagen. Acta Obstet Gynecol Scand. 1983;62:267-270.
43. Holst J, Cajander S, von Schoultz B. Endometrial response in post-menopausal women during treatment with percutaneous 17ß-oestradiol opposed by oral progesterone. Maturitas. 1986;8:201-207.
44. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370-375.
45. Gillet JY, Andre G, Faguer B, et al. Induction of amenorrhea during hormone replacement therapy: optimized micronized progesterone dose. A multicenter study. Maturitas. 1994;19:103-115.
46. Vilodre LC, et al. Endometrial response to a cyclic regimen of percutaneous 17ß-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension. Gynecol Endocrinol. 2003;17:323-328.
47. Suvanto-Luukkonen E, Kauppila A. The levonorgestrel intrauterine system in menopausal hormone replacement therapy: five-year experience. Fertil Steril. 1999;72:161-163.
1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
2. Moyer DL, de Lignieres B, Driguez P, et al. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril. 1993;59:992-997.
3. Hirvonen E, Cacciatore B, Wahlström T, et al. Effects of transdermal oestrogen therapy in postmenopausal women: a comparative study of an oestradiol gel and an oestradiol delivering patch. BJOG. 1997;104(Suppl 16):26-31.
4. Travassos de Figueiredo Alves S, et al. Comparison of gel and patch estradiol replacement in Brazil, a tropical country. Maturitas. 2000;36:69-74.
5. Henzl MR, Loomba PK. Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. J Reprod Med. 2003;48:525-540.
6. Holst J, et al. Serum estrogen levels after topic application of estradiol-17 beta on two different cutaneous areas. Acta Obstet Gynecol Scand. 1987;662:151-152.
7. Jarvinen A, Granander M, Nykanen S, Laine T, Geurts P, Viitanen A. Steady-state pharmacokinetics of oestradiol gel in post-menopausal women: effects of application area and washing. Br J Obstet Gynaecol. 1997;104(Suppl 16):14-18.
8. Scott RT, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991;77:758-764.
9. Dupont A, Dupont P, Cusan M, et al. Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women. Maturitas. 1991;13:297-311.
10. Palacios S, Menéndez C, Jurado AR, Vargas JC. Effects of percutaneous oestradiol versus oral oestrogens on bone density. Maturitas. 1995;20:209-213.
11. Basdevant A, de Lignieres B, Simon P, et al. Hepatic lipase activity during oral and parenteral 17ß-estradiol replacement therapy: high-density lipoprotein increase may not be antiatherogenic. Fertil Steril. 1991;55:1112-1117.
12. Simon JA, et al. Are there significant differences between patch and gel cutaneous estradiol therapy? In: Genazzani AR, Petraglia F, Volpe A, Facchinetti F, eds. Recent Research on Gynecological Endocrinology. Casterton Hall, Carnforth, Lancashire, UK: Parthenon Publishing, Casterton Hall; 1998;317-324.
13. Paoletti AM, et al. Comparison of pharmacokinetic profiles of 17ß-estradiol gel 0.6mg/g (Gelestra) with a transdermal delivery system (Estraderm TTS 50) in postmenopausal women at steady state. Maturitas. 2001;40:203-209.
14. Jensen PB, Jensen J, Riis BJ, et al. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas. 1987;9:207-215.
15. Archer DF. for the EstroGel Study Group. Percutaneous 17ß-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
16. Kornafel KL, March CM. Estradiol gel in the treatment of menopausal symptoms: a placebo-controlled double-blind case study of efficacy and safety. South Med J. 1992;85:270-273.
17. Hirvonen E, Lamberg-Allardt C, Lankinen KS, Geurts P, Wilén-Rosenqvist G. Transdermal oestradiol gel in the treatment of the climacterium: a comparison with oral therapy. BJOG. 1997;104(Suppl 16):19-25.
18. Foidart JM, Béliard A, Hedon B, et al. Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium. BJOG. 1997;104:305-310.
19. Suvanto-Luukkonen E, Sundström H, Penttinen J, et al. Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy. Maturitas. 1997;26:211-17.
20. Holst J, et al. Progestogen addition during oestrogen replacement therapy—effects on vasomotor symptoms and mood. Maturitas. 1989;11:13-20.
21. Hirvonen E, et al. Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding. Climacteric. 2000;3:262-270.
22. Ng HT, Chang SP, Yang TS, Cho MP, Wei TC. Estradiol administered in a percutaneous gel for the prevention of postmenopausal bone loss. Asia-Oceania J Obstet Gynaecol. 1993;19(2):115-119.
23. Riis B, Thomsen K, et al. Does calcium supplementation prevent postmenopausal bone loss? A double blind, controlled clinical study. N Engl J Med. 1987;316:173-177.
24. Devogelaer JP, Lecart C, Dupret P, De Nayer P, Nagant De Deuxchaisnes C. Long-term effects of percutaneous estradiol on bone loss and bone metabolism in post-menopausal hysterectomized women. Maturitas. 1998;28:243-249.
25. Wimalawansa SJ. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four year randomized study. Am J Med. 1995;99:36-42.
26. Sun A, Lin S, Yu W, et al. Percutaneous estrogen in prevention of early post-menopausal bone loss in Chinese women. Chin Med J. 2002;115:1790-1795.
27. Reginster JY, Sarlet N, Deroisy R, et al. Minimum levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int. 1992;51:340-343.
28. Cicinelli E, Cantatore FP, Galantino P, et al. Effects of continuous percutaneous estradiol administration on skeletal turnover in postmenopausal women: a 1-year prospective controlled study. Eur J Obstet Gynecol Reprod Biol. 1996;69(2):109-113.
29. Riis B, et al. The effect of percutaneous estradiol and natural progesterone on post-menopausal bone loss. Am J Obstet Gynecol. 1987;156:61-65.
30. Notelvitz M, John VA, Good WR. Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, post-menopausal women. Menopause. 2002;9:343-353.
31. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17ß-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003;290:1042-1048.
32. Hully S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.
33. Moorjani S, Dupont A, Labrie F, et al. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with Utrogestan in menopausal women. J Clin Endocrinol Metab. 1991;73:373-379.
34. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gyencol. 1987;156:66-71.
35. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17:3071-3078.
36. Karjalainen A, Paassilta M, Heikkinen J, et al. Effects of peroral and transdermal oestrogen replacement therapy on glucose and insulin metabolism. Clin Endocrin. 2001;54:165-173.
37. Haines CJ, Chung TKH, Masarei JRL, Tomlinson B, Lau JTF. The effect of per-cutaneous oestrogen replacement therapy on Lp(a) and other lipoproteins. Maturitas. 1995;22:219-225.
38. Scarabin PY, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432.
39. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
40. Blanc B, Cravello L, Micheletti MC, et al. Continuous hormone replacement therapy for menopause combining nomegestrol acetate and gel, patch, or oral estrogen: a comparison of amenorrhea rates. Clin Therap. 1998;20(5):901-912.
41. Holst J. Percutaneous estrogen therapy. Endometrial response and metabolic effects. Acta Obstet Gynecol Scand Suppl. 1983;115:1-30
42. Holst J, Cajander S, von Schoultz B. Cellular morphometric analysis of the post-menopausal endometrium during treatment with percutaneous estradiol-17ß with and without oral gestagen. Acta Obstet Gynecol Scand. 1983;62:267-270.
43. Holst J, Cajander S, von Schoultz B. Endometrial response in post-menopausal women during treatment with percutaneous 17ß-oestradiol opposed by oral progesterone. Maturitas. 1986;8:201-207.
44. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370-375.
45. Gillet JY, Andre G, Faguer B, et al. Induction of amenorrhea during hormone replacement therapy: optimized micronized progesterone dose. A multicenter study. Maturitas. 1994;19:103-115.
46. Vilodre LC, et al. Endometrial response to a cyclic regimen of percutaneous 17ß-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension. Gynecol Endocrinol. 2003;17:323-328.
47. Suvanto-Luukkonen E, Kauppila A. The levonorgestrel intrauterine system in menopausal hormone replacement therapy: five-year experience. Fertil Steril. 1999;72:161-163.
Cutting the medicolegal risk of shoulder dystocia
Clip-and-save shoulder dystocia documentation form
Practice recommendations
Among the intrapartum events that constitute bona fide emergencies, shoulder dystocia stands out. This obstetric emergency is the focus of an increasing number of medical liability cases. Most lawsuits involving shoulder dystocia allege negligence as the cause of the brachial plexus injury, fractured clavicle or humerus, or other injury. The defendant physicians named in these suits are often accused of inappropriately managing the prenatal or intrapartum course or the dystocia itself—or of inadequately documenting the steps taken to resolve the emergency.
To glean insights into the litigation process as it involves shoulder dystocia, we retrospectively reviewed all cases closed by the Boston-based ProMutual Group, a major liability insurance carrier, over a 7-year period. We wanted to learn more about the plaintiffs themselves, as well as the clinical and medicolegal factors that led to jury awards or indemnity payments. We also wanted data that could serve as the foundation for guidelines on how to proceed in the event of shoulder dystocia, as well as a documentation tool.
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Nurse and physician document different times
A 31-year-old woman in her 10th week of pregnancy had one prior uncomplicated vaginal delivery of a 9 lb 7 oz infant. Her prenatal course proceeds unremarkably, with a normal glucose tolerance test and total weight gain of 36 lb. At 41 weeks and 2 days, the estimated fetal weight is documented as 4,120 g. Labor is induced with oxytocin. Because of maternal fatigue, vacuum delivery is attempted.
Notes of the physician and the nurse differ regarding the time of the first of 3 vacuum applications.
After delivery of the head, shoulder dystocia is encountered. In a note handwritten immediately after delivery, the physician states that the head was “reconstituted as right occiput anterior with the left shoulder anterior.”
In a note dictated later, however, the same physician states the right shoulder was anterior.
Help is summoned and arrives 20 minutes after the dystocia is first encountered. The time that help was summoned is in question since there is an 18-minute discrepancy between the times the physician and the nurse note that assistance was called.
Despite the use of suprapubic pressure and maneuvers including McRoberts and Wood’s corkscrew, shoulder dystocia persists for 24 minutes. Apgars of the 11 lb 3 oz infant are 0, 1, and 3. The child is resuscitated but dies within 2 days of birth.
Outcome
Settled with a 7-figure indemnity payment.
What the defense experts said
The key issues involve documentation and summoning assistance. Discrepancies in documentation almost always cast doubt upon the credibility of a defendant. Ideally, there should be no discrepancies between nurse and physician notes and, certainly, no discrepancies between 2 notes on the same case by the same physician. If, in this case, the physician realized after writing the first note that the anterior shoulder had been incorrectly identified, a correction should have been written as a separate note.
Use of the shoulder dystocia documentation tool (see) helps create a chronology of events, which may prove vital to a successful defense.
The call for help might not have been delayed if the labor and delivery unit had had a shoulder dystocia protocol including “drills” for all team members. Help should be called as soon as a shoulder dystocia is encountered so that, when needed, it is available. Under no circumstances should it take 20 minutes for assistance to arrive.
Brachial plexus injury not always caused by shoulder dystocia
Between 21% and 42% of shoulder dystocias involve an injury1—usually brachial plexus injury. Plaintiff attorneys have manipulated this fact to attribute many cases of neonatal brachial plexus injury to mismanagement of shoulder dystocia by the obstetrician.
They fault the physician for failing to estimate fetal weight, perform a timely cesarean, use appropriate maneuvers correctly, or have a pediatrician present. They criticize nothing more resoundingly than use of “inappropriate” or “excessive” lateral traction to the fetal head.2
Nontraction injuries. The reality can be strikingly different, however. Some cases of brachial plexus injury involve no traction at all.
- Brachial plexus injuries have been reported in infants who had precipitate vaginal deliveries without any physical intervention by the obstetrician.2
- These injuries also have occurred in infants delivered via cesarean section.1,3,4
- In some cases, brachial plexus injuries have affected the posterior arm of neonates whose anterior arm was involved in shoulder dystocia.1,2,5-7
A retrospective study4 found that, of 39 cases of brachial plexus injury, only 17 were associated with shoulder dystocia. Similar findings have emerged from other studies.2,3,8
Other causes. It is unclear how brachial plexus injuries occur in the absence of shoulder dystocia. Some think they arise in response to infectious agents such as toxoplasmosis, coxsackievirus, mumps, pertussis, or mycoplasma pneumonia.2 Some assume a mechanical cause, such as fetal response to longstanding abnormal intrauterine pressure exerted by maternal conditions such as bicornate uterus and uterine fibroids, especially in the lower segment.1,2
When brachial plexus injuries occur in the absence of shoulder dystocia, they likely originated before labor and delivery.4 Some experts suggest serial electromyelograms within the first 7 days of life to establish a prenatal rather than intrapartum etiology. A positive electromyelogram within 1 week of birth would suggest antepartum causation.2,9
Recognizing risk factors for shoulder dystocia best way to reduce injury
Most brachial plexus injuries or impairments are associated with shoulder dystocia,9 and shoulder dystocia is the most common way brachial plexus injuries are introduced into litigation.
Decreasing the number of brachial plexusrelated liability cases, therefore, depends on decreasing the incidence of shoulder dystocia. Unfortunately, a failsafe method continues to elude both clinicians and researchers.10-12
Retrospective studies have identified certain factors that may—but do not necessarily—increase the risk of shoulder dystocia.
Prenatal risk factors include high maternal or paternal birth weight, maternal obesity, excessive weight gain during pregnancy, advanced age, short stature, multiparity, postdates, prior shoulder dystocia, small pelvis, prior delivery of a macrosomic infant, gestational diabetes in an earlier pregnancy, abnormal blood sugars in the current pregnancy, or fetal macrosomia.13,14-16
Intrapartum risk factors include a rapid or prolonged second stage, failure or arrest of descent, presence of considerable molding, and need for a midpelvic delivery.10,15
Predictability. Prospective studies have not established the predictability of shoulder dystocia. A 2000 study17 showed that 55% of cases with 1 or more risk factors experienced shoulder dystocia. Predictability increases somewhat when both maternal diabetes and fetal macrosomia complicate pregnancy, since the rate of shoulder dystocia in women with diabetes is consistently higher than in nondiabetic gravidas. This becomes a significant issue when the infant weighs more than 4,000 g.
Indications for prophylactic cesarean in women with diabetes
In 1999, Wagner et al9 found that 70% of shoulder dystocias in women with diabetes occurred when the fetal weight exceeded 4,000 g. They concluded that cesarean delivery for infants with an estimated weight over 4,250 g would reduce the rate of shoulder dystocia by 75% and increase the cesarean delivery rate by 1%.
Others are more conservative. Gross and colleagues11 suggested that, for every additional 26 cesarean deliveries, only 1 case of shoulder dystocia would be prevented.
Macrosomia. Most obstetricians and researchers still do not advocate prophylactic cesarean delivery for macrosomia alone because, by some estimates, 98% of macrosomic infants are delivered without difficulty.18 However, they do suggest that obstetricians at least consider the possibility of cesarean delivery for a macrosomic fetus when the woman has diabetes.
In a study completed in 2000, Skolbekken19 suggested a cutoff of 4,250 g for women with diabetes. Dildy20 suggested limits of more than 4,500 g for diabetic women and more than 5,000 g for nondiabetic gravidas. However, Conway and Langer21 assert that a cutoff of 4,500 g is too liberal for women with diabetes and maintain that, at this cutoff, 40% of shoulder dystocias would not be prevented.
• Ultrasound measurements. Since estimates of fetal weight have a margin of error approaching 40%,9 others have chosen different parameters for determining fetal macrosomia in women with diabetes. In a retrospective study involving 31 women with gestational diabetes, Cohen et al22 found that subtracting the fetal biparietal diameter from the abdominal diameter—with both measurements obtained via ultrasound—yields a predictability score higher than estimated fetal weight. Specifically, if the difference between the 2 measurements is 2.6 cm or more, the rate of shoulder dystocia is high enough to warrant elective cesarean (FIGURE ).
FIGURE Using ultrasound measurements to predict macrosomia
A simple way to predict fetal macrosomia in women with diabetes is to subtract the fetal biparietal diameter (9.3 cm in the scan at left) from the abdominal diameter (average of 12.44 cm in the scan at right). If the difference exceeds 2.6 cm, elective cesarean is warranted. In this case it is 3.14 cm, indicating elective cesarean is warranted.
When dystocia occurs, have a plan and stick to it
Shoulder dystocia immediately places both mother and neonate at risk for temporary or permanent injury. Thus, it is imperative that all obstetricians and other health-care providers who deliver infants have a well developed plan of action for this emergency. They should immediately ask for obstetric assistance and instruct the mother to discontinue any pushing.
Attempts at vigorous downward traction should be avoided, and no fundal pressure should be applied, as these are known to increase the potential for brachial plexus injury. Gentle downward traction is considered the standard of care.17
The obstetrician’s goal is to free the impacted shoulder as quickly as possible, since a fetus can endure only 8 to 10 minutes of asphyxia before permanent neurologic damage occurs.17 The standard of care requires the obstetrician to know and use certain maneuvers to relieve shoulder dystocia. These maneuvers are designed to facilitate vaginal delivery and reduce the risk of permanent brachial plexus injury. The McRoberts maneuver, with flexion and slight rotation of the maternal hips onto the maternal abdomen, is the standard for initial relief of shoulder dystocia.17,23
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Prompt maneuvers, good outcome
A 28-year-old gravida weighing 214 lb has had 2 previous spontaneous deliveries of infants weighing 8 lb 5 oz and 9 lb 3 oz. Except for a weight gain of more than 60 lb, the pregnancy progressed without complications, and a 3-hour glucose tolerance test was normal. At 40 weeks, the obstetrician notes “concern” about an estimated fetal weight of 10 lb. Induction is planned, but spontaneous labor begins before oxytocin can be given. After 5 hours, the head is delivered without difficulty, but shoulder dystocia follows. The obstetrician extends the episiotomy and performs McRoberts and Wood’s corkscrew maneuvers, but the dystocia persists. Upon noting cyanosis, the obstetrician fractures the infant’s clavicle and quickly delivers a 10 lb 9 oz infant with Apgar scores of 8 and 10. Pediatricians examine the child immediately and diagnose Erb’s palsy, which subsequently resolves. X-rays confirm an undisplaced fracture of the right clavicle. Although the child recovers completely, the family sues, alleging a failure to perform cesarean delivery.
Outcome
Case closed with no payment.
What the defense experts said
Key issues are documentation and informed consent. The overriding opinion of 3 experts who reviewed the case for the defense was that cesarean delivery was not indicated and that in fracturing the clavicle, the physician acted responsibly, quickly, and within the standard of care. One defense expert said failure to document exact maneuvers used to relieve shoulder dystocia deviated from the standard of care. Another defense expert said the physician should have obtained informed consent from this at-risk patient, and explained the risks of shoulder dystocia, including neonatal injury, so that the she might have been better able to appreciate the fact that the obstetrician’s fast action may have saved her child from brain damage or death.
Factors that lead to litigation
In a review article, Hickson24 cited factors that prompted families to file medical liability claims following perinatal injury. Some families observed that, in their search for the cause of an injury, they found 1 or more aspects of care to be inappropriate.
The desire for information, perception of being misled, anger with the medical profession, desire to prevent injuries to others, recognition of long-term sequelae, and advice by knowledgeable acquaintances, as well as the need for money, all appeared to contribute to the decision to file medical liability claims.
Convey the risks, and listen carefully. Communication problems between physicians and patients are a contributing factor. Even when physicians provide technically adequate care, families expect answers to their questions and want to feel as though they have been consulted about important medical decisions.24 If these expectations are not met, even patients who have not experienced an adverse outcome may become angry and express dissatisfaction with care.24
The need for communication is critical when shoulder dystocia results in neonatal injury. Empathizing with the family, helping them understand that most brachial plexus injuries are not long-term, and offering to answer their questions both at the moment and later, may help prevent litigation.
This type of communication can be difficult. It helps to realize that an acknowledgment of distress and concern is not an admission of guilt, and an explanation is not an apology.15 However, an absence of communication or an attempt by the physician to place blame may be perceived as an admission of guilt that gives rise to a lawsuit.
Action plan is what counts in court. A review by Gross et al11 concluded that obstetricians should have a shoulder dystocia plan that enables an instant and orderly response. Also recommended is a protocol to help anticipate clinical problems and prevent medicolegal problems.
Gross and colleagues11 found that the Ob/Gyns with the most defensible cases paid close attention to the patient’s history and prenatal course and, upon encountering dystocia, implemented at least 2 maneuvers (if necessary) and thoroughly documented their actions immediately after delivery.
Fetterman15 agreed, asserting that what counts in court is not so much whether the obstetrician employed the McRoberts maneuver before or after the Wood’s corkscrew maneuver but whether he or she had an action plan in mind, implemented that plan properly, and thoroughly documented the actions taken and the reasons underlying them.
Dissecting legal cases for clues to reduced risk
In the review of medicolegal cases for this article, we limited our search to cases closed between Jan 1, 1995, and Dec 31, 2002, using a computer to search for codes specific to shoulder dystocia as well as the phrases “shoulder dystocia,” “Erb’s palsy,” and “brachial plexus injury.” We identified 61 cases involving 117 defendants and created a data sheet to gather information on patient and physician demographics, medical and obstetric history, description of the incident, analysis rendered by defense and plaintiff experts, and legal and financial outcomes.
Of 117 defendants, 76 were obstetricians. There also were 16 hospitals, 15 corporations, 5 certified nurse-midwives, 1 family physician, 1 emergency physician, and 3 persons categorized as “other.” Age, race, and parity of the 61 plaintiffs are given in TABLE 1.
Twenty-six of the 61 cases, involving 74 defendants, closed with no payment. That is, they were either dismissed or closed with a jury verdict for the defense. The remaining 35 cases involved 43 defendants and were closed with an aggregate indemnity payment of $19.2 million. The mean payment was $445,000 per defendant.
These guidelines are recommended to help prevent, predict, and manage shoulder dystocia and brachial plexus injury.
Obtain a prenatal history that includes the birth weights of both parents and any history of prior shoulder dystocia or cesarean delivery performed for “failure to progress.”
Estimate the fetal weight and take into account the risk for shoulder dystocia when the fetus is determined by ultrasound to be macrosomic.
Perform glucose testing on all patients, and follow up on even a single abnormal glucose reading. Discuss the possibility of shoulder dystocia and the accompanying risk of neonatal injury with “at risk” patients.
Consider obtaining informed consent for vaginal delivery of a patient with risk factors for shoulder dystocia.
Consider cesarean delivery for :
- nondiabetic women when the estimated fetal weight (EFW) exceeds 4,500 g,
- diabetic gravidas when the EFW exceeds 4,000 g,
- women with a prior delivery complicated by shoulder dystocia or brachial plexus palsy,
- gravidas with a prolonged second stage and nonprogression of labor, and
- patients who express fear and doubt about vaginal delivery.
Be sparing with the use of oxytocin when the fetus is known or suspected to be macrosomic, taking special care not to be aggressive with induction.
Use forceps or vacuum extraction with caution, and limit the number of attempts with each.
Minimize traction on the fetal head. Traction that is deemed to be “excessive” may be used against the physician in a liability suit. Gentle traction is acceptable.
Do not use or order fundal pressure. It will almost invariably be used against you in a lawsuit.
Be able to define and correctly describe maneuvers generally accepted as the standard for shoulder dystocia and, when necessary, use and document them appropriately. These include the McRoberts, Wood’s corkscrew, Rubin, and Zavanelli maneuvers; extended episiotomy; suprapubic pressure; and fracture of the anterior clavicle.
Be alert to the possibility of brachial plexus injury in the absence of shoulder dystocia. Obstetricians have been erroneously accused of causing brachial plexus injury by plaintiff attorneys who do not understand that this injury is not always the result of dystocia. Thorough contemporaneous documentation is key in these instances.
Request immediate pediatric assessment of a newborn involved in shoulder dystocia. Have the placenta sent for examination, and request cord blood gases.
Communicate openly and honestly with the parents of a child who has suffered a brachial plexus injury. This may be the single greatest tool for reducing the risk of liability litigation.
Consider serial electromyelograms during the first 7 days of life for a neonate with a brachial plexus palsy. These studies can help determine the etiology of the injury.
Use a shoulder dystocia documentation tool such as the one on page 91. Thorough documentation of all relevant prenatal and intrapartum events is critical to a successful defense. A 12-point detailed delivery note as recommended by Fetterman will also prevent or reduce legal risk.15
Schedule shoulder dystocia “drills” in the labor and delivery unit to familiarize obstetric team members with their roles.
Require comanagement of any midwifery patient at increased risk for shoulder dystocia.
Neonatal injury occurred in all 61 cases. Erb’s palsy was the overwhelming pediatric outcome (57 of 61 cases, or 93.4%), with an aggregate indemnity payment of $17.6 million. Fractured humerus was the outcome in 1 case, and 3 cases involved neonatal deaths.
Reasons for indemnity payments included:
- probable liability (18 defendants),
- plaintiff was sympathetic, likely to evoke an emotional response from the jury (8 defendants),
- clear liability (7 defendants),
- defendant would not have made a strong witness in his or her own defense (5 defendants),
- defendant had died or was too ill to stand trial (3 defendants),
- medical record had been altered (2 defendants),
- case was considered too inflammatory to risk a jury award (2 defendants), and
- policy limits were too low to risk a potentially high jury award (1 defendant).
Five defendants were involved in cases with multiple medicolegal issues that argued for settlement.
The effect of birth weight. Notably, 74% of infants involved in these cases were macrosomic (birth weight over 4,000 g). Except for neonatal injury (100%), no single maternal or fetal variable appears with greater frequency.
The mean indemnity in closed cases increased in direct proportion to fetal weight, ranging from $500,000 in cases involving infants whose birth weight was less than 4,000 g to $950,000 when the birth weight was 5,000 g or more.
Maternal factors seen with greatest frequency included obesity, excessive weight gain in pregnancy, and gestational diabetes. Analysis of prepregnant body mass index found that 19 women had a weight within the “obese” category, 18 of whom gave birth to macrosomic infants. Eight of these cases closed without indemnity payment and 10 closed with an aggregate indemnity payment of $6.5 million.
Forty-eight of the 61 plaintiffs (78.8%) exceeded the normal weight gain in pregnancy based on height and prepregnant weight. Twenty-nine of these cases closed with an aggregate indemnity payment of $16.6 million.
Influence of diabetes. Fifty-two of 61 plaintiffs underwent a glucose screening test. Of these, 23 went on to have a glucose tolerance test, with 12 testing positive for gestational diabetes. Further analysis revealed borderline screening glucose values in an additional 16 cases. These women were not considered diabetic by their obstetricians, were not retested for diabetes, and did not receive nutritional counseling. Macrosomic infants were born to 9 of the 12 patients with gestational diabetes and to 13 of the 16 borderline cases.
Of 28 cases with confirmed or suspected gestational diabetes, 14 women delivered infants weighing over 4,250 g; 11 of the 14 weighed more than 4,500 g.
In a comparison of cases involving diabetic and nondiabetic women who delivered infants weighing more than 4,250 g, 82% of the cases involving nondiabetic women closed without payment. Among cases involving diabetes (actual or borderline), the corresponding figure was 27.3%.
Labor and delivery interventions were cited in all cases. Oxytocin was used in 42 of the 61 cases (68.9%), forceps in 9 (14.8%), and vacuum extraction in 7 (11.5%). Suprapubic pressure was used in 37 cases (60.7%), fundal pressure in 9 (14.8%), and traction on the fetal head in 16 cases (26.2%).
In addition, defense experts determined that the McRoberts maneuver was used in 41 cases (67.2%) and the Wood’s corkscrew maneuver in 28 (45.9%).
Seven cases involved a second stage of labor exceeding 2.5 hours. The ratio of wins to losses decreased substantially with the use of oxytocin, forceps, fundal pressure, or a prolonged second stage.
Data were analyzed using selected variables thought to have an association with winning or losing cases and with indemnity (TABLE 2). No statistically significant models emerged. This is likely due to inadequate power (low number of cases) and the large number of interactions between variables relative to the outcomes evaluated.
TABLE 1
Plaintiff demographics
| CHARACTERISTIC | ALL CASES (n = 61) | CASES WITH INDEMNITY (n = 35) |
|---|---|---|
| Mean age, in years (range) | 28 (17–40) | 29 (18–38) |
| Race (%) | ||
| White | 35 (57) | 21 (60) |
| Black | 12 (20) | 7 (20) |
| Hispanic | 11 (18) | 6 (17) |
| Asian | 1 (2) | — |
| Unknown | 2 (3) | 1 (3) |
| Parity (%) | ||
| 0 | 19 (31) | 11 (31) |
| 1 | 26 (43) | 16 (46) |
| 2 | 11 (18) | 7 (20) |
| 3 | 2 (3) | 1 (3) |
| 4 | 2 (3) | — |
| 5 | 1 (2) | — |
TABLE 2
Litigation outcomes for selected prenatal and intrapartum variables
| CHARACTERISTIC | CLOSED WITHOUT INDEMNITY | CLOSED WITHOUT INDEMNITY PAYMENT | MEAN INDEMNITY ($) | TOTAL INDEMNITY ($) |
|---|---|---|---|---|
| Prenatal factors | ||||
| Gestational diabetes | 5 | 7 | 413,300 | 2,893,000 |
| Adjusted diabetes | 10 | 18 | 521,400 | 9,386,000 |
| Obesity | 8 | 13 | 651,300 | 8,466,000 |
| Intrapartum factors | ||||
| Prolonged second stage | 1 | 6 | 707,700 | 4,247,000 |
| Oxytocin induction | 2 | 10 | 406,500 | 4,065,300 |
| Oxytocin augmentation | 15 | 15 | 737,000 | 11,100,000 |
| Forceps delivery | 1 | 8 | 552,100 | 4,416,800 |
| Vacuum extraction | 3 | 4 | 531,300 | 2,125,000 |
| Episiotomy | 20 | 30 | 579,400 | 17,382,100 |
| McRoberts maneuver | 20 | 21 | 542,900 | 11,400,300 |
| Wood’s corkscrew maneuver | 12 | 16 | 652,300 | 10,436,200 |
| Suprapubic pressure | 17 | 20 | 629,000 | 12,579,400 |
| Traction to fetal head | 7 | 9 | 665,500 | 5,989,500 |
| Fundal pressure | 4 | 7 | 660,700 | 4,625,000 |
4 factors raise risk of litigation
After reviewing the literature and analyzing the ProMutual data, we concluded that shoulder dystocia remains largely unpredictable. However, certain clinical factors are clearly associated with an increased risk for litigation:
- prenatal factors,
- labor and delivery interventions,
- maneuvers performed at the time of the dystocia, and
- fetal outcomes.
Prenatal factors. The most significant prenatal factors were maternal obesity, excessive weight gain in pregnancy, and, especially, diabetes and fetal macrosomia.
• Fetal macrosomia. Although most macrosomic infants deliver without complication, fetal macrosomia was involved in more than 72% of the cases reviewed. Because macrosomia represents a risk not only for shoulder dystocia but also for the litigation that may arise from it, it is important to:
- know and document the estimated fetal weight (EFW);
- discuss the risk of dystocia and its sequelae with the mother and her partner; and
- consider cesarean delivery for estimated fetal weights that suggest macrosomia (see the recommendations on page 82 for specifics).
It also is advisable to mobilize a team for the possibility of shoulder dystocia if vaginal delivery is attempted.
Preparing for the increased risk of a macrosomic fetus can be successful only if macrosomia is both diagnosed and anticipated.
Because macrosomia often is accompanied by maternal diabetes, serum glucose testing is recommended for all gravidas, with follow-up of both abnormal and borderline values.
Labor and delivery interventions were cited in all cases, with data indicating a decreasing ratio of wins to losses with the use of oxytocin, forceps, or fundal pressure, and prolonged second stage.
- Use of oxytocin to augment an already established labor carried less risk than oxytocin for labor induction. Ten of the 12 cases (83.3%) in which oxytocin was used for induction closed with an indemnity payment. However, of the 30 cases in which oxytocin was used for labor augmentation, 50% closed with payment.
- • Forceps and a prolonged second stage. Eight of 9 cases (88.9%) involving forceps and 6 of 7 cases (85.7%) involving a prolonged second stage closed with indemnity payment.
Consider cesarean delivery when the second stage is prolonged or labor fails to progress. Be cautious using forceps and vacuum extraction in these circumstances, and limit the number of attempts with either.
Maneuvers performed at the time of dystocia. The most common maneuverswere McRoberts, suprapubic pressure, and Wood’s corkscrew. The ratio of wins to losses decreased with traction of the fetal head and use of fundal pressure.
Part of the risk-management protocol for obstetricians should be appropriate use of McRoberts maneuver, suprapubic pressure, and Wood’s corkscrew, and cutting a large episiotomy. In addition, be careful not to push, pull, rotate the head, or apply fundal pressure.
Fetal outcomes. All cases involved neonatal injury (Erb’s palsy, fractured humerus) or death.
For this reason, we recommend an action plan that includes immediate pediatric or neonatal assessment of neuromuscular function of the infant’s anterior shoulder. Assess the Moro reflex and the possibility of brachial plexus injury and fractures of the clavicle and humerus. Also examine the placenta, send it to pathology, and perform a cord blood gas analysis.
Last words
Shoulder dystocia is the unfortunate complication of a small number of deliveries, but the focus of an increasing number of lawsuits. Because the neonatal injuries that so often accompany shoulder dystocia often lead to litigation, obstetricians should prepare to identify risk and help patients make informed choices. We should be prepared to manage this emergency whenever it occurs and thoroughly document actions.
Dr. Zylstra reports no financial relationships relevant to this article.
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5. Hankins GDV, Clark SL. Brachial plexus palsy involving the posterior shoulder at spontaneous vaginal delivery. Am J Perinatol. 1995;12:44-45.
6. Gherman RB, Ouzounian JG, Miller DA, Kwok L, Goodwin TM. Spontaneous vaginal delivery: a risk factor for Erb’s palsy? Am J Obstet Gynecol. 1998;178:423-427.
7. Dodds SD, Wolfe SW. Perinatal brachial plexus palsy. Curr Opin Pediatrics. 2000;23:40-47.
8. Wade DM. A Comment on the Trial of Brachial Plexus/Erb’s Palsy Medical Malpractice Cases. Evidence Technologies, Inc. 1994.
9. Wagner RK, Nielsen PE, Gonik B. Controversies in labor management: shoulder dystocia. Obstet Gynecol Clin. 1999;26(2):371-382.
10. McFarland M, Hod M, Piper JM, Xenakis EM-J, Langer O. Are labor abnormalities more common in shoulder dystocia? Am J ObstetGynecol. 1995;173:1211-1214.
11. Gross TL, Sokol RJ, Williams T, Thompson K. Shoulder dystocia: A fetal-physician risk. Am J Obstet Gynecol. 1987;156:1408-1418.
12. Acker DB, Sachs BP, Friedman EA. Risk factors for shoulder dystocia. Obstet Gynecol. 1985;66:762-768.
13. Shoulder dystocia and Erb’s palsy. The Keenan Law Firm. 2002. Available at www.shoulderdystociaattorney.com. Accessed July 23, 2004.
14. Acker DB, Gregory KD, Sachs BP, Friedman EA. Risk factors for Erb-Duchenne palsy. Obstet Gynecol. 1988;71(Part l):390-392.
15. Fetterman HH. Cutting the legal risks of shoulder dystocia. OBG Management. March 1995;41-51.
16. Iffy L, Varadi V, Jakobovits A. Common intrapartum denominators of shoulder dystocia related birth injuries. Zentralbl Gynakol. 1994;116(1):33-37.
17. Calhoun BC, Hume RR, Walters JL. Shoulder Dystocia as a risk for obstetric liability. Legal Medicine. 2000;12-15.
18. Jennett RJ, Tarby TJ. Brachial plexus palsy: an old problem revisited again. Am J Obstet Gynecol. 1997;176:1354-1357.
19. Skolbekken JA. Shoulder dystocia—malpractice or acceptable risk? Acta Obstet Gynecol Scand. 2000;79:750-756.
20. Dildy GA. Fetal macrosomia [slide presentation]. Presented at the 18th Annual Conference on Obstetrics, Gynecology, Perinatal Medicine, and the Law, Boston University School of Medicine and the Center for Human Genetics, January 2002, Kauai, Hawaii.
21. Conway D, Langer O. Elective delivery of infants with macrosomia in diabetic women: reduced shoulder dystocia versus increased cesarean deliveries. Am J Obstet Gynecol. 1998;178(5):922-925.
22. Cohen B, Penning S, Major C, Ansley D, Porto M, Garite T. Sonographic prediction of shoulder dystocia in infants of diabetic mothers. Obstet Gynecol. 1998;88:10-13.
23. Gherman RB, Goodwin TM, Souter I, Neumann K, Ouzounian JG, Paul RH. The McRoberts’ maneuver for the alleviation of shoulder dystocia: how successful is it? Am J Obstet Gynecol. 1997;176:656-661.
24. Hickson GB, Clayton DW, Githens PB, Sloan FA. Factors that prompted families to file medical malpractice claims following perinatal injuries. JAMA. 1992;267:1359-1363.
Clip-and-save shoulder dystocia documentation form
Practice recommendations
Among the intrapartum events that constitute bona fide emergencies, shoulder dystocia stands out. This obstetric emergency is the focus of an increasing number of medical liability cases. Most lawsuits involving shoulder dystocia allege negligence as the cause of the brachial plexus injury, fractured clavicle or humerus, or other injury. The defendant physicians named in these suits are often accused of inappropriately managing the prenatal or intrapartum course or the dystocia itself—or of inadequately documenting the steps taken to resolve the emergency.
To glean insights into the litigation process as it involves shoulder dystocia, we retrospectively reviewed all cases closed by the Boston-based ProMutual Group, a major liability insurance carrier, over a 7-year period. We wanted to learn more about the plaintiffs themselves, as well as the clinical and medicolegal factors that led to jury awards or indemnity payments. We also wanted data that could serve as the foundation for guidelines on how to proceed in the event of shoulder dystocia, as well as a documentation tool.
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Nurse and physician document different times
A 31-year-old woman in her 10th week of pregnancy had one prior uncomplicated vaginal delivery of a 9 lb 7 oz infant. Her prenatal course proceeds unremarkably, with a normal glucose tolerance test and total weight gain of 36 lb. At 41 weeks and 2 days, the estimated fetal weight is documented as 4,120 g. Labor is induced with oxytocin. Because of maternal fatigue, vacuum delivery is attempted.
Notes of the physician and the nurse differ regarding the time of the first of 3 vacuum applications.
After delivery of the head, shoulder dystocia is encountered. In a note handwritten immediately after delivery, the physician states that the head was “reconstituted as right occiput anterior with the left shoulder anterior.”
In a note dictated later, however, the same physician states the right shoulder was anterior.
Help is summoned and arrives 20 minutes after the dystocia is first encountered. The time that help was summoned is in question since there is an 18-minute discrepancy between the times the physician and the nurse note that assistance was called.
Despite the use of suprapubic pressure and maneuvers including McRoberts and Wood’s corkscrew, shoulder dystocia persists for 24 minutes. Apgars of the 11 lb 3 oz infant are 0, 1, and 3. The child is resuscitated but dies within 2 days of birth.
Outcome
Settled with a 7-figure indemnity payment.
What the defense experts said
The key issues involve documentation and summoning assistance. Discrepancies in documentation almost always cast doubt upon the credibility of a defendant. Ideally, there should be no discrepancies between nurse and physician notes and, certainly, no discrepancies between 2 notes on the same case by the same physician. If, in this case, the physician realized after writing the first note that the anterior shoulder had been incorrectly identified, a correction should have been written as a separate note.
Use of the shoulder dystocia documentation tool (see) helps create a chronology of events, which may prove vital to a successful defense.
The call for help might not have been delayed if the labor and delivery unit had had a shoulder dystocia protocol including “drills” for all team members. Help should be called as soon as a shoulder dystocia is encountered so that, when needed, it is available. Under no circumstances should it take 20 minutes for assistance to arrive.
Brachial plexus injury not always caused by shoulder dystocia
Between 21% and 42% of shoulder dystocias involve an injury1—usually brachial plexus injury. Plaintiff attorneys have manipulated this fact to attribute many cases of neonatal brachial plexus injury to mismanagement of shoulder dystocia by the obstetrician.
They fault the physician for failing to estimate fetal weight, perform a timely cesarean, use appropriate maneuvers correctly, or have a pediatrician present. They criticize nothing more resoundingly than use of “inappropriate” or “excessive” lateral traction to the fetal head.2
Nontraction injuries. The reality can be strikingly different, however. Some cases of brachial plexus injury involve no traction at all.
- Brachial plexus injuries have been reported in infants who had precipitate vaginal deliveries without any physical intervention by the obstetrician.2
- These injuries also have occurred in infants delivered via cesarean section.1,3,4
- In some cases, brachial plexus injuries have affected the posterior arm of neonates whose anterior arm was involved in shoulder dystocia.1,2,5-7
A retrospective study4 found that, of 39 cases of brachial plexus injury, only 17 were associated with shoulder dystocia. Similar findings have emerged from other studies.2,3,8
Other causes. It is unclear how brachial plexus injuries occur in the absence of shoulder dystocia. Some think they arise in response to infectious agents such as toxoplasmosis, coxsackievirus, mumps, pertussis, or mycoplasma pneumonia.2 Some assume a mechanical cause, such as fetal response to longstanding abnormal intrauterine pressure exerted by maternal conditions such as bicornate uterus and uterine fibroids, especially in the lower segment.1,2
When brachial plexus injuries occur in the absence of shoulder dystocia, they likely originated before labor and delivery.4 Some experts suggest serial electromyelograms within the first 7 days of life to establish a prenatal rather than intrapartum etiology. A positive electromyelogram within 1 week of birth would suggest antepartum causation.2,9
Recognizing risk factors for shoulder dystocia best way to reduce injury
Most brachial plexus injuries or impairments are associated with shoulder dystocia,9 and shoulder dystocia is the most common way brachial plexus injuries are introduced into litigation.
Decreasing the number of brachial plexusrelated liability cases, therefore, depends on decreasing the incidence of shoulder dystocia. Unfortunately, a failsafe method continues to elude both clinicians and researchers.10-12
Retrospective studies have identified certain factors that may—but do not necessarily—increase the risk of shoulder dystocia.
Prenatal risk factors include high maternal or paternal birth weight, maternal obesity, excessive weight gain during pregnancy, advanced age, short stature, multiparity, postdates, prior shoulder dystocia, small pelvis, prior delivery of a macrosomic infant, gestational diabetes in an earlier pregnancy, abnormal blood sugars in the current pregnancy, or fetal macrosomia.13,14-16
Intrapartum risk factors include a rapid or prolonged second stage, failure or arrest of descent, presence of considerable molding, and need for a midpelvic delivery.10,15
Predictability. Prospective studies have not established the predictability of shoulder dystocia. A 2000 study17 showed that 55% of cases with 1 or more risk factors experienced shoulder dystocia. Predictability increases somewhat when both maternal diabetes and fetal macrosomia complicate pregnancy, since the rate of shoulder dystocia in women with diabetes is consistently higher than in nondiabetic gravidas. This becomes a significant issue when the infant weighs more than 4,000 g.
Indications for prophylactic cesarean in women with diabetes
In 1999, Wagner et al9 found that 70% of shoulder dystocias in women with diabetes occurred when the fetal weight exceeded 4,000 g. They concluded that cesarean delivery for infants with an estimated weight over 4,250 g would reduce the rate of shoulder dystocia by 75% and increase the cesarean delivery rate by 1%.
Others are more conservative. Gross and colleagues11 suggested that, for every additional 26 cesarean deliveries, only 1 case of shoulder dystocia would be prevented.
Macrosomia. Most obstetricians and researchers still do not advocate prophylactic cesarean delivery for macrosomia alone because, by some estimates, 98% of macrosomic infants are delivered without difficulty.18 However, they do suggest that obstetricians at least consider the possibility of cesarean delivery for a macrosomic fetus when the woman has diabetes.
In a study completed in 2000, Skolbekken19 suggested a cutoff of 4,250 g for women with diabetes. Dildy20 suggested limits of more than 4,500 g for diabetic women and more than 5,000 g for nondiabetic gravidas. However, Conway and Langer21 assert that a cutoff of 4,500 g is too liberal for women with diabetes and maintain that, at this cutoff, 40% of shoulder dystocias would not be prevented.
• Ultrasound measurements. Since estimates of fetal weight have a margin of error approaching 40%,9 others have chosen different parameters for determining fetal macrosomia in women with diabetes. In a retrospective study involving 31 women with gestational diabetes, Cohen et al22 found that subtracting the fetal biparietal diameter from the abdominal diameter—with both measurements obtained via ultrasound—yields a predictability score higher than estimated fetal weight. Specifically, if the difference between the 2 measurements is 2.6 cm or more, the rate of shoulder dystocia is high enough to warrant elective cesarean (FIGURE ).
FIGURE Using ultrasound measurements to predict macrosomia
A simple way to predict fetal macrosomia in women with diabetes is to subtract the fetal biparietal diameter (9.3 cm in the scan at left) from the abdominal diameter (average of 12.44 cm in the scan at right). If the difference exceeds 2.6 cm, elective cesarean is warranted. In this case it is 3.14 cm, indicating elective cesarean is warranted.
When dystocia occurs, have a plan and stick to it
Shoulder dystocia immediately places both mother and neonate at risk for temporary or permanent injury. Thus, it is imperative that all obstetricians and other health-care providers who deliver infants have a well developed plan of action for this emergency. They should immediately ask for obstetric assistance and instruct the mother to discontinue any pushing.
Attempts at vigorous downward traction should be avoided, and no fundal pressure should be applied, as these are known to increase the potential for brachial plexus injury. Gentle downward traction is considered the standard of care.17
The obstetrician’s goal is to free the impacted shoulder as quickly as possible, since a fetus can endure only 8 to 10 minutes of asphyxia before permanent neurologic damage occurs.17 The standard of care requires the obstetrician to know and use certain maneuvers to relieve shoulder dystocia. These maneuvers are designed to facilitate vaginal delivery and reduce the risk of permanent brachial plexus injury. The McRoberts maneuver, with flexion and slight rotation of the maternal hips onto the maternal abdomen, is the standard for initial relief of shoulder dystocia.17,23
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Prompt maneuvers, good outcome
A 28-year-old gravida weighing 214 lb has had 2 previous spontaneous deliveries of infants weighing 8 lb 5 oz and 9 lb 3 oz. Except for a weight gain of more than 60 lb, the pregnancy progressed without complications, and a 3-hour glucose tolerance test was normal. At 40 weeks, the obstetrician notes “concern” about an estimated fetal weight of 10 lb. Induction is planned, but spontaneous labor begins before oxytocin can be given. After 5 hours, the head is delivered without difficulty, but shoulder dystocia follows. The obstetrician extends the episiotomy and performs McRoberts and Wood’s corkscrew maneuvers, but the dystocia persists. Upon noting cyanosis, the obstetrician fractures the infant’s clavicle and quickly delivers a 10 lb 9 oz infant with Apgar scores of 8 and 10. Pediatricians examine the child immediately and diagnose Erb’s palsy, which subsequently resolves. X-rays confirm an undisplaced fracture of the right clavicle. Although the child recovers completely, the family sues, alleging a failure to perform cesarean delivery.
Outcome
Case closed with no payment.
What the defense experts said
Key issues are documentation and informed consent. The overriding opinion of 3 experts who reviewed the case for the defense was that cesarean delivery was not indicated and that in fracturing the clavicle, the physician acted responsibly, quickly, and within the standard of care. One defense expert said failure to document exact maneuvers used to relieve shoulder dystocia deviated from the standard of care. Another defense expert said the physician should have obtained informed consent from this at-risk patient, and explained the risks of shoulder dystocia, including neonatal injury, so that the she might have been better able to appreciate the fact that the obstetrician’s fast action may have saved her child from brain damage or death.
Factors that lead to litigation
In a review article, Hickson24 cited factors that prompted families to file medical liability claims following perinatal injury. Some families observed that, in their search for the cause of an injury, they found 1 or more aspects of care to be inappropriate.
The desire for information, perception of being misled, anger with the medical profession, desire to prevent injuries to others, recognition of long-term sequelae, and advice by knowledgeable acquaintances, as well as the need for money, all appeared to contribute to the decision to file medical liability claims.
Convey the risks, and listen carefully. Communication problems between physicians and patients are a contributing factor. Even when physicians provide technically adequate care, families expect answers to their questions and want to feel as though they have been consulted about important medical decisions.24 If these expectations are not met, even patients who have not experienced an adverse outcome may become angry and express dissatisfaction with care.24
The need for communication is critical when shoulder dystocia results in neonatal injury. Empathizing with the family, helping them understand that most brachial plexus injuries are not long-term, and offering to answer their questions both at the moment and later, may help prevent litigation.
This type of communication can be difficult. It helps to realize that an acknowledgment of distress and concern is not an admission of guilt, and an explanation is not an apology.15 However, an absence of communication or an attempt by the physician to place blame may be perceived as an admission of guilt that gives rise to a lawsuit.
Action plan is what counts in court. A review by Gross et al11 concluded that obstetricians should have a shoulder dystocia plan that enables an instant and orderly response. Also recommended is a protocol to help anticipate clinical problems and prevent medicolegal problems.
Gross and colleagues11 found that the Ob/Gyns with the most defensible cases paid close attention to the patient’s history and prenatal course and, upon encountering dystocia, implemented at least 2 maneuvers (if necessary) and thoroughly documented their actions immediately after delivery.
Fetterman15 agreed, asserting that what counts in court is not so much whether the obstetrician employed the McRoberts maneuver before or after the Wood’s corkscrew maneuver but whether he or she had an action plan in mind, implemented that plan properly, and thoroughly documented the actions taken and the reasons underlying them.
Dissecting legal cases for clues to reduced risk
In the review of medicolegal cases for this article, we limited our search to cases closed between Jan 1, 1995, and Dec 31, 2002, using a computer to search for codes specific to shoulder dystocia as well as the phrases “shoulder dystocia,” “Erb’s palsy,” and “brachial plexus injury.” We identified 61 cases involving 117 defendants and created a data sheet to gather information on patient and physician demographics, medical and obstetric history, description of the incident, analysis rendered by defense and plaintiff experts, and legal and financial outcomes.
Of 117 defendants, 76 were obstetricians. There also were 16 hospitals, 15 corporations, 5 certified nurse-midwives, 1 family physician, 1 emergency physician, and 3 persons categorized as “other.” Age, race, and parity of the 61 plaintiffs are given in TABLE 1.
Twenty-six of the 61 cases, involving 74 defendants, closed with no payment. That is, they were either dismissed or closed with a jury verdict for the defense. The remaining 35 cases involved 43 defendants and were closed with an aggregate indemnity payment of $19.2 million. The mean payment was $445,000 per defendant.
These guidelines are recommended to help prevent, predict, and manage shoulder dystocia and brachial plexus injury.
Obtain a prenatal history that includes the birth weights of both parents and any history of prior shoulder dystocia or cesarean delivery performed for “failure to progress.”
Estimate the fetal weight and take into account the risk for shoulder dystocia when the fetus is determined by ultrasound to be macrosomic.
Perform glucose testing on all patients, and follow up on even a single abnormal glucose reading. Discuss the possibility of shoulder dystocia and the accompanying risk of neonatal injury with “at risk” patients.
Consider obtaining informed consent for vaginal delivery of a patient with risk factors for shoulder dystocia.
Consider cesarean delivery for :
- nondiabetic women when the estimated fetal weight (EFW) exceeds 4,500 g,
- diabetic gravidas when the EFW exceeds 4,000 g,
- women with a prior delivery complicated by shoulder dystocia or brachial plexus palsy,
- gravidas with a prolonged second stage and nonprogression of labor, and
- patients who express fear and doubt about vaginal delivery.
Be sparing with the use of oxytocin when the fetus is known or suspected to be macrosomic, taking special care not to be aggressive with induction.
Use forceps or vacuum extraction with caution, and limit the number of attempts with each.
Minimize traction on the fetal head. Traction that is deemed to be “excessive” may be used against the physician in a liability suit. Gentle traction is acceptable.
Do not use or order fundal pressure. It will almost invariably be used against you in a lawsuit.
Be able to define and correctly describe maneuvers generally accepted as the standard for shoulder dystocia and, when necessary, use and document them appropriately. These include the McRoberts, Wood’s corkscrew, Rubin, and Zavanelli maneuvers; extended episiotomy; suprapubic pressure; and fracture of the anterior clavicle.
Be alert to the possibility of brachial plexus injury in the absence of shoulder dystocia. Obstetricians have been erroneously accused of causing brachial plexus injury by plaintiff attorneys who do not understand that this injury is not always the result of dystocia. Thorough contemporaneous documentation is key in these instances.
Request immediate pediatric assessment of a newborn involved in shoulder dystocia. Have the placenta sent for examination, and request cord blood gases.
Communicate openly and honestly with the parents of a child who has suffered a brachial plexus injury. This may be the single greatest tool for reducing the risk of liability litigation.
Consider serial electromyelograms during the first 7 days of life for a neonate with a brachial plexus palsy. These studies can help determine the etiology of the injury.
Use a shoulder dystocia documentation tool such as the one on page 91. Thorough documentation of all relevant prenatal and intrapartum events is critical to a successful defense. A 12-point detailed delivery note as recommended by Fetterman will also prevent or reduce legal risk.15
Schedule shoulder dystocia “drills” in the labor and delivery unit to familiarize obstetric team members with their roles.
Require comanagement of any midwifery patient at increased risk for shoulder dystocia.
Neonatal injury occurred in all 61 cases. Erb’s palsy was the overwhelming pediatric outcome (57 of 61 cases, or 93.4%), with an aggregate indemnity payment of $17.6 million. Fractured humerus was the outcome in 1 case, and 3 cases involved neonatal deaths.
Reasons for indemnity payments included:
- probable liability (18 defendants),
- plaintiff was sympathetic, likely to evoke an emotional response from the jury (8 defendants),
- clear liability (7 defendants),
- defendant would not have made a strong witness in his or her own defense (5 defendants),
- defendant had died or was too ill to stand trial (3 defendants),
- medical record had been altered (2 defendants),
- case was considered too inflammatory to risk a jury award (2 defendants), and
- policy limits were too low to risk a potentially high jury award (1 defendant).
Five defendants were involved in cases with multiple medicolegal issues that argued for settlement.
The effect of birth weight. Notably, 74% of infants involved in these cases were macrosomic (birth weight over 4,000 g). Except for neonatal injury (100%), no single maternal or fetal variable appears with greater frequency.
The mean indemnity in closed cases increased in direct proportion to fetal weight, ranging from $500,000 in cases involving infants whose birth weight was less than 4,000 g to $950,000 when the birth weight was 5,000 g or more.
Maternal factors seen with greatest frequency included obesity, excessive weight gain in pregnancy, and gestational diabetes. Analysis of prepregnant body mass index found that 19 women had a weight within the “obese” category, 18 of whom gave birth to macrosomic infants. Eight of these cases closed without indemnity payment and 10 closed with an aggregate indemnity payment of $6.5 million.
Forty-eight of the 61 plaintiffs (78.8%) exceeded the normal weight gain in pregnancy based on height and prepregnant weight. Twenty-nine of these cases closed with an aggregate indemnity payment of $16.6 million.
Influence of diabetes. Fifty-two of 61 plaintiffs underwent a glucose screening test. Of these, 23 went on to have a glucose tolerance test, with 12 testing positive for gestational diabetes. Further analysis revealed borderline screening glucose values in an additional 16 cases. These women were not considered diabetic by their obstetricians, were not retested for diabetes, and did not receive nutritional counseling. Macrosomic infants were born to 9 of the 12 patients with gestational diabetes and to 13 of the 16 borderline cases.
Of 28 cases with confirmed or suspected gestational diabetes, 14 women delivered infants weighing over 4,250 g; 11 of the 14 weighed more than 4,500 g.
In a comparison of cases involving diabetic and nondiabetic women who delivered infants weighing more than 4,250 g, 82% of the cases involving nondiabetic women closed without payment. Among cases involving diabetes (actual or borderline), the corresponding figure was 27.3%.
Labor and delivery interventions were cited in all cases. Oxytocin was used in 42 of the 61 cases (68.9%), forceps in 9 (14.8%), and vacuum extraction in 7 (11.5%). Suprapubic pressure was used in 37 cases (60.7%), fundal pressure in 9 (14.8%), and traction on the fetal head in 16 cases (26.2%).
In addition, defense experts determined that the McRoberts maneuver was used in 41 cases (67.2%) and the Wood’s corkscrew maneuver in 28 (45.9%).
Seven cases involved a second stage of labor exceeding 2.5 hours. The ratio of wins to losses decreased substantially with the use of oxytocin, forceps, fundal pressure, or a prolonged second stage.
Data were analyzed using selected variables thought to have an association with winning or losing cases and with indemnity (TABLE 2). No statistically significant models emerged. This is likely due to inadequate power (low number of cases) and the large number of interactions between variables relative to the outcomes evaluated.
TABLE 1
Plaintiff demographics
| CHARACTERISTIC | ALL CASES (n = 61) | CASES WITH INDEMNITY (n = 35) |
|---|---|---|
| Mean age, in years (range) | 28 (17–40) | 29 (18–38) |
| Race (%) | ||
| White | 35 (57) | 21 (60) |
| Black | 12 (20) | 7 (20) |
| Hispanic | 11 (18) | 6 (17) |
| Asian | 1 (2) | — |
| Unknown | 2 (3) | 1 (3) |
| Parity (%) | ||
| 0 | 19 (31) | 11 (31) |
| 1 | 26 (43) | 16 (46) |
| 2 | 11 (18) | 7 (20) |
| 3 | 2 (3) | 1 (3) |
| 4 | 2 (3) | — |
| 5 | 1 (2) | — |
TABLE 2
Litigation outcomes for selected prenatal and intrapartum variables
| CHARACTERISTIC | CLOSED WITHOUT INDEMNITY | CLOSED WITHOUT INDEMNITY PAYMENT | MEAN INDEMNITY ($) | TOTAL INDEMNITY ($) |
|---|---|---|---|---|
| Prenatal factors | ||||
| Gestational diabetes | 5 | 7 | 413,300 | 2,893,000 |
| Adjusted diabetes | 10 | 18 | 521,400 | 9,386,000 |
| Obesity | 8 | 13 | 651,300 | 8,466,000 |
| Intrapartum factors | ||||
| Prolonged second stage | 1 | 6 | 707,700 | 4,247,000 |
| Oxytocin induction | 2 | 10 | 406,500 | 4,065,300 |
| Oxytocin augmentation | 15 | 15 | 737,000 | 11,100,000 |
| Forceps delivery | 1 | 8 | 552,100 | 4,416,800 |
| Vacuum extraction | 3 | 4 | 531,300 | 2,125,000 |
| Episiotomy | 20 | 30 | 579,400 | 17,382,100 |
| McRoberts maneuver | 20 | 21 | 542,900 | 11,400,300 |
| Wood’s corkscrew maneuver | 12 | 16 | 652,300 | 10,436,200 |
| Suprapubic pressure | 17 | 20 | 629,000 | 12,579,400 |
| Traction to fetal head | 7 | 9 | 665,500 | 5,989,500 |
| Fundal pressure | 4 | 7 | 660,700 | 4,625,000 |
4 factors raise risk of litigation
After reviewing the literature and analyzing the ProMutual data, we concluded that shoulder dystocia remains largely unpredictable. However, certain clinical factors are clearly associated with an increased risk for litigation:
- prenatal factors,
- labor and delivery interventions,
- maneuvers performed at the time of the dystocia, and
- fetal outcomes.
Prenatal factors. The most significant prenatal factors were maternal obesity, excessive weight gain in pregnancy, and, especially, diabetes and fetal macrosomia.
• Fetal macrosomia. Although most macrosomic infants deliver without complication, fetal macrosomia was involved in more than 72% of the cases reviewed. Because macrosomia represents a risk not only for shoulder dystocia but also for the litigation that may arise from it, it is important to:
- know and document the estimated fetal weight (EFW);
- discuss the risk of dystocia and its sequelae with the mother and her partner; and
- consider cesarean delivery for estimated fetal weights that suggest macrosomia (see the recommendations on page 82 for specifics).
It also is advisable to mobilize a team for the possibility of shoulder dystocia if vaginal delivery is attempted.
Preparing for the increased risk of a macrosomic fetus can be successful only if macrosomia is both diagnosed and anticipated.
Because macrosomia often is accompanied by maternal diabetes, serum glucose testing is recommended for all gravidas, with follow-up of both abnormal and borderline values.
Labor and delivery interventions were cited in all cases, with data indicating a decreasing ratio of wins to losses with the use of oxytocin, forceps, or fundal pressure, and prolonged second stage.
- Use of oxytocin to augment an already established labor carried less risk than oxytocin for labor induction. Ten of the 12 cases (83.3%) in which oxytocin was used for induction closed with an indemnity payment. However, of the 30 cases in which oxytocin was used for labor augmentation, 50% closed with payment.
- • Forceps and a prolonged second stage. Eight of 9 cases (88.9%) involving forceps and 6 of 7 cases (85.7%) involving a prolonged second stage closed with indemnity payment.
Consider cesarean delivery when the second stage is prolonged or labor fails to progress. Be cautious using forceps and vacuum extraction in these circumstances, and limit the number of attempts with either.
Maneuvers performed at the time of dystocia. The most common maneuverswere McRoberts, suprapubic pressure, and Wood’s corkscrew. The ratio of wins to losses decreased with traction of the fetal head and use of fundal pressure.
Part of the risk-management protocol for obstetricians should be appropriate use of McRoberts maneuver, suprapubic pressure, and Wood’s corkscrew, and cutting a large episiotomy. In addition, be careful not to push, pull, rotate the head, or apply fundal pressure.
Fetal outcomes. All cases involved neonatal injury (Erb’s palsy, fractured humerus) or death.
For this reason, we recommend an action plan that includes immediate pediatric or neonatal assessment of neuromuscular function of the infant’s anterior shoulder. Assess the Moro reflex and the possibility of brachial plexus injury and fractures of the clavicle and humerus. Also examine the placenta, send it to pathology, and perform a cord blood gas analysis.
Last words
Shoulder dystocia is the unfortunate complication of a small number of deliveries, but the focus of an increasing number of lawsuits. Because the neonatal injuries that so often accompany shoulder dystocia often lead to litigation, obstetricians should prepare to identify risk and help patients make informed choices. We should be prepared to manage this emergency whenever it occurs and thoroughly document actions.
Dr. Zylstra reports no financial relationships relevant to this article.
Clip-and-save shoulder dystocia documentation form
Practice recommendations
Among the intrapartum events that constitute bona fide emergencies, shoulder dystocia stands out. This obstetric emergency is the focus of an increasing number of medical liability cases. Most lawsuits involving shoulder dystocia allege negligence as the cause of the brachial plexus injury, fractured clavicle or humerus, or other injury. The defendant physicians named in these suits are often accused of inappropriately managing the prenatal or intrapartum course or the dystocia itself—or of inadequately documenting the steps taken to resolve the emergency.
To glean insights into the litigation process as it involves shoulder dystocia, we retrospectively reviewed all cases closed by the Boston-based ProMutual Group, a major liability insurance carrier, over a 7-year period. We wanted to learn more about the plaintiffs themselves, as well as the clinical and medicolegal factors that led to jury awards or indemnity payments. We also wanted data that could serve as the foundation for guidelines on how to proceed in the event of shoulder dystocia, as well as a documentation tool.
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Nurse and physician document different times
A 31-year-old woman in her 10th week of pregnancy had one prior uncomplicated vaginal delivery of a 9 lb 7 oz infant. Her prenatal course proceeds unremarkably, with a normal glucose tolerance test and total weight gain of 36 lb. At 41 weeks and 2 days, the estimated fetal weight is documented as 4,120 g. Labor is induced with oxytocin. Because of maternal fatigue, vacuum delivery is attempted.
Notes of the physician and the nurse differ regarding the time of the first of 3 vacuum applications.
After delivery of the head, shoulder dystocia is encountered. In a note handwritten immediately after delivery, the physician states that the head was “reconstituted as right occiput anterior with the left shoulder anterior.”
In a note dictated later, however, the same physician states the right shoulder was anterior.
Help is summoned and arrives 20 minutes after the dystocia is first encountered. The time that help was summoned is in question since there is an 18-minute discrepancy between the times the physician and the nurse note that assistance was called.
Despite the use of suprapubic pressure and maneuvers including McRoberts and Wood’s corkscrew, shoulder dystocia persists for 24 minutes. Apgars of the 11 lb 3 oz infant are 0, 1, and 3. The child is resuscitated but dies within 2 days of birth.
Outcome
Settled with a 7-figure indemnity payment.
What the defense experts said
The key issues involve documentation and summoning assistance. Discrepancies in documentation almost always cast doubt upon the credibility of a defendant. Ideally, there should be no discrepancies between nurse and physician notes and, certainly, no discrepancies between 2 notes on the same case by the same physician. If, in this case, the physician realized after writing the first note that the anterior shoulder had been incorrectly identified, a correction should have been written as a separate note.
Use of the shoulder dystocia documentation tool (see) helps create a chronology of events, which may prove vital to a successful defense.
The call for help might not have been delayed if the labor and delivery unit had had a shoulder dystocia protocol including “drills” for all team members. Help should be called as soon as a shoulder dystocia is encountered so that, when needed, it is available. Under no circumstances should it take 20 minutes for assistance to arrive.
Brachial plexus injury not always caused by shoulder dystocia
Between 21% and 42% of shoulder dystocias involve an injury1—usually brachial plexus injury. Plaintiff attorneys have manipulated this fact to attribute many cases of neonatal brachial plexus injury to mismanagement of shoulder dystocia by the obstetrician.
They fault the physician for failing to estimate fetal weight, perform a timely cesarean, use appropriate maneuvers correctly, or have a pediatrician present. They criticize nothing more resoundingly than use of “inappropriate” or “excessive” lateral traction to the fetal head.2
Nontraction injuries. The reality can be strikingly different, however. Some cases of brachial plexus injury involve no traction at all.
- Brachial plexus injuries have been reported in infants who had precipitate vaginal deliveries without any physical intervention by the obstetrician.2
- These injuries also have occurred in infants delivered via cesarean section.1,3,4
- In some cases, brachial plexus injuries have affected the posterior arm of neonates whose anterior arm was involved in shoulder dystocia.1,2,5-7
A retrospective study4 found that, of 39 cases of brachial plexus injury, only 17 were associated with shoulder dystocia. Similar findings have emerged from other studies.2,3,8
Other causes. It is unclear how brachial plexus injuries occur in the absence of shoulder dystocia. Some think they arise in response to infectious agents such as toxoplasmosis, coxsackievirus, mumps, pertussis, or mycoplasma pneumonia.2 Some assume a mechanical cause, such as fetal response to longstanding abnormal intrauterine pressure exerted by maternal conditions such as bicornate uterus and uterine fibroids, especially in the lower segment.1,2
When brachial plexus injuries occur in the absence of shoulder dystocia, they likely originated before labor and delivery.4 Some experts suggest serial electromyelograms within the first 7 days of life to establish a prenatal rather than intrapartum etiology. A positive electromyelogram within 1 week of birth would suggest antepartum causation.2,9
Recognizing risk factors for shoulder dystocia best way to reduce injury
Most brachial plexus injuries or impairments are associated with shoulder dystocia,9 and shoulder dystocia is the most common way brachial plexus injuries are introduced into litigation.
Decreasing the number of brachial plexusrelated liability cases, therefore, depends on decreasing the incidence of shoulder dystocia. Unfortunately, a failsafe method continues to elude both clinicians and researchers.10-12
Retrospective studies have identified certain factors that may—but do not necessarily—increase the risk of shoulder dystocia.
Prenatal risk factors include high maternal or paternal birth weight, maternal obesity, excessive weight gain during pregnancy, advanced age, short stature, multiparity, postdates, prior shoulder dystocia, small pelvis, prior delivery of a macrosomic infant, gestational diabetes in an earlier pregnancy, abnormal blood sugars in the current pregnancy, or fetal macrosomia.13,14-16
Intrapartum risk factors include a rapid or prolonged second stage, failure or arrest of descent, presence of considerable molding, and need for a midpelvic delivery.10,15
Predictability. Prospective studies have not established the predictability of shoulder dystocia. A 2000 study17 showed that 55% of cases with 1 or more risk factors experienced shoulder dystocia. Predictability increases somewhat when both maternal diabetes and fetal macrosomia complicate pregnancy, since the rate of shoulder dystocia in women with diabetes is consistently higher than in nondiabetic gravidas. This becomes a significant issue when the infant weighs more than 4,000 g.
Indications for prophylactic cesarean in women with diabetes
In 1999, Wagner et al9 found that 70% of shoulder dystocias in women with diabetes occurred when the fetal weight exceeded 4,000 g. They concluded that cesarean delivery for infants with an estimated weight over 4,250 g would reduce the rate of shoulder dystocia by 75% and increase the cesarean delivery rate by 1%.
Others are more conservative. Gross and colleagues11 suggested that, for every additional 26 cesarean deliveries, only 1 case of shoulder dystocia would be prevented.
Macrosomia. Most obstetricians and researchers still do not advocate prophylactic cesarean delivery for macrosomia alone because, by some estimates, 98% of macrosomic infants are delivered without difficulty.18 However, they do suggest that obstetricians at least consider the possibility of cesarean delivery for a macrosomic fetus when the woman has diabetes.
In a study completed in 2000, Skolbekken19 suggested a cutoff of 4,250 g for women with diabetes. Dildy20 suggested limits of more than 4,500 g for diabetic women and more than 5,000 g for nondiabetic gravidas. However, Conway and Langer21 assert that a cutoff of 4,500 g is too liberal for women with diabetes and maintain that, at this cutoff, 40% of shoulder dystocias would not be prevented.
• Ultrasound measurements. Since estimates of fetal weight have a margin of error approaching 40%,9 others have chosen different parameters for determining fetal macrosomia in women with diabetes. In a retrospective study involving 31 women with gestational diabetes, Cohen et al22 found that subtracting the fetal biparietal diameter from the abdominal diameter—with both measurements obtained via ultrasound—yields a predictability score higher than estimated fetal weight. Specifically, if the difference between the 2 measurements is 2.6 cm or more, the rate of shoulder dystocia is high enough to warrant elective cesarean (FIGURE ).
FIGURE Using ultrasound measurements to predict macrosomia
A simple way to predict fetal macrosomia in women with diabetes is to subtract the fetal biparietal diameter (9.3 cm in the scan at left) from the abdominal diameter (average of 12.44 cm in the scan at right). If the difference exceeds 2.6 cm, elective cesarean is warranted. In this case it is 3.14 cm, indicating elective cesarean is warranted.
When dystocia occurs, have a plan and stick to it
Shoulder dystocia immediately places both mother and neonate at risk for temporary or permanent injury. Thus, it is imperative that all obstetricians and other health-care providers who deliver infants have a well developed plan of action for this emergency. They should immediately ask for obstetric assistance and instruct the mother to discontinue any pushing.
Attempts at vigorous downward traction should be avoided, and no fundal pressure should be applied, as these are known to increase the potential for brachial plexus injury. Gentle downward traction is considered the standard of care.17
The obstetrician’s goal is to free the impacted shoulder as quickly as possible, since a fetus can endure only 8 to 10 minutes of asphyxia before permanent neurologic damage occurs.17 The standard of care requires the obstetrician to know and use certain maneuvers to relieve shoulder dystocia. These maneuvers are designed to facilitate vaginal delivery and reduce the risk of permanent brachial plexus injury. The McRoberts maneuver, with flexion and slight rotation of the maternal hips onto the maternal abdomen, is the standard for initial relief of shoulder dystocia.17,23
This shoulder dystocia case from an insurer’s closed claim file illustrates a problem often linked to litigation. Minor changes were made to conceal the identities of the involved parties.
Prompt maneuvers, good outcome
A 28-year-old gravida weighing 214 lb has had 2 previous spontaneous deliveries of infants weighing 8 lb 5 oz and 9 lb 3 oz. Except for a weight gain of more than 60 lb, the pregnancy progressed without complications, and a 3-hour glucose tolerance test was normal. At 40 weeks, the obstetrician notes “concern” about an estimated fetal weight of 10 lb. Induction is planned, but spontaneous labor begins before oxytocin can be given. After 5 hours, the head is delivered without difficulty, but shoulder dystocia follows. The obstetrician extends the episiotomy and performs McRoberts and Wood’s corkscrew maneuvers, but the dystocia persists. Upon noting cyanosis, the obstetrician fractures the infant’s clavicle and quickly delivers a 10 lb 9 oz infant with Apgar scores of 8 and 10. Pediatricians examine the child immediately and diagnose Erb’s palsy, which subsequently resolves. X-rays confirm an undisplaced fracture of the right clavicle. Although the child recovers completely, the family sues, alleging a failure to perform cesarean delivery.
Outcome
Case closed with no payment.
What the defense experts said
Key issues are documentation and informed consent. The overriding opinion of 3 experts who reviewed the case for the defense was that cesarean delivery was not indicated and that in fracturing the clavicle, the physician acted responsibly, quickly, and within the standard of care. One defense expert said failure to document exact maneuvers used to relieve shoulder dystocia deviated from the standard of care. Another defense expert said the physician should have obtained informed consent from this at-risk patient, and explained the risks of shoulder dystocia, including neonatal injury, so that the she might have been better able to appreciate the fact that the obstetrician’s fast action may have saved her child from brain damage or death.
Factors that lead to litigation
In a review article, Hickson24 cited factors that prompted families to file medical liability claims following perinatal injury. Some families observed that, in their search for the cause of an injury, they found 1 or more aspects of care to be inappropriate.
The desire for information, perception of being misled, anger with the medical profession, desire to prevent injuries to others, recognition of long-term sequelae, and advice by knowledgeable acquaintances, as well as the need for money, all appeared to contribute to the decision to file medical liability claims.
Convey the risks, and listen carefully. Communication problems between physicians and patients are a contributing factor. Even when physicians provide technically adequate care, families expect answers to their questions and want to feel as though they have been consulted about important medical decisions.24 If these expectations are not met, even patients who have not experienced an adverse outcome may become angry and express dissatisfaction with care.24
The need for communication is critical when shoulder dystocia results in neonatal injury. Empathizing with the family, helping them understand that most brachial plexus injuries are not long-term, and offering to answer their questions both at the moment and later, may help prevent litigation.
This type of communication can be difficult. It helps to realize that an acknowledgment of distress and concern is not an admission of guilt, and an explanation is not an apology.15 However, an absence of communication or an attempt by the physician to place blame may be perceived as an admission of guilt that gives rise to a lawsuit.
Action plan is what counts in court. A review by Gross et al11 concluded that obstetricians should have a shoulder dystocia plan that enables an instant and orderly response. Also recommended is a protocol to help anticipate clinical problems and prevent medicolegal problems.
Gross and colleagues11 found that the Ob/Gyns with the most defensible cases paid close attention to the patient’s history and prenatal course and, upon encountering dystocia, implemented at least 2 maneuvers (if necessary) and thoroughly documented their actions immediately after delivery.
Fetterman15 agreed, asserting that what counts in court is not so much whether the obstetrician employed the McRoberts maneuver before or after the Wood’s corkscrew maneuver but whether he or she had an action plan in mind, implemented that plan properly, and thoroughly documented the actions taken and the reasons underlying them.
Dissecting legal cases for clues to reduced risk
In the review of medicolegal cases for this article, we limited our search to cases closed between Jan 1, 1995, and Dec 31, 2002, using a computer to search for codes specific to shoulder dystocia as well as the phrases “shoulder dystocia,” “Erb’s palsy,” and “brachial plexus injury.” We identified 61 cases involving 117 defendants and created a data sheet to gather information on patient and physician demographics, medical and obstetric history, description of the incident, analysis rendered by defense and plaintiff experts, and legal and financial outcomes.
Of 117 defendants, 76 were obstetricians. There also were 16 hospitals, 15 corporations, 5 certified nurse-midwives, 1 family physician, 1 emergency physician, and 3 persons categorized as “other.” Age, race, and parity of the 61 plaintiffs are given in TABLE 1.
Twenty-six of the 61 cases, involving 74 defendants, closed with no payment. That is, they were either dismissed or closed with a jury verdict for the defense. The remaining 35 cases involved 43 defendants and were closed with an aggregate indemnity payment of $19.2 million. The mean payment was $445,000 per defendant.
These guidelines are recommended to help prevent, predict, and manage shoulder dystocia and brachial plexus injury.
Obtain a prenatal history that includes the birth weights of both parents and any history of prior shoulder dystocia or cesarean delivery performed for “failure to progress.”
Estimate the fetal weight and take into account the risk for shoulder dystocia when the fetus is determined by ultrasound to be macrosomic.
Perform glucose testing on all patients, and follow up on even a single abnormal glucose reading. Discuss the possibility of shoulder dystocia and the accompanying risk of neonatal injury with “at risk” patients.
Consider obtaining informed consent for vaginal delivery of a patient with risk factors for shoulder dystocia.
Consider cesarean delivery for :
- nondiabetic women when the estimated fetal weight (EFW) exceeds 4,500 g,
- diabetic gravidas when the EFW exceeds 4,000 g,
- women with a prior delivery complicated by shoulder dystocia or brachial plexus palsy,
- gravidas with a prolonged second stage and nonprogression of labor, and
- patients who express fear and doubt about vaginal delivery.
Be sparing with the use of oxytocin when the fetus is known or suspected to be macrosomic, taking special care not to be aggressive with induction.
Use forceps or vacuum extraction with caution, and limit the number of attempts with each.
Minimize traction on the fetal head. Traction that is deemed to be “excessive” may be used against the physician in a liability suit. Gentle traction is acceptable.
Do not use or order fundal pressure. It will almost invariably be used against you in a lawsuit.
Be able to define and correctly describe maneuvers generally accepted as the standard for shoulder dystocia and, when necessary, use and document them appropriately. These include the McRoberts, Wood’s corkscrew, Rubin, and Zavanelli maneuvers; extended episiotomy; suprapubic pressure; and fracture of the anterior clavicle.
Be alert to the possibility of brachial plexus injury in the absence of shoulder dystocia. Obstetricians have been erroneously accused of causing brachial plexus injury by plaintiff attorneys who do not understand that this injury is not always the result of dystocia. Thorough contemporaneous documentation is key in these instances.
Request immediate pediatric assessment of a newborn involved in shoulder dystocia. Have the placenta sent for examination, and request cord blood gases.
Communicate openly and honestly with the parents of a child who has suffered a brachial plexus injury. This may be the single greatest tool for reducing the risk of liability litigation.
Consider serial electromyelograms during the first 7 days of life for a neonate with a brachial plexus palsy. These studies can help determine the etiology of the injury.
Use a shoulder dystocia documentation tool such as the one on page 91. Thorough documentation of all relevant prenatal and intrapartum events is critical to a successful defense. A 12-point detailed delivery note as recommended by Fetterman will also prevent or reduce legal risk.15
Schedule shoulder dystocia “drills” in the labor and delivery unit to familiarize obstetric team members with their roles.
Require comanagement of any midwifery patient at increased risk for shoulder dystocia.
Neonatal injury occurred in all 61 cases. Erb’s palsy was the overwhelming pediatric outcome (57 of 61 cases, or 93.4%), with an aggregate indemnity payment of $17.6 million. Fractured humerus was the outcome in 1 case, and 3 cases involved neonatal deaths.
Reasons for indemnity payments included:
- probable liability (18 defendants),
- plaintiff was sympathetic, likely to evoke an emotional response from the jury (8 defendants),
- clear liability (7 defendants),
- defendant would not have made a strong witness in his or her own defense (5 defendants),
- defendant had died or was too ill to stand trial (3 defendants),
- medical record had been altered (2 defendants),
- case was considered too inflammatory to risk a jury award (2 defendants), and
- policy limits were too low to risk a potentially high jury award (1 defendant).
Five defendants were involved in cases with multiple medicolegal issues that argued for settlement.
The effect of birth weight. Notably, 74% of infants involved in these cases were macrosomic (birth weight over 4,000 g). Except for neonatal injury (100%), no single maternal or fetal variable appears with greater frequency.
The mean indemnity in closed cases increased in direct proportion to fetal weight, ranging from $500,000 in cases involving infants whose birth weight was less than 4,000 g to $950,000 when the birth weight was 5,000 g or more.
Maternal factors seen with greatest frequency included obesity, excessive weight gain in pregnancy, and gestational diabetes. Analysis of prepregnant body mass index found that 19 women had a weight within the “obese” category, 18 of whom gave birth to macrosomic infants. Eight of these cases closed without indemnity payment and 10 closed with an aggregate indemnity payment of $6.5 million.
Forty-eight of the 61 plaintiffs (78.8%) exceeded the normal weight gain in pregnancy based on height and prepregnant weight. Twenty-nine of these cases closed with an aggregate indemnity payment of $16.6 million.
Influence of diabetes. Fifty-two of 61 plaintiffs underwent a glucose screening test. Of these, 23 went on to have a glucose tolerance test, with 12 testing positive for gestational diabetes. Further analysis revealed borderline screening glucose values in an additional 16 cases. These women were not considered diabetic by their obstetricians, were not retested for diabetes, and did not receive nutritional counseling. Macrosomic infants were born to 9 of the 12 patients with gestational diabetes and to 13 of the 16 borderline cases.
Of 28 cases with confirmed or suspected gestational diabetes, 14 women delivered infants weighing over 4,250 g; 11 of the 14 weighed more than 4,500 g.
In a comparison of cases involving diabetic and nondiabetic women who delivered infants weighing more than 4,250 g, 82% of the cases involving nondiabetic women closed without payment. Among cases involving diabetes (actual or borderline), the corresponding figure was 27.3%.
Labor and delivery interventions were cited in all cases. Oxytocin was used in 42 of the 61 cases (68.9%), forceps in 9 (14.8%), and vacuum extraction in 7 (11.5%). Suprapubic pressure was used in 37 cases (60.7%), fundal pressure in 9 (14.8%), and traction on the fetal head in 16 cases (26.2%).
In addition, defense experts determined that the McRoberts maneuver was used in 41 cases (67.2%) and the Wood’s corkscrew maneuver in 28 (45.9%).
Seven cases involved a second stage of labor exceeding 2.5 hours. The ratio of wins to losses decreased substantially with the use of oxytocin, forceps, fundal pressure, or a prolonged second stage.
Data were analyzed using selected variables thought to have an association with winning or losing cases and with indemnity (TABLE 2). No statistically significant models emerged. This is likely due to inadequate power (low number of cases) and the large number of interactions between variables relative to the outcomes evaluated.
TABLE 1
Plaintiff demographics
| CHARACTERISTIC | ALL CASES (n = 61) | CASES WITH INDEMNITY (n = 35) |
|---|---|---|
| Mean age, in years (range) | 28 (17–40) | 29 (18–38) |
| Race (%) | ||
| White | 35 (57) | 21 (60) |
| Black | 12 (20) | 7 (20) |
| Hispanic | 11 (18) | 6 (17) |
| Asian | 1 (2) | — |
| Unknown | 2 (3) | 1 (3) |
| Parity (%) | ||
| 0 | 19 (31) | 11 (31) |
| 1 | 26 (43) | 16 (46) |
| 2 | 11 (18) | 7 (20) |
| 3 | 2 (3) | 1 (3) |
| 4 | 2 (3) | — |
| 5 | 1 (2) | — |
TABLE 2
Litigation outcomes for selected prenatal and intrapartum variables
| CHARACTERISTIC | CLOSED WITHOUT INDEMNITY | CLOSED WITHOUT INDEMNITY PAYMENT | MEAN INDEMNITY ($) | TOTAL INDEMNITY ($) |
|---|---|---|---|---|
| Prenatal factors | ||||
| Gestational diabetes | 5 | 7 | 413,300 | 2,893,000 |
| Adjusted diabetes | 10 | 18 | 521,400 | 9,386,000 |
| Obesity | 8 | 13 | 651,300 | 8,466,000 |
| Intrapartum factors | ||||
| Prolonged second stage | 1 | 6 | 707,700 | 4,247,000 |
| Oxytocin induction | 2 | 10 | 406,500 | 4,065,300 |
| Oxytocin augmentation | 15 | 15 | 737,000 | 11,100,000 |
| Forceps delivery | 1 | 8 | 552,100 | 4,416,800 |
| Vacuum extraction | 3 | 4 | 531,300 | 2,125,000 |
| Episiotomy | 20 | 30 | 579,400 | 17,382,100 |
| McRoberts maneuver | 20 | 21 | 542,900 | 11,400,300 |
| Wood’s corkscrew maneuver | 12 | 16 | 652,300 | 10,436,200 |
| Suprapubic pressure | 17 | 20 | 629,000 | 12,579,400 |
| Traction to fetal head | 7 | 9 | 665,500 | 5,989,500 |
| Fundal pressure | 4 | 7 | 660,700 | 4,625,000 |
4 factors raise risk of litigation
After reviewing the literature and analyzing the ProMutual data, we concluded that shoulder dystocia remains largely unpredictable. However, certain clinical factors are clearly associated with an increased risk for litigation:
- prenatal factors,
- labor and delivery interventions,
- maneuvers performed at the time of the dystocia, and
- fetal outcomes.
Prenatal factors. The most significant prenatal factors were maternal obesity, excessive weight gain in pregnancy, and, especially, diabetes and fetal macrosomia.
• Fetal macrosomia. Although most macrosomic infants deliver without complication, fetal macrosomia was involved in more than 72% of the cases reviewed. Because macrosomia represents a risk not only for shoulder dystocia but also for the litigation that may arise from it, it is important to:
- know and document the estimated fetal weight (EFW);
- discuss the risk of dystocia and its sequelae with the mother and her partner; and
- consider cesarean delivery for estimated fetal weights that suggest macrosomia (see the recommendations on page 82 for specifics).
It also is advisable to mobilize a team for the possibility of shoulder dystocia if vaginal delivery is attempted.
Preparing for the increased risk of a macrosomic fetus can be successful only if macrosomia is both diagnosed and anticipated.
Because macrosomia often is accompanied by maternal diabetes, serum glucose testing is recommended for all gravidas, with follow-up of both abnormal and borderline values.
Labor and delivery interventions were cited in all cases, with data indicating a decreasing ratio of wins to losses with the use of oxytocin, forceps, or fundal pressure, and prolonged second stage.
- Use of oxytocin to augment an already established labor carried less risk than oxytocin for labor induction. Ten of the 12 cases (83.3%) in which oxytocin was used for induction closed with an indemnity payment. However, of the 30 cases in which oxytocin was used for labor augmentation, 50% closed with payment.
- • Forceps and a prolonged second stage. Eight of 9 cases (88.9%) involving forceps and 6 of 7 cases (85.7%) involving a prolonged second stage closed with indemnity payment.
Consider cesarean delivery when the second stage is prolonged or labor fails to progress. Be cautious using forceps and vacuum extraction in these circumstances, and limit the number of attempts with either.
Maneuvers performed at the time of dystocia. The most common maneuverswere McRoberts, suprapubic pressure, and Wood’s corkscrew. The ratio of wins to losses decreased with traction of the fetal head and use of fundal pressure.
Part of the risk-management protocol for obstetricians should be appropriate use of McRoberts maneuver, suprapubic pressure, and Wood’s corkscrew, and cutting a large episiotomy. In addition, be careful not to push, pull, rotate the head, or apply fundal pressure.
Fetal outcomes. All cases involved neonatal injury (Erb’s palsy, fractured humerus) or death.
For this reason, we recommend an action plan that includes immediate pediatric or neonatal assessment of neuromuscular function of the infant’s anterior shoulder. Assess the Moro reflex and the possibility of brachial plexus injury and fractures of the clavicle and humerus. Also examine the placenta, send it to pathology, and perform a cord blood gas analysis.
Last words
Shoulder dystocia is the unfortunate complication of a small number of deliveries, but the focus of an increasing number of lawsuits. Because the neonatal injuries that so often accompany shoulder dystocia often lead to litigation, obstetricians should prepare to identify risk and help patients make informed choices. We should be prepared to manage this emergency whenever it occurs and thoroughly document actions.
Dr. Zylstra reports no financial relationships relevant to this article.
1. Gherman RB, Goodwin TM, Ouzounian JG, Miller DA, Paul RH. Brachial plexus palsy associated with cesarean section: an in utero injury? Am J Obstet Gynecol. 1997;177:1162-1164.
2. Gherman RB, Ouzounian JG, Goodwin TM. Brachial plexus palsy: an in utero injury? Am J Obstet Gynecol. 1999;180:1303-1307.
3. Gilbert WM, Nesbitt TS, Danielsen B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol. 1999;93:536-540.
4. Jennett RJ, Tarby TJ, Kreinick CJ. Brachial plexus palsy: an old problem revisited. Am J Obstet Gynecol. 1992;166:1673-1677.
5. Hankins GDV, Clark SL. Brachial plexus palsy involving the posterior shoulder at spontaneous vaginal delivery. Am J Perinatol. 1995;12:44-45.
6. Gherman RB, Ouzounian JG, Miller DA, Kwok L, Goodwin TM. Spontaneous vaginal delivery: a risk factor for Erb’s palsy? Am J Obstet Gynecol. 1998;178:423-427.
7. Dodds SD, Wolfe SW. Perinatal brachial plexus palsy. Curr Opin Pediatrics. 2000;23:40-47.
8. Wade DM. A Comment on the Trial of Brachial Plexus/Erb’s Palsy Medical Malpractice Cases. Evidence Technologies, Inc. 1994.
9. Wagner RK, Nielsen PE, Gonik B. Controversies in labor management: shoulder dystocia. Obstet Gynecol Clin. 1999;26(2):371-382.
10. McFarland M, Hod M, Piper JM, Xenakis EM-J, Langer O. Are labor abnormalities more common in shoulder dystocia? Am J ObstetGynecol. 1995;173:1211-1214.
11. Gross TL, Sokol RJ, Williams T, Thompson K. Shoulder dystocia: A fetal-physician risk. Am J Obstet Gynecol. 1987;156:1408-1418.
12. Acker DB, Sachs BP, Friedman EA. Risk factors for shoulder dystocia. Obstet Gynecol. 1985;66:762-768.
13. Shoulder dystocia and Erb’s palsy. The Keenan Law Firm. 2002. Available at www.shoulderdystociaattorney.com. Accessed July 23, 2004.
14. Acker DB, Gregory KD, Sachs BP, Friedman EA. Risk factors for Erb-Duchenne palsy. Obstet Gynecol. 1988;71(Part l):390-392.
15. Fetterman HH. Cutting the legal risks of shoulder dystocia. OBG Management. March 1995;41-51.
16. Iffy L, Varadi V, Jakobovits A. Common intrapartum denominators of shoulder dystocia related birth injuries. Zentralbl Gynakol. 1994;116(1):33-37.
17. Calhoun BC, Hume RR, Walters JL. Shoulder Dystocia as a risk for obstetric liability. Legal Medicine. 2000;12-15.
18. Jennett RJ, Tarby TJ. Brachial plexus palsy: an old problem revisited again. Am J Obstet Gynecol. 1997;176:1354-1357.
19. Skolbekken JA. Shoulder dystocia—malpractice or acceptable risk? Acta Obstet Gynecol Scand. 2000;79:750-756.
20. Dildy GA. Fetal macrosomia [slide presentation]. Presented at the 18th Annual Conference on Obstetrics, Gynecology, Perinatal Medicine, and the Law, Boston University School of Medicine and the Center for Human Genetics, January 2002, Kauai, Hawaii.
21. Conway D, Langer O. Elective delivery of infants with macrosomia in diabetic women: reduced shoulder dystocia versus increased cesarean deliveries. Am J Obstet Gynecol. 1998;178(5):922-925.
22. Cohen B, Penning S, Major C, Ansley D, Porto M, Garite T. Sonographic prediction of shoulder dystocia in infants of diabetic mothers. Obstet Gynecol. 1998;88:10-13.
23. Gherman RB, Goodwin TM, Souter I, Neumann K, Ouzounian JG, Paul RH. The McRoberts’ maneuver for the alleviation of shoulder dystocia: how successful is it? Am J Obstet Gynecol. 1997;176:656-661.
24. Hickson GB, Clayton DW, Githens PB, Sloan FA. Factors that prompted families to file medical malpractice claims following perinatal injuries. JAMA. 1992;267:1359-1363.
1. Gherman RB, Goodwin TM, Ouzounian JG, Miller DA, Paul RH. Brachial plexus palsy associated with cesarean section: an in utero injury? Am J Obstet Gynecol. 1997;177:1162-1164.
2. Gherman RB, Ouzounian JG, Goodwin TM. Brachial plexus palsy: an in utero injury? Am J Obstet Gynecol. 1999;180:1303-1307.
3. Gilbert WM, Nesbitt TS, Danielsen B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol. 1999;93:536-540.
4. Jennett RJ, Tarby TJ, Kreinick CJ. Brachial plexus palsy: an old problem revisited. Am J Obstet Gynecol. 1992;166:1673-1677.
5. Hankins GDV, Clark SL. Brachial plexus palsy involving the posterior shoulder at spontaneous vaginal delivery. Am J Perinatol. 1995;12:44-45.
6. Gherman RB, Ouzounian JG, Miller DA, Kwok L, Goodwin TM. Spontaneous vaginal delivery: a risk factor for Erb’s palsy? Am J Obstet Gynecol. 1998;178:423-427.
7. Dodds SD, Wolfe SW. Perinatal brachial plexus palsy. Curr Opin Pediatrics. 2000;23:40-47.
8. Wade DM. A Comment on the Trial of Brachial Plexus/Erb’s Palsy Medical Malpractice Cases. Evidence Technologies, Inc. 1994.
9. Wagner RK, Nielsen PE, Gonik B. Controversies in labor management: shoulder dystocia. Obstet Gynecol Clin. 1999;26(2):371-382.
10. McFarland M, Hod M, Piper JM, Xenakis EM-J, Langer O. Are labor abnormalities more common in shoulder dystocia? Am J ObstetGynecol. 1995;173:1211-1214.
11. Gross TL, Sokol RJ, Williams T, Thompson K. Shoulder dystocia: A fetal-physician risk. Am J Obstet Gynecol. 1987;156:1408-1418.
12. Acker DB, Sachs BP, Friedman EA. Risk factors for shoulder dystocia. Obstet Gynecol. 1985;66:762-768.
13. Shoulder dystocia and Erb’s palsy. The Keenan Law Firm. 2002. Available at www.shoulderdystociaattorney.com. Accessed July 23, 2004.
14. Acker DB, Gregory KD, Sachs BP, Friedman EA. Risk factors for Erb-Duchenne palsy. Obstet Gynecol. 1988;71(Part l):390-392.
15. Fetterman HH. Cutting the legal risks of shoulder dystocia. OBG Management. March 1995;41-51.
16. Iffy L, Varadi V, Jakobovits A. Common intrapartum denominators of shoulder dystocia related birth injuries. Zentralbl Gynakol. 1994;116(1):33-37.
17. Calhoun BC, Hume RR, Walters JL. Shoulder Dystocia as a risk for obstetric liability. Legal Medicine. 2000;12-15.
18. Jennett RJ, Tarby TJ. Brachial plexus palsy: an old problem revisited again. Am J Obstet Gynecol. 1997;176:1354-1357.
19. Skolbekken JA. Shoulder dystocia—malpractice or acceptable risk? Acta Obstet Gynecol Scand. 2000;79:750-756.
20. Dildy GA. Fetal macrosomia [slide presentation]. Presented at the 18th Annual Conference on Obstetrics, Gynecology, Perinatal Medicine, and the Law, Boston University School of Medicine and the Center for Human Genetics, January 2002, Kauai, Hawaii.
21. Conway D, Langer O. Elective delivery of infants with macrosomia in diabetic women: reduced shoulder dystocia versus increased cesarean deliveries. Am J Obstet Gynecol. 1998;178(5):922-925.
22. Cohen B, Penning S, Major C, Ansley D, Porto M, Garite T. Sonographic prediction of shoulder dystocia in infants of diabetic mothers. Obstet Gynecol. 1998;88:10-13.
23. Gherman RB, Goodwin TM, Souter I, Neumann K, Ouzounian JG, Paul RH. The McRoberts’ maneuver for the alleviation of shoulder dystocia: how successful is it? Am J Obstet Gynecol. 1997;176:656-661.
24. Hickson GB, Clayton DW, Githens PB, Sloan FA. Factors that prompted families to file medical malpractice claims following perinatal injuries. JAMA. 1992;267:1359-1363.
Primary Care Panels in the VA [published correction appears in: Fed Pract. 2004;21(9):99.]
Carbon Monoxide Monitoring
Atypical Presentations of Clostridium difficile
• New routes, new regimens • Array of options for emergency contraception clip-and-save chart • The IUD makes a comeback
It’s surprising to realize that the birth control pill, which launched a revolution in women’s sexuality and health, has been around for less than 50 years—especially considering the myriad of methods and products on the market today. New types of contraceptives have become available, more are on the way, and noncontraceptive benefits continue to accrue. This article reviews noteworthy changes and upcoming products.
Continuous contraception: New routes, new regimens
When it was introduced in 1960, the oral contraceptive (OC) consisted of 20 or 21 active pills followed by a pill-free interval of 7 or 8 days. No medical reason justified the pill-free interval; it was devised simply to trigger menses and reassure the woman she was not pregnant.
That pill-free interval shrank as we gained awareness of the benefits of continuous OC regimens, particularly in the treatment of endometriosis. Advantages—well documented by Sulak1—include marked reduction or elimination of menses-related symptoms such as menorrhagia, dysmenorrhea, and menstrual migraines.
Continuous OCs became “official” in 2003 with the introduction of Seasonale (ethinyl estradiol, 0.03 mg/levonorgestrel, 0.15 mg), a continuous regimen taken for 84 days, followed by a 7-day pill-free interval.2
This regimen reduces the number of periods to 4 each year.
Breakthrough bleeding diminishes over time. Although breakthrough bleeding is a common side effect of continuous oral contraception—as it is with conventional regimens—it decreases with each successive cycle of Seasonale. By the fourth cycle, it is comparable to the level reported by women on a conventional regimen. Prolonged and heavy bleeding also can be managed by discontinuing pills for 7 days.
Other methods also can be used continuously. Continuous contraception is not limited to oral contraception.
The contraceptive ring (Nuvaring; ethinyl estradiol/etonogestrel) can be left in place for 4 weeks instead of 3 without decreasing efficacy. Both hormone levels are sufficient to prevent pregnancy throughout these weeks.3
Nor is there any reason to doubt the efficacy of continuous use of the contraceptive patch (Evra; ethinyl estradiol/norelgestromin).
New regimens. A regimen of 24 active pills and a 4-day pill-free interval is available in Europe. The shorter pill-free interval allows further reduction of the active components ethinyl estradiol and gestadene. This agent contains 15 μg estradiol per pill.4
A version of Yasmin that contains only 20 μg of ethinyl estradiol, should be released in the United States later this year. It will consist of 24 active pills and a 4-day pill-free interval.
New implantable rod. Implanon, a new single-rod contraceptive implant containing etonogestrel, is available outside the United States and may become available here in the near future.5,6 It can be inserted in 1.6 minutes, removed in 2.6 minutes, and lasts 3 years. No pregnancies were reported in clinical trials.
Lower dose of Depo-Provera effective for 3 months. A new dose and route of administration for Depo-Provera (depotmedroxyprogesterone acetate) is just as effective as the 150-mg intramuscular dose.
The new dose is 104 mg administered subcutaneously every 3 months. When it becomes available in the near future, this preparation should allow women to administer the drug at home.7
Emergency contraception: A variety of methods, but still need a prescription
The different methods of emergency contraception are listed in a clip-and-save chart on page 46, which can be photocopied for convenient reference.
Trussell and colleagues’8 excellent review prefers the term emergency contraception to refer to contraceptive use after intercourse has occurred. The term “morning-after pill” is confusing because the method can be used any time after intercourse for up to 72 hours. It can even be used after 72 hours, albeit at reduced efficacy.
The Yuzpe regimen is the oldest and probably most popular form of contraception. It involves taking 2 Ovral tablets (ethinyl estradiol/levonorgestrel) followed by 2 more tablets 12 hours later. Each dose consists of 100 μg of estradiol and 0.5 mg of norgestrel.
Unfortunately, Ovral is not readily available in pharmacies. An alternative is taking enough OCs to equal the 100-μg dose of ethinyl estradiol and the 0.5 mg dose of norgestrel. For example, 5 tablets of Alesse or Levlite can be substituted for the 2 Ovral.
Efficacy is 75%. That is, if 100 women have unprotected intercourse once during the second or third week of their cycle, about 8 will become pregnant without treatment, and only 2 will become pregnant after treatment—a 75% reduction.
OCs that contain different progestins have not been studied extensively. They appear to work with lower efficacy than pills containing levonorgestrel.
- Common side effects include nausea and vomiting. Co-administration of an anti-nausea agent may be necessary. About 50% of women experience nausea and 20% vomit within 2 hours of taking a dose; some clinicians recommend repeating that dose to assure efficacy. One option is giving two 25-mg tablets of the over-the-counter drug meclizine 1 hour before combined emergency contraceptive pills; this reduces the risk of nausea by 27% and vomiting by 64%, but the risk of drowsiness doubles. Taking the medicine with a meal does not lower the rate of nausea.
- Contraindications. The only contraindication is an established pregnancy, since the drugs are taken so briefly.
Plan B Consists of 0.75 mg levonorgestrel taken within 72 hours of intercourse, followed by a second dose 12 hours later. This regimen has fewer side effects than the Yuzpe plan and may be slightly more effective. Unfortunately, the US Food and Drug Administration failed to approve over-the-counter status for this drug, so a prescription is still necessary.
IUDs. Insertion of a copper IUD (Paraguard)—but not a levonorgestrel-containing device (Mirena)—within 72 hours after intercourse is almost completely effective in preventing pregnancy. It also provides continuing contraception. Its mechanism of action is preventing implantation of a fertilized egg. Mirena has no efficacy in this regard.
“Every Woman, Every Visit,” the American College of Obstetricians and Gynecologists’ public education campaign, urges Ob/Gyns to provide advance prescriptions for emergency contraception at every office visit.
After many years of declining choices in the realm of intrauterine devices (IUDs), the Mirena levonorgestrel-containing system was released in the US market in 2000. Like the Paraguard copper IUD, the Mirena prevents pregnancy at a rate equivalent to tubal ligation. These devices last for 5 and 10 years, respectively.9,10
In the United States, interest in IUDs declined after they were associated with salpingitis and tubo-ovarian abscess. More recent epidemiological evidence indicates that IUDs do not increase the risk of infection over the general population, but the rate is higher than with other forms of contraception, which offer some protection against salpingitis. Antibiotic prophylaxis is not necessary.
The removal rate for pelvic inflammatory disease is much lower for Mirena than for the copper IUD and may be related to the low levels of levonorgestrel, which thicken cervical mucus and prevent sperm transport.9
Ectopic pregnancy rates with the Mirena are about 1/8 to 1/10 those observed in the general population. Once the Mirena device is removed, fertility returns rapidly9-11
Recommended for the chronically ill. According to the World Health Organization, IUDs are the safest form of contraception for medically complicated patients.12 Certainly, they are underutilized in this circumstance.
Noncontraceptive benefits. Slow release of low doses of levonorgestrel by Mirena reduces endometrial thickness and menstrual blood loss.13 In fact, several studies have found the Mirena to be equivalent to endometrial ablation.14 In a randomized study, two thirds of the women scheduled for hysterectomy for abnormal uterine bleeding cancelled surgery due to satisfaction with Mirena’s bleeding profile.15
Ovarian cancer also is reduced.16
Does obesity limit contraceptive efficacy?
Decreased efficacy of the contraceptive patch, observed in overweight women,17 especially those heavier than 198 lb, prompted reevaluation of other forms. In a retrospective analysis, Holt and colleagues18 found a higher pregnancy rate in women heavier than 155 lb as the estrogen dose decreased. In contrast, no pregnancies occurred in women weighing more than 198 lb in a randomized trial2 of 30 μg ethinyl estradiol/150 μg levonorgestrel (Seasonale). It is unclear why Holt failed to analyze progestin content, since it is the progestin that inhibits ovulation and prevents pregnancy.
Unfortunately, few clinical trials involve obese women. For example, the contraceptive ring was not evaluated in obese women.
Despite this shortcoming, I have not changed my prescribing of contraceptives in obese women, but await better, more convincing data. Until then, it seems wise to include a broad range of body weights in future trials.
The author serves on the Speakers Bureau for Barr, Berlex, and Wyeth-Ayerst.
1. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
2. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.
3. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinyl estradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinetics. 2000;39:233-242.
4. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21 day and 24 day oral contraceptive regimens containing gestodene (60 μg) and ethinyl estradiol (15 μg) on ovarian activity. Fertil Steril. 1999;72:115-120.
5. Croxatto HB, Urbancsek J, Massai R, Coelingh BH, van Beek A. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Implanon Study Group. Hum Reprod. 1999;14:976-981.
6. Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant. Contraception. 1999;60:1-8.
7. Jain J, Dutton C, Nicosia A, Wajszczuk C, Dode FR, Mishell DR. Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera. Contraception. 2004;70:11-18.
8. Trussell J, Ellertson C, Stewart F, Raymond EG, Shochet T. The role of emergency contraception. Am J Obstet Gynecol. 2004;190:S30-S38.
9. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49:56-72.
10. Peterson HB, Xia Z, Hughes JM, Wilcox LS, Tylor LR, Trussell J. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization [see comment]. Am J Obstet Gynecol. 1996;174:1161-1168.
11. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrelreleasing intrauterine device and Nova-T. Contraception. 1992;46:575-584.
12. World Health Organization. Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use. Geneva: WHO; 2000.
13. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol. 1991;164:879-883.
14. Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol. 1997;90:257-263.
15. Lahteenmaki P, Haukkamaa M, Puolakka J, et al. Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy [see comment]. BMJ. 1998;316:1122-1126.
16. Ness RB, Grisso JA, Vergona R, et al. Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer [see comment]. Epidemiology. 2001;12:307-312.
17. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77:S13-S18.
18. Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol. 2002;99:820-827.
It’s surprising to realize that the birth control pill, which launched a revolution in women’s sexuality and health, has been around for less than 50 years—especially considering the myriad of methods and products on the market today. New types of contraceptives have become available, more are on the way, and noncontraceptive benefits continue to accrue. This article reviews noteworthy changes and upcoming products.
Continuous contraception: New routes, new regimens
When it was introduced in 1960, the oral contraceptive (OC) consisted of 20 or 21 active pills followed by a pill-free interval of 7 or 8 days. No medical reason justified the pill-free interval; it was devised simply to trigger menses and reassure the woman she was not pregnant.
That pill-free interval shrank as we gained awareness of the benefits of continuous OC regimens, particularly in the treatment of endometriosis. Advantages—well documented by Sulak1—include marked reduction or elimination of menses-related symptoms such as menorrhagia, dysmenorrhea, and menstrual migraines.
Continuous OCs became “official” in 2003 with the introduction of Seasonale (ethinyl estradiol, 0.03 mg/levonorgestrel, 0.15 mg), a continuous regimen taken for 84 days, followed by a 7-day pill-free interval.2
This regimen reduces the number of periods to 4 each year.
Breakthrough bleeding diminishes over time. Although breakthrough bleeding is a common side effect of continuous oral contraception—as it is with conventional regimens—it decreases with each successive cycle of Seasonale. By the fourth cycle, it is comparable to the level reported by women on a conventional regimen. Prolonged and heavy bleeding also can be managed by discontinuing pills for 7 days.
Other methods also can be used continuously. Continuous contraception is not limited to oral contraception.
The contraceptive ring (Nuvaring; ethinyl estradiol/etonogestrel) can be left in place for 4 weeks instead of 3 without decreasing efficacy. Both hormone levels are sufficient to prevent pregnancy throughout these weeks.3
Nor is there any reason to doubt the efficacy of continuous use of the contraceptive patch (Evra; ethinyl estradiol/norelgestromin).
New regimens. A regimen of 24 active pills and a 4-day pill-free interval is available in Europe. The shorter pill-free interval allows further reduction of the active components ethinyl estradiol and gestadene. This agent contains 15 μg estradiol per pill.4
A version of Yasmin that contains only 20 μg of ethinyl estradiol, should be released in the United States later this year. It will consist of 24 active pills and a 4-day pill-free interval.
New implantable rod. Implanon, a new single-rod contraceptive implant containing etonogestrel, is available outside the United States and may become available here in the near future.5,6 It can be inserted in 1.6 minutes, removed in 2.6 minutes, and lasts 3 years. No pregnancies were reported in clinical trials.
Lower dose of Depo-Provera effective for 3 months. A new dose and route of administration for Depo-Provera (depotmedroxyprogesterone acetate) is just as effective as the 150-mg intramuscular dose.
The new dose is 104 mg administered subcutaneously every 3 months. When it becomes available in the near future, this preparation should allow women to administer the drug at home.7
Emergency contraception: A variety of methods, but still need a prescription
The different methods of emergency contraception are listed in a clip-and-save chart on page 46, which can be photocopied for convenient reference.
Trussell and colleagues’8 excellent review prefers the term emergency contraception to refer to contraceptive use after intercourse has occurred. The term “morning-after pill” is confusing because the method can be used any time after intercourse for up to 72 hours. It can even be used after 72 hours, albeit at reduced efficacy.
The Yuzpe regimen is the oldest and probably most popular form of contraception. It involves taking 2 Ovral tablets (ethinyl estradiol/levonorgestrel) followed by 2 more tablets 12 hours later. Each dose consists of 100 μg of estradiol and 0.5 mg of norgestrel.
Unfortunately, Ovral is not readily available in pharmacies. An alternative is taking enough OCs to equal the 100-μg dose of ethinyl estradiol and the 0.5 mg dose of norgestrel. For example, 5 tablets of Alesse or Levlite can be substituted for the 2 Ovral.
Efficacy is 75%. That is, if 100 women have unprotected intercourse once during the second or third week of their cycle, about 8 will become pregnant without treatment, and only 2 will become pregnant after treatment—a 75% reduction.
OCs that contain different progestins have not been studied extensively. They appear to work with lower efficacy than pills containing levonorgestrel.
- Common side effects include nausea and vomiting. Co-administration of an anti-nausea agent may be necessary. About 50% of women experience nausea and 20% vomit within 2 hours of taking a dose; some clinicians recommend repeating that dose to assure efficacy. One option is giving two 25-mg tablets of the over-the-counter drug meclizine 1 hour before combined emergency contraceptive pills; this reduces the risk of nausea by 27% and vomiting by 64%, but the risk of drowsiness doubles. Taking the medicine with a meal does not lower the rate of nausea.
- Contraindications. The only contraindication is an established pregnancy, since the drugs are taken so briefly.
Plan B Consists of 0.75 mg levonorgestrel taken within 72 hours of intercourse, followed by a second dose 12 hours later. This regimen has fewer side effects than the Yuzpe plan and may be slightly more effective. Unfortunately, the US Food and Drug Administration failed to approve over-the-counter status for this drug, so a prescription is still necessary.
IUDs. Insertion of a copper IUD (Paraguard)—but not a levonorgestrel-containing device (Mirena)—within 72 hours after intercourse is almost completely effective in preventing pregnancy. It also provides continuing contraception. Its mechanism of action is preventing implantation of a fertilized egg. Mirena has no efficacy in this regard.
“Every Woman, Every Visit,” the American College of Obstetricians and Gynecologists’ public education campaign, urges Ob/Gyns to provide advance prescriptions for emergency contraception at every office visit.
After many years of declining choices in the realm of intrauterine devices (IUDs), the Mirena levonorgestrel-containing system was released in the US market in 2000. Like the Paraguard copper IUD, the Mirena prevents pregnancy at a rate equivalent to tubal ligation. These devices last for 5 and 10 years, respectively.9,10
In the United States, interest in IUDs declined after they were associated with salpingitis and tubo-ovarian abscess. More recent epidemiological evidence indicates that IUDs do not increase the risk of infection over the general population, but the rate is higher than with other forms of contraception, which offer some protection against salpingitis. Antibiotic prophylaxis is not necessary.
The removal rate for pelvic inflammatory disease is much lower for Mirena than for the copper IUD and may be related to the low levels of levonorgestrel, which thicken cervical mucus and prevent sperm transport.9
Ectopic pregnancy rates with the Mirena are about 1/8 to 1/10 those observed in the general population. Once the Mirena device is removed, fertility returns rapidly9-11
Recommended for the chronically ill. According to the World Health Organization, IUDs are the safest form of contraception for medically complicated patients.12 Certainly, they are underutilized in this circumstance.
Noncontraceptive benefits. Slow release of low doses of levonorgestrel by Mirena reduces endometrial thickness and menstrual blood loss.13 In fact, several studies have found the Mirena to be equivalent to endometrial ablation.14 In a randomized study, two thirds of the women scheduled for hysterectomy for abnormal uterine bleeding cancelled surgery due to satisfaction with Mirena’s bleeding profile.15
Ovarian cancer also is reduced.16
Does obesity limit contraceptive efficacy?
Decreased efficacy of the contraceptive patch, observed in overweight women,17 especially those heavier than 198 lb, prompted reevaluation of other forms. In a retrospective analysis, Holt and colleagues18 found a higher pregnancy rate in women heavier than 155 lb as the estrogen dose decreased. In contrast, no pregnancies occurred in women weighing more than 198 lb in a randomized trial2 of 30 μg ethinyl estradiol/150 μg levonorgestrel (Seasonale). It is unclear why Holt failed to analyze progestin content, since it is the progestin that inhibits ovulation and prevents pregnancy.
Unfortunately, few clinical trials involve obese women. For example, the contraceptive ring was not evaluated in obese women.
Despite this shortcoming, I have not changed my prescribing of contraceptives in obese women, but await better, more convincing data. Until then, it seems wise to include a broad range of body weights in future trials.
The author serves on the Speakers Bureau for Barr, Berlex, and Wyeth-Ayerst.
It’s surprising to realize that the birth control pill, which launched a revolution in women’s sexuality and health, has been around for less than 50 years—especially considering the myriad of methods and products on the market today. New types of contraceptives have become available, more are on the way, and noncontraceptive benefits continue to accrue. This article reviews noteworthy changes and upcoming products.
Continuous contraception: New routes, new regimens
When it was introduced in 1960, the oral contraceptive (OC) consisted of 20 or 21 active pills followed by a pill-free interval of 7 or 8 days. No medical reason justified the pill-free interval; it was devised simply to trigger menses and reassure the woman she was not pregnant.
That pill-free interval shrank as we gained awareness of the benefits of continuous OC regimens, particularly in the treatment of endometriosis. Advantages—well documented by Sulak1—include marked reduction or elimination of menses-related symptoms such as menorrhagia, dysmenorrhea, and menstrual migraines.
Continuous OCs became “official” in 2003 with the introduction of Seasonale (ethinyl estradiol, 0.03 mg/levonorgestrel, 0.15 mg), a continuous regimen taken for 84 days, followed by a 7-day pill-free interval.2
This regimen reduces the number of periods to 4 each year.
Breakthrough bleeding diminishes over time. Although breakthrough bleeding is a common side effect of continuous oral contraception—as it is with conventional regimens—it decreases with each successive cycle of Seasonale. By the fourth cycle, it is comparable to the level reported by women on a conventional regimen. Prolonged and heavy bleeding also can be managed by discontinuing pills for 7 days.
Other methods also can be used continuously. Continuous contraception is not limited to oral contraception.
The contraceptive ring (Nuvaring; ethinyl estradiol/etonogestrel) can be left in place for 4 weeks instead of 3 without decreasing efficacy. Both hormone levels are sufficient to prevent pregnancy throughout these weeks.3
Nor is there any reason to doubt the efficacy of continuous use of the contraceptive patch (Evra; ethinyl estradiol/norelgestromin).
New regimens. A regimen of 24 active pills and a 4-day pill-free interval is available in Europe. The shorter pill-free interval allows further reduction of the active components ethinyl estradiol and gestadene. This agent contains 15 μg estradiol per pill.4
A version of Yasmin that contains only 20 μg of ethinyl estradiol, should be released in the United States later this year. It will consist of 24 active pills and a 4-day pill-free interval.
New implantable rod. Implanon, a new single-rod contraceptive implant containing etonogestrel, is available outside the United States and may become available here in the near future.5,6 It can be inserted in 1.6 minutes, removed in 2.6 minutes, and lasts 3 years. No pregnancies were reported in clinical trials.
Lower dose of Depo-Provera effective for 3 months. A new dose and route of administration for Depo-Provera (depotmedroxyprogesterone acetate) is just as effective as the 150-mg intramuscular dose.
The new dose is 104 mg administered subcutaneously every 3 months. When it becomes available in the near future, this preparation should allow women to administer the drug at home.7
Emergency contraception: A variety of methods, but still need a prescription
The different methods of emergency contraception are listed in a clip-and-save chart on page 46, which can be photocopied for convenient reference.
Trussell and colleagues’8 excellent review prefers the term emergency contraception to refer to contraceptive use after intercourse has occurred. The term “morning-after pill” is confusing because the method can be used any time after intercourse for up to 72 hours. It can even be used after 72 hours, albeit at reduced efficacy.
The Yuzpe regimen is the oldest and probably most popular form of contraception. It involves taking 2 Ovral tablets (ethinyl estradiol/levonorgestrel) followed by 2 more tablets 12 hours later. Each dose consists of 100 μg of estradiol and 0.5 mg of norgestrel.
Unfortunately, Ovral is not readily available in pharmacies. An alternative is taking enough OCs to equal the 100-μg dose of ethinyl estradiol and the 0.5 mg dose of norgestrel. For example, 5 tablets of Alesse or Levlite can be substituted for the 2 Ovral.
Efficacy is 75%. That is, if 100 women have unprotected intercourse once during the second or third week of their cycle, about 8 will become pregnant without treatment, and only 2 will become pregnant after treatment—a 75% reduction.
OCs that contain different progestins have not been studied extensively. They appear to work with lower efficacy than pills containing levonorgestrel.
- Common side effects include nausea and vomiting. Co-administration of an anti-nausea agent may be necessary. About 50% of women experience nausea and 20% vomit within 2 hours of taking a dose; some clinicians recommend repeating that dose to assure efficacy. One option is giving two 25-mg tablets of the over-the-counter drug meclizine 1 hour before combined emergency contraceptive pills; this reduces the risk of nausea by 27% and vomiting by 64%, but the risk of drowsiness doubles. Taking the medicine with a meal does not lower the rate of nausea.
- Contraindications. The only contraindication is an established pregnancy, since the drugs are taken so briefly.
Plan B Consists of 0.75 mg levonorgestrel taken within 72 hours of intercourse, followed by a second dose 12 hours later. This regimen has fewer side effects than the Yuzpe plan and may be slightly more effective. Unfortunately, the US Food and Drug Administration failed to approve over-the-counter status for this drug, so a prescription is still necessary.
IUDs. Insertion of a copper IUD (Paraguard)—but not a levonorgestrel-containing device (Mirena)—within 72 hours after intercourse is almost completely effective in preventing pregnancy. It also provides continuing contraception. Its mechanism of action is preventing implantation of a fertilized egg. Mirena has no efficacy in this regard.
“Every Woman, Every Visit,” the American College of Obstetricians and Gynecologists’ public education campaign, urges Ob/Gyns to provide advance prescriptions for emergency contraception at every office visit.
After many years of declining choices in the realm of intrauterine devices (IUDs), the Mirena levonorgestrel-containing system was released in the US market in 2000. Like the Paraguard copper IUD, the Mirena prevents pregnancy at a rate equivalent to tubal ligation. These devices last for 5 and 10 years, respectively.9,10
In the United States, interest in IUDs declined after they were associated with salpingitis and tubo-ovarian abscess. More recent epidemiological evidence indicates that IUDs do not increase the risk of infection over the general population, but the rate is higher than with other forms of contraception, which offer some protection against salpingitis. Antibiotic prophylaxis is not necessary.
The removal rate for pelvic inflammatory disease is much lower for Mirena than for the copper IUD and may be related to the low levels of levonorgestrel, which thicken cervical mucus and prevent sperm transport.9
Ectopic pregnancy rates with the Mirena are about 1/8 to 1/10 those observed in the general population. Once the Mirena device is removed, fertility returns rapidly9-11
Recommended for the chronically ill. According to the World Health Organization, IUDs are the safest form of contraception for medically complicated patients.12 Certainly, they are underutilized in this circumstance.
Noncontraceptive benefits. Slow release of low doses of levonorgestrel by Mirena reduces endometrial thickness and menstrual blood loss.13 In fact, several studies have found the Mirena to be equivalent to endometrial ablation.14 In a randomized study, two thirds of the women scheduled for hysterectomy for abnormal uterine bleeding cancelled surgery due to satisfaction with Mirena’s bleeding profile.15
Ovarian cancer also is reduced.16
Does obesity limit contraceptive efficacy?
Decreased efficacy of the contraceptive patch, observed in overweight women,17 especially those heavier than 198 lb, prompted reevaluation of other forms. In a retrospective analysis, Holt and colleagues18 found a higher pregnancy rate in women heavier than 155 lb as the estrogen dose decreased. In contrast, no pregnancies occurred in women weighing more than 198 lb in a randomized trial2 of 30 μg ethinyl estradiol/150 μg levonorgestrel (Seasonale). It is unclear why Holt failed to analyze progestin content, since it is the progestin that inhibits ovulation and prevents pregnancy.
Unfortunately, few clinical trials involve obese women. For example, the contraceptive ring was not evaluated in obese women.
Despite this shortcoming, I have not changed my prescribing of contraceptives in obese women, but await better, more convincing data. Until then, it seems wise to include a broad range of body weights in future trials.
The author serves on the Speakers Bureau for Barr, Berlex, and Wyeth-Ayerst.
1. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
2. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.
3. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinyl estradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinetics. 2000;39:233-242.
4. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21 day and 24 day oral contraceptive regimens containing gestodene (60 μg) and ethinyl estradiol (15 μg) on ovarian activity. Fertil Steril. 1999;72:115-120.
5. Croxatto HB, Urbancsek J, Massai R, Coelingh BH, van Beek A. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Implanon Study Group. Hum Reprod. 1999;14:976-981.
6. Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant. Contraception. 1999;60:1-8.
7. Jain J, Dutton C, Nicosia A, Wajszczuk C, Dode FR, Mishell DR. Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera. Contraception. 2004;70:11-18.
8. Trussell J, Ellertson C, Stewart F, Raymond EG, Shochet T. The role of emergency contraception. Am J Obstet Gynecol. 2004;190:S30-S38.
9. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49:56-72.
10. Peterson HB, Xia Z, Hughes JM, Wilcox LS, Tylor LR, Trussell J. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization [see comment]. Am J Obstet Gynecol. 1996;174:1161-1168.
11. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrelreleasing intrauterine device and Nova-T. Contraception. 1992;46:575-584.
12. World Health Organization. Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use. Geneva: WHO; 2000.
13. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol. 1991;164:879-883.
14. Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol. 1997;90:257-263.
15. Lahteenmaki P, Haukkamaa M, Puolakka J, et al. Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy [see comment]. BMJ. 1998;316:1122-1126.
16. Ness RB, Grisso JA, Vergona R, et al. Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer [see comment]. Epidemiology. 2001;12:307-312.
17. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77:S13-S18.
18. Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol. 2002;99:820-827.
1. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
2. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.
3. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinyl estradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinetics. 2000;39:233-242.
4. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21 day and 24 day oral contraceptive regimens containing gestodene (60 μg) and ethinyl estradiol (15 μg) on ovarian activity. Fertil Steril. 1999;72:115-120.
5. Croxatto HB, Urbancsek J, Massai R, Coelingh BH, van Beek A. A multicentre efficacy and safety study of the single contraceptive implant Implanon. Implanon Study Group. Hum Reprod. 1999;14:976-981.
6. Zheng SR, Zheng HM, Qian SZ, Sang GW, Kaper RF. A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant. Contraception. 1999;60:1-8.
7. Jain J, Dutton C, Nicosia A, Wajszczuk C, Dode FR, Mishell DR. Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera. Contraception. 2004;70:11-18.
8. Trussell J, Ellertson C, Stewart F, Raymond EG, Shochet T. The role of emergency contraception. Am J Obstet Gynecol. 2004;190:S30-S38.
9. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49:56-72.
10. Peterson HB, Xia Z, Hughes JM, Wilcox LS, Tylor LR, Trussell J. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization [see comment]. Am J Obstet Gynecol. 1996;174:1161-1168.
11. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrelreleasing intrauterine device and Nova-T. Contraception. 1992;46:575-584.
12. World Health Organization. Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use. Geneva: WHO; 2000.
13. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol. 1991;164:879-883.
14. Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol. 1997;90:257-263.
15. Lahteenmaki P, Haukkamaa M, Puolakka J, et al. Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy [see comment]. BMJ. 1998;316:1122-1126.
16. Ness RB, Grisso JA, Vergona R, et al. Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer [see comment]. Epidemiology. 2001;12:307-312.
17. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77:S13-S18.
18. Holt VL, Cushing-Haugen KL, Daling JR. Body weight and risk of oral contraceptive failure. Obstet Gynecol. 2002;99:820-827.