Clinical Review

Episodic heavy drinking, like alcoholism and drug addiction, is increasingly recognized as a medical problem that primary care physicians can, and should, address.¹ But it is rarely the chief reason for an office visit. Nor is it a subject patients are likely to bring up.

However, patients are generally willing to talk to a trusted doctor who asks about their use (or misuse) of alcohol or other substances. And primary care physicians can do much to help—with brief interventions, a growing armamentarium of pharmacotherapy, and referrals as needed. In the pages that follow, you’ll find easy-to-use screening tools and effective intervention strategies.

SCREENING NEEDN'T BE TIME-CONSUMING

Screening for substance use isn’t difficult. In fact, it can usually be accomplished with 2 targeted questions—one for alcohol use and one for drugs.

Alcohol. Two single-question screens to detect hazardous drinking have been validated, despite having different parameters. Ask either:

Q: When was the last time you had more than ____ drinks (4 for women and 5 for men) in one day?

Q: How many times in the past year have you had ___ or more drinks (4 for women and 5 for men) in one day?

For the first question, any answer within the past 3 months is a positive screen for hazardous drinking.² For the second, anything other than zero is positive.^3,4

Initial screening can also be done with the AUDIT-C (TABLE), a validated short (3-question) version of the Alcohol Use Disorders Identification Test that can be self-administered.^5,6

Drugs. Only one single-question screen for drug use has been validated:

Q: How many times in the past year have you used an illegal drug or taken a prescription medication for nonmedical reasons?

Any answer other than never is a positive screen for hazardous drug use.⁷

CASE Jason F, a healthy and fit 28-year-old, has been your patient, along with his family, for years. He’s in your office because of a knee injury he incurred while running, and you take a moment to ask him, for the first time, how much he drinks and whether he takes drugs. His answer—that he drinks 3 or 4 times a week and often has multiple drinks at parties or nights out with the guys—takes you a bit by surprise.

Now what?

Watch the video

TABLE

3-question AUDIT-C screen for alcohol dependence^5,6

TELL ME MORE ABOUT IT

It is important to respond to a positive screen by requesting more information. In the conversation that ensues, the patient may provide the details you need to determine whether the drinking or drug use is indicative of a diagnosable substance use disorder, an umbrella term for alcohol or drug abuse and alcohol or drug dependence.

Alcohol or drug abuse vs dependence. Criteria for alcohol or drug abuse in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision (DSM-IV-TR) include risky behavior, such as drinking and driving; problems with work and/or close relationships; or run-ins with the law, such as an arrest for driving while intoxicated. Criteria for alcohol or drug dependence include the inability to cut down or stop using the substance; evidence of tolerance and withdrawal; spending more time ingesting the substance; increasing attention to substance use while interest in other activities diminishes; and continued use despite recurrent problems.⁸

Tools zero in on extent of problem

To learn more about your patient’s situation, consider using the following criteria and tools:

DSM criteria. Ask the following 2 questions, which are among DSM-IV-TR criteria for alcohol dependence:

1. How many times in the last year have you had a lot more to drink than you intended?
2. How many times in the last year have you been drinking in situations where it could have been hazardous, where you could have caused an accident or gotten hurt?

Any answer other than zero to either question is suggestive of a substance use disorder. In exploratory analyses, this approach had positive likelihood ratios of 4.7 to 16 and negative likelihood ratios of 0.05 to 0.30.^9,10

Although the above questions refer to alcohol use, they could be revised to learn more about a patient’s use of marijuana or other drugs, as well. (There are few tools for the assessment of drug use, because any illegal or nonmedical use of controlled substances has clear risks of major harm.)

CAGE. Another tool that is effective in assessing alcohol use is the 4-question CAGE—an acronym for Cut down, Annoyed, Guilty, and Eye opener:

• Have you ever felt that you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt bad or guilty about your drinking?
• Have you ever had a drink in the morning to get rid of a hangover?

One meta-analysis found that a positive CAGE test—ie, a positive response to one or more of the questions—had a sensitivity of 0.85 and a specificity of 0.78 in identifying alcohol dependence in a primary care setting (using DSM criteria as the gold standard).¹¹

AUDIT. This 10-item tool, a longer version of the AUDIT-C (available at http://www.medstudentlearning.com/node/6556), can also be used to determine the extent of alcohol use. This test provides detailed information about the quantity and frequency of alcohol use; however, it does not clearly distinguish between hazardous drinking and alcohol use disorders.¹²

If the patient is a teen

Assessment methods can be adjusted without difficulty to fit the age of the patient. The National Institute on Alcohol Abuse and Alcoholism has published the Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide, available at http://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/Pages/YouthGuide.aspx. The 6-question CRAFFT (for Car, Relax, Alone, Forget, Friends, Trouble) is a validated tool designed to assess adolescents’ use of both alcohol and drugs (http://www.ceasar-boston.org/clinicians/crafft.php).^13,14

CASE You give Mr. F the CAGE test, and he answers No to all 4 questions. You conclude that while his drinking may be hazardous, he does not appear to have alcohol abuse or dependence.

FOLLOW UP WITH A BRIEF INTERVENTION

For decades, evidence has shown that brief interventions are often effective in helping hazardous drinkers like Mr. F cut back to safer levels.^15-18 In some cases, the impact has been great enough to reduce health care and societal costs for up to 4 years¹⁹ and to cut the risk of alcohol-related death by about half.²⁰ As a result, the US Preventive Services Task Force has given a B rating to counseling to reduce alcohol misuse by primary care providers.²¹ (There is less evidence that brief interventions are effective for drug problems,²² or in settings other than primary care.²³)

Treat drug/alcohol problems

If you determine that your patient is engaging in hazardous alcohol or drug use or has a diagnosable substance use disorder, you do not have to drop everything else or treat it as an acute event. What matters is long-term success, which is best achieved by partnering with the patient.

Start by approaching drug and alcohol problems as you would a case of newly elevated blood pressure. Bring up the problem, seeking to engage the patient in addres- sing it.

If he or she does not agree to quit or cut back on drinking the first time you broach the subject, don’t be surprised or discouraged. Keep in mind that patients do not always respond positively to advice about handling chronic medical conditions either, particularly at first, and that you’ll be working together over time. What’s important, in the jargon of the Stages of Change model,²⁴ is to help the patient move from precontemplation to contemplation, and perhaps beyond that to planning or action.

Use motivational interviewing to partner with patients

Motivational interviewing is useful in helping patients change health-related behaviors. The technique, which is not hard to learn or apply, is based on the recognition that a simple shift in style toward a guiding (rather than directive) approach can often reap benefits that are immediately apparent. ^25-28

Motivational Interviewing: Helping People Change (3rd ed, by William R. Miller and Stephen Rollnick; Guilford Press, 2013) is an excellent resource for clinicians who wish to master this technique. An online tutorial in screening and brief intervention for alcohol or drug misuse is available free at https://adept.missouri.edu. Video demonstrations of motivational interviewing to address these issues are also available here ; to access them, click on “Training”, then on “Go to SBIRT videos”).

CASE Before Mr. F’s visit is concluded, you initiate a conversation about alcohol use, stating: “As your doctor, I’m concerned that the amount of alcohol you’re drinking could be hazardous to your health. I recommend that you cut down to no more than 4 drinks in any one day and to no more than 14 drinks a week.” You make it clear that change is up to him, and ask what he thinks about what you’ve said.

You also schedule a return visit in one month, at which time you will continue the conversation.

PHARMACOTHERAPY IS A USEFUL TOOL

Increasingly, alcohol and drug dependence—like other chronic conditions—can be effectively addressed with medication.

Drugs to treat alcohol dependence

Naltrexone. A daily dose of naltrexone, starting at 25 mg daily for a few days and going as high as 100 mg/d, can help patients with alcohol dependence limit their drinking to safe levels (number needed to treat [NNT]=9).²⁹ This will reduce the risk of alcohol-related harm while the patient considers quitting.

The most common adverse effect is nausea, but a low starting dose may alleviate it. Naltrexone, also available as a 380-mg intramuscular (IM) depot injection once every 4 weeks, is an opioid antagonist and should not be given to any patient who’s taking opioids.

A 2010 Cochrane review found only 4 trials of naltrexone IM, and failed to show significant reductions in drinking.²⁹ But post hoc analyses of trials of both oral and IM naltrexone found that those in which compliance was assured (either by direct observation or IM administration) had better outcomes than those in which it was not.³⁰ Another post hoc analysis found that patients whose alcohol dependence was more severe derived greater benefits from the drug than those who were less severely affected.³¹

Acamprosate. Two 333-mg pills tid can help newly abstinent drinkers remain alcohol-free (NNT=9).^32,33 The most common adverse effect is diarrhea, which may subside with continued use.

Combining acamprosate and naltrexone does not appear to be more effective than either drug alone. In a recently published meta-analysis comparing the 2 drugs, those taking acamprosate had slightly better rates of abstinence from alcohol, while naltrexone was slightly better in reducing heavy drinking.³⁴

Disulfiram Unlike naltrexone and acamprosate, which work by altering the brain’s reward circuits, disulfiram blocks metabolism of ethanol, leading to the accumulation of a toxic metabolite and its punishing syndrome. The major problem with the drug is noncompliance, which can be addressed by enlisting the help of a caregiver or partner to ensure that it is taken daily. ^35-37

Other medications that have been tested (though not approved by the US Food and Drug Administration [FDA]) as a treatment for alcohol dependence include:

• topiramate, which has been found to have modest efficacy in increasing the number of abstinent days and decreasing heavy-drinking days;³⁸
• baclofen, which has shown efficacy in small clinical trials;³⁹ and
• ondansetron, which has been shown to effectively treat early-onset alcohol dependence.^40,41

For patients with depression and alcohol dependence, the combination of naltrexone and sertraline has been found to be superior to either drug by itself—and to have fewer adverse effects. ⁴² Gabapentin and lorazepam have been compared in treating alcohol withdrawal, with gabapentin resulting in greater efficacy and fewer adverse effects than lorazepam.^43,44

Pharmacotherapy for drug abuse, dependence

For methamphetamine abuse and dependence. Two randomized clinical trials have studied medications for methamphetamine abuse and dependence. In one small study, topiramate did not increase the proportion of patients who achieved abstinence, but in a post hoc subgroup analysis, it did appear to help newly abstinent patients avoid relapse.⁴⁵

In another study, mirtazapine significantly decreased the proportion of patients whose weekly urine tests were positive for methamphetamine (from 73% to 44%); no significant change was found among those on placebo.⁴⁶

Both drugs were well tolerated, but compliance was low in both trials despite weekly counseling. Each has only one clinical trial to support its use, and neither has FDA approval for addiction treatment.

For marijuana dependence. In a study of 50 people seeking treatment for marijuana dependence, gabapentin 400 mg 3 times a day significantly improved the proportion reporting no cannabis use and whose urine tested negative for the drug.⁴⁷

Another recent trial randomized adolescents dependent on cannabis to placebo or N-acetylcysteine 1200 mg twice a day. Those on the active drug were 2.4 times more likely than those on placebo to have negative urine tests with a number needed to treat of 7.⁴⁸ Both trials ran for about 3 months. Neither drug is FDA approved to treat marijuana dependence.

For opioid dependence. As maintenance medication for patients dependent on opioids, both methadone and buprenorphine have been shown to reduce the use of illicit opioids, lower mortality, and improve retention compared with treatment without medication.⁴⁹ Methadone would be a better choice than buprenorphine, which is a partial agonist with a ceiling on both its good (eg, stopping craving) and bad (eg, overdose risk) effects. In an open-label observational study of patients’ preferences, those who chose methadone maintenance over buprenorphine were twice as likely to remain in treatment.⁵⁰ Both drugs are FDA-approved for treating opioid dependence.

Methadone is a full agonist that can be given for opioid dependence only in a federally licensed methadone maintenance clinic. It has been shown to reduce the use of other opioids, reduce criminal behaviors,⁵¹ improve function in many areas,⁵² and reduce mortality.⁵³ In a cohort study of Massachusetts Medicaid data, methadone reduced mortality, which was 75% higher among those receiving abstinence-based treatment.^52,54

Buprenorphine (alone and in combination with naloxone), effectively reduces the use of illicit opioids and improves functional status.^55-57

Naltrexone, an opioid antagonist, may be effective in the treatment of opioid dependence. As with disulfiram for alcohol dependence, a major limitation of naltrexone for opioid dependence is noncompliance. But once a patient has been on oral naltrexone, he or she can be switched to naltrexone IM, which can be administered every 4 weeks. A Cochrane review published in 2011 found no evidence that naltrexone was superior to placebo, ⁵⁸ but since then another randomized clinical trial has been published that found naltrexone 380 mg IM every 4 weeks was superior to IM placebo. Patients on naltrexone were more likely to remain in treatment and have opioid-free urine tests, and reported less craving for opioids.⁵⁹ Both oral and depot injection naltrexone are FDA approved for treatment of opioid dependence. No comparisons of naltrexone vs either methadone or buprenorphine have been published.

To learn more about pharmacotherapy for opioid dependence, see “Diagnosing and treating opioid dependence” (J Fam Pract. 2012;61:588-596).

DEALING WITH THE CHALLENGES

As noted earlier, some patients with substance use disorders, like some patients with depression or hypertension, respond well to care and counseling, and some do not. Just as with other conditions, consultation with a specialist often helps.

A major difference in arranging consultations for patients with substance use disorders, however, is that clinicians who specialize in substance abuse and dependence often work in health care systems that are largely, or entirely, separate from those in which primary care physicians typically work. This, plus the stigma that surrounds problems with substance use, presents barriers to patients, who may shy away from going across town or to another city to see a provider they don’t know for a problem they’re either resistant to “owning” or ashamed of.

Yet it is possible to reach across this divide and make it easier for patients. One way to do that might be to partner with a local alcohol- and drug-treatment program so that your patients are referred, not to a faceless agency, but rather to a specific clinician; you might even call the provider while the patient is in your office so they can “meet.” Another approach, taken by some multispecialty practices, is to add psychotherapists to the staff so that patients can simply walk down the hall to obtain the mental health care they need.

Reaching across this divide is also a useful strategy for primary care physicians, who may welcome opportunities to meet with someone from a local treatment agency, not just for referrals but to learn more about treating patients with substance use problems. The Patient Protection and Affordable Care Act, which cites substance use disorders as one of 6 chronic health conditions that primary care medical homes are expected to address, may lead to better integration of health care systems that address physical health, as well as mental health and substance use disorders.

Episodic heavy drinking, like alcoholism and drug addiction, is increasingly recognized as a medical problem that primary care physicians can, and should, address.¹ But it is rarely the chief reason for an office visit. Nor is it a subject patients are likely to bring up.

However, patients are generally willing to talk to a trusted doctor who asks about their use (or misuse) of alcohol or other substances. And primary care physicians can do much to help—with brief interventions, a growing armamentarium of pharmacotherapy, and referrals as needed. In the pages that follow, you’ll find easy-to-use screening tools and effective intervention strategies.

SCREENING NEEDN'T BE TIME-CONSUMING

Screening for substance use isn’t difficult. In fact, it can usually be accomplished with 2 targeted questions—one for alcohol use and one for drugs.

Alcohol. Two single-question screens to detect hazardous drinking have been validated, despite having different parameters. Ask either:

Q: When was the last time you had more than ____ drinks (4 for women and 5 for men) in one day?

Q: How many times in the past year have you had ___ or more drinks (4 for women and 5 for men) in one day?

For the first question, any answer within the past 3 months is a positive screen for hazardous drinking.² For the second, anything other than zero is positive.^3,4

Initial screening can also be done with the AUDIT-C (TABLE), a validated short (3-question) version of the Alcohol Use Disorders Identification Test that can be self-administered.^5,6

Drugs. Only one single-question screen for drug use has been validated:

Q: How many times in the past year have you used an illegal drug or taken a prescription medication for nonmedical reasons?

Any answer other than never is a positive screen for hazardous drug use.⁷

CASE Jason F, a healthy and fit 28-year-old, has been your patient, along with his family, for years. He’s in your office because of a knee injury he incurred while running, and you take a moment to ask him, for the first time, how much he drinks and whether he takes drugs. His answer—that he drinks 3 or 4 times a week and often has multiple drinks at parties or nights out with the guys—takes you a bit by surprise.

Now what?

Watch the video

TABLE

3-question AUDIT-C screen for alcohol dependence^5,6

TELL ME MORE ABOUT IT

It is important to respond to a positive screen by requesting more information. In the conversation that ensues, the patient may provide the details you need to determine whether the drinking or drug use is indicative of a diagnosable substance use disorder, an umbrella term for alcohol or drug abuse and alcohol or drug dependence.

Alcohol or drug abuse vs dependence. Criteria for alcohol or drug abuse in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision (DSM-IV-TR) include risky behavior, such as drinking and driving; problems with work and/or close relationships; or run-ins with the law, such as an arrest for driving while intoxicated. Criteria for alcohol or drug dependence include the inability to cut down or stop using the substance; evidence of tolerance and withdrawal; spending more time ingesting the substance; increasing attention to substance use while interest in other activities diminishes; and continued use despite recurrent problems.⁸

Tools zero in on extent of problem

To learn more about your patient’s situation, consider using the following criteria and tools:

DSM criteria. Ask the following 2 questions, which are among DSM-IV-TR criteria for alcohol dependence:

1. How many times in the last year have you had a lot more to drink than you intended?
2. How many times in the last year have you been drinking in situations where it could have been hazardous, where you could have caused an accident or gotten hurt?

Any answer other than zero to either question is suggestive of a substance use disorder. In exploratory analyses, this approach had positive likelihood ratios of 4.7 to 16 and negative likelihood ratios of 0.05 to 0.30.^9,10

Although the above questions refer to alcohol use, they could be revised to learn more about a patient’s use of marijuana or other drugs, as well. (There are few tools for the assessment of drug use, because any illegal or nonmedical use of controlled substances has clear risks of major harm.)

CAGE. Another tool that is effective in assessing alcohol use is the 4-question CAGE—an acronym for Cut down, Annoyed, Guilty, and Eye opener:

• Have you ever felt that you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt bad or guilty about your drinking?
• Have you ever had a drink in the morning to get rid of a hangover?

One meta-analysis found that a positive CAGE test—ie, a positive response to one or more of the questions—had a sensitivity of 0.85 and a specificity of 0.78 in identifying alcohol dependence in a primary care setting (using DSM criteria as the gold standard).¹¹

AUDIT. This 10-item tool, a longer version of the AUDIT-C (available at http://www.medstudentlearning.com/node/6556), can also be used to determine the extent of alcohol use. This test provides detailed information about the quantity and frequency of alcohol use; however, it does not clearly distinguish between hazardous drinking and alcohol use disorders.¹²

If the patient is a teen

Assessment methods can be adjusted without difficulty to fit the age of the patient. The National Institute on Alcohol Abuse and Alcoholism has published the Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide, available at http://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/Pages/YouthGuide.aspx. The 6-question CRAFFT (for Car, Relax, Alone, Forget, Friends, Trouble) is a validated tool designed to assess adolescents’ use of both alcohol and drugs (http://www.ceasar-boston.org/clinicians/crafft.php).^13,14

CASE You give Mr. F the CAGE test, and he answers No to all 4 questions. You conclude that while his drinking may be hazardous, he does not appear to have alcohol abuse or dependence.

FOLLOW UP WITH A BRIEF INTERVENTION

For decades, evidence has shown that brief interventions are often effective in helping hazardous drinkers like Mr. F cut back to safer levels.^15-18 In some cases, the impact has been great enough to reduce health care and societal costs for up to 4 years¹⁹ and to cut the risk of alcohol-related death by about half.²⁰ As a result, the US Preventive Services Task Force has given a B rating to counseling to reduce alcohol misuse by primary care providers.²¹ (There is less evidence that brief interventions are effective for drug problems,²² or in settings other than primary care.²³)

Treat drug/alcohol problems

If you determine that your patient is engaging in hazardous alcohol or drug use or has a diagnosable substance use disorder, you do not have to drop everything else or treat it as an acute event. What matters is long-term success, which is best achieved by partnering with the patient.

Start by approaching drug and alcohol problems as you would a case of newly elevated blood pressure. Bring up the problem, seeking to engage the patient in addres- sing it.

If he or she does not agree to quit or cut back on drinking the first time you broach the subject, don’t be surprised or discouraged. Keep in mind that patients do not always respond positively to advice about handling chronic medical conditions either, particularly at first, and that you’ll be working together over time. What’s important, in the jargon of the Stages of Change model,²⁴ is to help the patient move from precontemplation to contemplation, and perhaps beyond that to planning or action.

Use motivational interviewing to partner with patients

Motivational interviewing is useful in helping patients change health-related behaviors. The technique, which is not hard to learn or apply, is based on the recognition that a simple shift in style toward a guiding (rather than directive) approach can often reap benefits that are immediately apparent. ^25-28

Motivational Interviewing: Helping People Change (3rd ed, by William R. Miller and Stephen Rollnick; Guilford Press, 2013) is an excellent resource for clinicians who wish to master this technique. An online tutorial in screening and brief intervention for alcohol or drug misuse is available free at https://adept.missouri.edu. Video demonstrations of motivational interviewing to address these issues are also available here ; to access them, click on “Training”, then on “Go to SBIRT videos”).

CASE Before Mr. F’s visit is concluded, you initiate a conversation about alcohol use, stating: “As your doctor, I’m concerned that the amount of alcohol you’re drinking could be hazardous to your health. I recommend that you cut down to no more than 4 drinks in any one day and to no more than 14 drinks a week.” You make it clear that change is up to him, and ask what he thinks about what you’ve said.

You also schedule a return visit in one month, at which time you will continue the conversation.

PHARMACOTHERAPY IS A USEFUL TOOL

Increasingly, alcohol and drug dependence—like other chronic conditions—can be effectively addressed with medication.

Drugs to treat alcohol dependence

Naltrexone. A daily dose of naltrexone, starting at 25 mg daily for a few days and going as high as 100 mg/d, can help patients with alcohol dependence limit their drinking to safe levels (number needed to treat [NNT]=9).²⁹ This will reduce the risk of alcohol-related harm while the patient considers quitting.

The most common adverse effect is nausea, but a low starting dose may alleviate it. Naltrexone, also available as a 380-mg intramuscular (IM) depot injection once every 4 weeks, is an opioid antagonist and should not be given to any patient who’s taking opioids.

A 2010 Cochrane review found only 4 trials of naltrexone IM, and failed to show significant reductions in drinking.²⁹ But post hoc analyses of trials of both oral and IM naltrexone found that those in which compliance was assured (either by direct observation or IM administration) had better outcomes than those in which it was not.³⁰ Another post hoc analysis found that patients whose alcohol dependence was more severe derived greater benefits from the drug than those who were less severely affected.³¹

Acamprosate. Two 333-mg pills tid can help newly abstinent drinkers remain alcohol-free (NNT=9).^32,33 The most common adverse effect is diarrhea, which may subside with continued use.

Combining acamprosate and naltrexone does not appear to be more effective than either drug alone. In a recently published meta-analysis comparing the 2 drugs, those taking acamprosate had slightly better rates of abstinence from alcohol, while naltrexone was slightly better in reducing heavy drinking.³⁴

Disulfiram Unlike naltrexone and acamprosate, which work by altering the brain’s reward circuits, disulfiram blocks metabolism of ethanol, leading to the accumulation of a toxic metabolite and its punishing syndrome. The major problem with the drug is noncompliance, which can be addressed by enlisting the help of a caregiver or partner to ensure that it is taken daily. ^35-37

Other medications that have been tested (though not approved by the US Food and Drug Administration [FDA]) as a treatment for alcohol dependence include:

• topiramate, which has been found to have modest efficacy in increasing the number of abstinent days and decreasing heavy-drinking days;³⁸
• baclofen, which has shown efficacy in small clinical trials;³⁹ and
• ondansetron, which has been shown to effectively treat early-onset alcohol dependence.^40,41

For patients with depression and alcohol dependence, the combination of naltrexone and sertraline has been found to be superior to either drug by itself—and to have fewer adverse effects. ⁴² Gabapentin and lorazepam have been compared in treating alcohol withdrawal, with gabapentin resulting in greater efficacy and fewer adverse effects than lorazepam.^43,44

Pharmacotherapy for drug abuse, dependence

For methamphetamine abuse and dependence. Two randomized clinical trials have studied medications for methamphetamine abuse and dependence. In one small study, topiramate did not increase the proportion of patients who achieved abstinence, but in a post hoc subgroup analysis, it did appear to help newly abstinent patients avoid relapse.⁴⁵

In another study, mirtazapine significantly decreased the proportion of patients whose weekly urine tests were positive for methamphetamine (from 73% to 44%); no significant change was found among those on placebo.⁴⁶

Both drugs were well tolerated, but compliance was low in both trials despite weekly counseling. Each has only one clinical trial to support its use, and neither has FDA approval for addiction treatment.

For marijuana dependence. In a study of 50 people seeking treatment for marijuana dependence, gabapentin 400 mg 3 times a day significantly improved the proportion reporting no cannabis use and whose urine tested negative for the drug.⁴⁷

Another recent trial randomized adolescents dependent on cannabis to placebo or N-acetylcysteine 1200 mg twice a day. Those on the active drug were 2.4 times more likely than those on placebo to have negative urine tests with a number needed to treat of 7.⁴⁸ Both trials ran for about 3 months. Neither drug is FDA approved to treat marijuana dependence.

For opioid dependence. As maintenance medication for patients dependent on opioids, both methadone and buprenorphine have been shown to reduce the use of illicit opioids, lower mortality, and improve retention compared with treatment without medication.⁴⁹ Methadone would be a better choice than buprenorphine, which is a partial agonist with a ceiling on both its good (eg, stopping craving) and bad (eg, overdose risk) effects. In an open-label observational study of patients’ preferences, those who chose methadone maintenance over buprenorphine were twice as likely to remain in treatment.⁵⁰ Both drugs are FDA-approved for treating opioid dependence.

Methadone is a full agonist that can be given for opioid dependence only in a federally licensed methadone maintenance clinic. It has been shown to reduce the use of other opioids, reduce criminal behaviors,⁵¹ improve function in many areas,⁵² and reduce mortality.⁵³ In a cohort study of Massachusetts Medicaid data, methadone reduced mortality, which was 75% higher among those receiving abstinence-based treatment.^52,54

Buprenorphine (alone and in combination with naloxone), effectively reduces the use of illicit opioids and improves functional status.^55-57

Naltrexone, an opioid antagonist, may be effective in the treatment of opioid dependence. As with disulfiram for alcohol dependence, a major limitation of naltrexone for opioid dependence is noncompliance. But once a patient has been on oral naltrexone, he or she can be switched to naltrexone IM, which can be administered every 4 weeks. A Cochrane review published in 2011 found no evidence that naltrexone was superior to placebo, ⁵⁸ but since then another randomized clinical trial has been published that found naltrexone 380 mg IM every 4 weeks was superior to IM placebo. Patients on naltrexone were more likely to remain in treatment and have opioid-free urine tests, and reported less craving for opioids.⁵⁹ Both oral and depot injection naltrexone are FDA approved for treatment of opioid dependence. No comparisons of naltrexone vs either methadone or buprenorphine have been published.

To learn more about pharmacotherapy for opioid dependence, see “Diagnosing and treating opioid dependence” (J Fam Pract. 2012;61:588-596).

DEALING WITH THE CHALLENGES

As noted earlier, some patients with substance use disorders, like some patients with depression or hypertension, respond well to care and counseling, and some do not. Just as with other conditions, consultation with a specialist often helps.

A major difference in arranging consultations for patients with substance use disorders, however, is that clinicians who specialize in substance abuse and dependence often work in health care systems that are largely, or entirely, separate from those in which primary care physicians typically work. This, plus the stigma that surrounds problems with substance use, presents barriers to patients, who may shy away from going across town or to another city to see a provider they don’t know for a problem they’re either resistant to “owning” or ashamed of.

Yet it is possible to reach across this divide and make it easier for patients. One way to do that might be to partner with a local alcohol- and drug-treatment program so that your patients are referred, not to a faceless agency, but rather to a specific clinician; you might even call the provider while the patient is in your office so they can “meet.” Another approach, taken by some multispecialty practices, is to add psychotherapists to the staff so that patients can simply walk down the hall to obtain the mental health care they need.

Reaching across this divide is also a useful strategy for primary care physicians, who may welcome opportunities to meet with someone from a local treatment agency, not just for referrals but to learn more about treating patients with substance use problems. The Patient Protection and Affordable Care Act, which cites substance use disorders as one of 6 chronic health conditions that primary care medical homes are expected to address, may lead to better integration of health care systems that address physical health, as well as mental health and substance use disorders.

Episodic heavy drinking, like alcoholism and drug addiction, is increasingly recognized as a medical problem that primary care physicians can, and should, address.¹ But it is rarely the chief reason for an office visit. Nor is it a subject patients are likely to bring up.

However, patients are generally willing to talk to a trusted doctor who asks about their use (or misuse) of alcohol or other substances. And primary care physicians can do much to help—with brief interventions, a growing armamentarium of pharmacotherapy, and referrals as needed. In the pages that follow, you’ll find easy-to-use screening tools and effective intervention strategies.

SCREENING NEEDN'T BE TIME-CONSUMING

Screening for substance use isn’t difficult. In fact, it can usually be accomplished with 2 targeted questions—one for alcohol use and one for drugs.

Alcohol. Two single-question screens to detect hazardous drinking have been validated, despite having different parameters. Ask either:

Q: When was the last time you had more than ____ drinks (4 for women and 5 for men) in one day?

Q: How many times in the past year have you had ___ or more drinks (4 for women and 5 for men) in one day?

For the first question, any answer within the past 3 months is a positive screen for hazardous drinking.² For the second, anything other than zero is positive.^3,4

Initial screening can also be done with the AUDIT-C (TABLE), a validated short (3-question) version of the Alcohol Use Disorders Identification Test that can be self-administered.^5,6

Drugs. Only one single-question screen for drug use has been validated:

Q: How many times in the past year have you used an illegal drug or taken a prescription medication for nonmedical reasons?

Any answer other than never is a positive screen for hazardous drug use.⁷

CASE Jason F, a healthy and fit 28-year-old, has been your patient, along with his family, for years. He’s in your office because of a knee injury he incurred while running, and you take a moment to ask him, for the first time, how much he drinks and whether he takes drugs. His answer—that he drinks 3 or 4 times a week and often has multiple drinks at parties or nights out with the guys—takes you a bit by surprise.

Now what?

Watch the video

TABLE

3-question AUDIT-C screen for alcohol dependence^5,6

TELL ME MORE ABOUT IT

It is important to respond to a positive screen by requesting more information. In the conversation that ensues, the patient may provide the details you need to determine whether the drinking or drug use is indicative of a diagnosable substance use disorder, an umbrella term for alcohol or drug abuse and alcohol or drug dependence.

Alcohol or drug abuse vs dependence. Criteria for alcohol or drug abuse in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision (DSM-IV-TR) include risky behavior, such as drinking and driving; problems with work and/or close relationships; or run-ins with the law, such as an arrest for driving while intoxicated. Criteria for alcohol or drug dependence include the inability to cut down or stop using the substance; evidence of tolerance and withdrawal; spending more time ingesting the substance; increasing attention to substance use while interest in other activities diminishes; and continued use despite recurrent problems.⁸

Tools zero in on extent of problem

To learn more about your patient’s situation, consider using the following criteria and tools:

DSM criteria. Ask the following 2 questions, which are among DSM-IV-TR criteria for alcohol dependence:

1. How many times in the last year have you had a lot more to drink than you intended?
2. How many times in the last year have you been drinking in situations where it could have been hazardous, where you could have caused an accident or gotten hurt?

Any answer other than zero to either question is suggestive of a substance use disorder. In exploratory analyses, this approach had positive likelihood ratios of 4.7 to 16 and negative likelihood ratios of 0.05 to 0.30.^9,10

Although the above questions refer to alcohol use, they could be revised to learn more about a patient’s use of marijuana or other drugs, as well. (There are few tools for the assessment of drug use, because any illegal or nonmedical use of controlled substances has clear risks of major harm.)

CAGE. Another tool that is effective in assessing alcohol use is the 4-question CAGE—an acronym for Cut down, Annoyed, Guilty, and Eye opener:

• Have you ever felt that you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt bad or guilty about your drinking?
• Have you ever had a drink in the morning to get rid of a hangover?

One meta-analysis found that a positive CAGE test—ie, a positive response to one or more of the questions—had a sensitivity of 0.85 and a specificity of 0.78 in identifying alcohol dependence in a primary care setting (using DSM criteria as the gold standard).¹¹

AUDIT. This 10-item tool, a longer version of the AUDIT-C (available at http://www.medstudentlearning.com/node/6556), can also be used to determine the extent of alcohol use. This test provides detailed information about the quantity and frequency of alcohol use; however, it does not clearly distinguish between hazardous drinking and alcohol use disorders.¹²

If the patient is a teen

Assessment methods can be adjusted without difficulty to fit the age of the patient. The National Institute on Alcohol Abuse and Alcoholism has published the Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide, available at http://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/Pages/YouthGuide.aspx. The 6-question CRAFFT (for Car, Relax, Alone, Forget, Friends, Trouble) is a validated tool designed to assess adolescents’ use of both alcohol and drugs (http://www.ceasar-boston.org/clinicians/crafft.php).^13,14

CASE You give Mr. F the CAGE test, and he answers No to all 4 questions. You conclude that while his drinking may be hazardous, he does not appear to have alcohol abuse or dependence.

FOLLOW UP WITH A BRIEF INTERVENTION

For decades, evidence has shown that brief interventions are often effective in helping hazardous drinkers like Mr. F cut back to safer levels.^15-18 In some cases, the impact has been great enough to reduce health care and societal costs for up to 4 years¹⁹ and to cut the risk of alcohol-related death by about half.²⁰ As a result, the US Preventive Services Task Force has given a B rating to counseling to reduce alcohol misuse by primary care providers.²¹ (There is less evidence that brief interventions are effective for drug problems,²² or in settings other than primary care.²³)

Treat drug/alcohol problems

If you determine that your patient is engaging in hazardous alcohol or drug use or has a diagnosable substance use disorder, you do not have to drop everything else or treat it as an acute event. What matters is long-term success, which is best achieved by partnering with the patient.

Start by approaching drug and alcohol problems as you would a case of newly elevated blood pressure. Bring up the problem, seeking to engage the patient in addres- sing it.

If he or she does not agree to quit or cut back on drinking the first time you broach the subject, don’t be surprised or discouraged. Keep in mind that patients do not always respond positively to advice about handling chronic medical conditions either, particularly at first, and that you’ll be working together over time. What’s important, in the jargon of the Stages of Change model,²⁴ is to help the patient move from precontemplation to contemplation, and perhaps beyond that to planning or action.

Use motivational interviewing to partner with patients

Motivational interviewing is useful in helping patients change health-related behaviors. The technique, which is not hard to learn or apply, is based on the recognition that a simple shift in style toward a guiding (rather than directive) approach can often reap benefits that are immediately apparent. ^25-28

Motivational Interviewing: Helping People Change (3rd ed, by William R. Miller and Stephen Rollnick; Guilford Press, 2013) is an excellent resource for clinicians who wish to master this technique. An online tutorial in screening and brief intervention for alcohol or drug misuse is available free at https://adept.missouri.edu. Video demonstrations of motivational interviewing to address these issues are also available here ; to access them, click on “Training”, then on “Go to SBIRT videos”).

CASE Before Mr. F’s visit is concluded, you initiate a conversation about alcohol use, stating: “As your doctor, I’m concerned that the amount of alcohol you’re drinking could be hazardous to your health. I recommend that you cut down to no more than 4 drinks in any one day and to no more than 14 drinks a week.” You make it clear that change is up to him, and ask what he thinks about what you’ve said.

You also schedule a return visit in one month, at which time you will continue the conversation.

PHARMACOTHERAPY IS A USEFUL TOOL

Increasingly, alcohol and drug dependence—like other chronic conditions—can be effectively addressed with medication.

Drugs to treat alcohol dependence

Naltrexone. A daily dose of naltrexone, starting at 25 mg daily for a few days and going as high as 100 mg/d, can help patients with alcohol dependence limit their drinking to safe levels (number needed to treat [NNT]=9).²⁹ This will reduce the risk of alcohol-related harm while the patient considers quitting.

The most common adverse effect is nausea, but a low starting dose may alleviate it. Naltrexone, also available as a 380-mg intramuscular (IM) depot injection once every 4 weeks, is an opioid antagonist and should not be given to any patient who’s taking opioids.

A 2010 Cochrane review found only 4 trials of naltrexone IM, and failed to show significant reductions in drinking.²⁹ But post hoc analyses of trials of both oral and IM naltrexone found that those in which compliance was assured (either by direct observation or IM administration) had better outcomes than those in which it was not.³⁰ Another post hoc analysis found that patients whose alcohol dependence was more severe derived greater benefits from the drug than those who were less severely affected.³¹

Acamprosate. Two 333-mg pills tid can help newly abstinent drinkers remain alcohol-free (NNT=9).^32,33 The most common adverse effect is diarrhea, which may subside with continued use.

Combining acamprosate and naltrexone does not appear to be more effective than either drug alone. In a recently published meta-analysis comparing the 2 drugs, those taking acamprosate had slightly better rates of abstinence from alcohol, while naltrexone was slightly better in reducing heavy drinking.³⁴

Disulfiram Unlike naltrexone and acamprosate, which work by altering the brain’s reward circuits, disulfiram blocks metabolism of ethanol, leading to the accumulation of a toxic metabolite and its punishing syndrome. The major problem with the drug is noncompliance, which can be addressed by enlisting the help of a caregiver or partner to ensure that it is taken daily. ^35-37

Other medications that have been tested (though not approved by the US Food and Drug Administration [FDA]) as a treatment for alcohol dependence include:

• topiramate, which has been found to have modest efficacy in increasing the number of abstinent days and decreasing heavy-drinking days;³⁸
• baclofen, which has shown efficacy in small clinical trials;³⁹ and
• ondansetron, which has been shown to effectively treat early-onset alcohol dependence.^40,41

For patients with depression and alcohol dependence, the combination of naltrexone and sertraline has been found to be superior to either drug by itself—and to have fewer adverse effects. ⁴² Gabapentin and lorazepam have been compared in treating alcohol withdrawal, with gabapentin resulting in greater efficacy and fewer adverse effects than lorazepam.^43,44

Pharmacotherapy for drug abuse, dependence

For methamphetamine abuse and dependence. Two randomized clinical trials have studied medications for methamphetamine abuse and dependence. In one small study, topiramate did not increase the proportion of patients who achieved abstinence, but in a post hoc subgroup analysis, it did appear to help newly abstinent patients avoid relapse.⁴⁵

In another study, mirtazapine significantly decreased the proportion of patients whose weekly urine tests were positive for methamphetamine (from 73% to 44%); no significant change was found among those on placebo.⁴⁶

Both drugs were well tolerated, but compliance was low in both trials despite weekly counseling. Each has only one clinical trial to support its use, and neither has FDA approval for addiction treatment.

For marijuana dependence. In a study of 50 people seeking treatment for marijuana dependence, gabapentin 400 mg 3 times a day significantly improved the proportion reporting no cannabis use and whose urine tested negative for the drug.⁴⁷

Another recent trial randomized adolescents dependent on cannabis to placebo or N-acetylcysteine 1200 mg twice a day. Those on the active drug were 2.4 times more likely than those on placebo to have negative urine tests with a number needed to treat of 7.⁴⁸ Both trials ran for about 3 months. Neither drug is FDA approved to treat marijuana dependence.

For opioid dependence. As maintenance medication for patients dependent on opioids, both methadone and buprenorphine have been shown to reduce the use of illicit opioids, lower mortality, and improve retention compared with treatment without medication.⁴⁹ Methadone would be a better choice than buprenorphine, which is a partial agonist with a ceiling on both its good (eg, stopping craving) and bad (eg, overdose risk) effects. In an open-label observational study of patients’ preferences, those who chose methadone maintenance over buprenorphine were twice as likely to remain in treatment.⁵⁰ Both drugs are FDA-approved for treating opioid dependence.

Methadone is a full agonist that can be given for opioid dependence only in a federally licensed methadone maintenance clinic. It has been shown to reduce the use of other opioids, reduce criminal behaviors,⁵¹ improve function in many areas,⁵² and reduce mortality.⁵³ In a cohort study of Massachusetts Medicaid data, methadone reduced mortality, which was 75% higher among those receiving abstinence-based treatment.^52,54

Buprenorphine (alone and in combination with naloxone), effectively reduces the use of illicit opioids and improves functional status.^55-57

Naltrexone, an opioid antagonist, may be effective in the treatment of opioid dependence. As with disulfiram for alcohol dependence, a major limitation of naltrexone for opioid dependence is noncompliance. But once a patient has been on oral naltrexone, he or she can be switched to naltrexone IM, which can be administered every 4 weeks. A Cochrane review published in 2011 found no evidence that naltrexone was superior to placebo, ⁵⁸ but since then another randomized clinical trial has been published that found naltrexone 380 mg IM every 4 weeks was superior to IM placebo. Patients on naltrexone were more likely to remain in treatment and have opioid-free urine tests, and reported less craving for opioids.⁵⁹ Both oral and depot injection naltrexone are FDA approved for treatment of opioid dependence. No comparisons of naltrexone vs either methadone or buprenorphine have been published.

To learn more about pharmacotherapy for opioid dependence, see “Diagnosing and treating opioid dependence” (J Fam Pract. 2012;61:588-596).

DEALING WITH THE CHALLENGES

As noted earlier, some patients with substance use disorders, like some patients with depression or hypertension, respond well to care and counseling, and some do not. Just as with other conditions, consultation with a specialist often helps.

A major difference in arranging consultations for patients with substance use disorders, however, is that clinicians who specialize in substance abuse and dependence often work in health care systems that are largely, or entirely, separate from those in which primary care physicians typically work. This, plus the stigma that surrounds problems with substance use, presents barriers to patients, who may shy away from going across town or to another city to see a provider they don’t know for a problem they’re either resistant to “owning” or ashamed of.

Yet it is possible to reach across this divide and make it easier for patients. One way to do that might be to partner with a local alcohol- and drug-treatment program so that your patients are referred, not to a faceless agency, but rather to a specific clinician; you might even call the provider while the patient is in your office so they can “meet.” Another approach, taken by some multispecialty practices, is to add psychotherapists to the staff so that patients can simply walk down the hall to obtain the mental health care they need.

Reaching across this divide is also a useful strategy for primary care physicians, who may welcome opportunities to meet with someone from a local treatment agency, not just for referrals but to learn more about treating patients with substance use problems. The Patient Protection and Affordable Care Act, which cites substance use disorders as one of 6 chronic health conditions that primary care medical homes are expected to address, may lead to better integration of health care systems that address physical health, as well as mental health and substance use disorders.

Nearly 26 million US adults are estimated to have type 2 diabetes, including at least eight million who are unaware they have the disease.¹ An additional 80 million adults are affected by prediabetes, with above-average glucose levels that do not yet meet American Diabetes Association (ADA) criteria for type 2 diabetes.^1,2

In this context, the primary care provider is likely to encounter patients with a diagnosis of type 2 diabetes in its early stages. Which patients can be considered candidates for conservative management—that is, lifestyle modification—before antidiabetic medications are initiated?

Case Patient
A black woman, age 44, presented for a routine physical examination. She said she had been in good health until three months earlier, when she began to experience weakness and fatigue. She complained of increased thirst and frequent urination, requiring her to get up three or four times each night. She had increased her average fluid intake to nine glasses a day from the usual four. Despite a good appetite, she had lost about 7 lb over the previous three months.

The patient’s previous medical history was significant for four cesarean deliveries, gestational diabetes during all four pregnancies, hemorrhoids, constipation, keloid formation, and hyperlipidemia. Her family history was significant for diabetes (paternal side) and hyperlipidemia.

Findings from the patient’s physical exam included weight, 217 lb; height, 5’11”; BMI, 30.3; pulse, 80 beats/min and regular; and blood pressure, 138/78 mm Hg. With the exception of obesity and elevated systolic blood pressure, her physical exam findings were within normal limits.

Laboratory testing yielded the following results: urinalysis, 3+ glucose, negative for ketones and protein; fasting blood glucose, 145 mg/dL; hemoglobin A1C, 6.9%; total cholesterol, 230 mg/dL; HDL cholesterol (HDL-C), 21 mg/dL; LDL cholesterol (LDL-C), 144 mg/dL; and triglycerides, 400 mg/dL.

The patient’s history of gestational diabetes, her acknowledged sedentary lifestyle, body weight currently exceeding her ideal weight by 50 lb, and family history positive for diabetes put her at increased risk for diabetes. Also of concern was her elevated systolic blood pressure.

The patient’s A1C of 6.9% indicated that during the previous two months, her average blood glucose had been in excess of 125 mg/dL. A diagnosis of type 2 diabetes was made, based on the patient’s elevated fasting blood glucose and A1C, and the aforementioned symptoms of weight loss, fatigue, polydypsia, and polyuria. 

Because the patient was perceived as self-reliant and responsible, it was recommended that she be treated conservatively with a broad lifestyle modification regimen. Goals were to reduce all of her diabetes indicators, including weight,^3,4 blood pressure,⁵ and A1C, with an improved lipids profile—all, if possible, without the use of medication. The regimen comprised a low–glycemic index (GI) diet^6,7 to reduce her glucose level, and aerobic exercise and strength training⁸ to improve her cardiovascular health. With resulting weight loss and reduced salt intake,^3-5 it was expected that the patient would see reductions in her total cholesterol, LDL-C, and systolic blood pressure.

The patient’s management team recommended a daily plan of four small meals and one or two small snacks. She was advised to control portions by visually dividing her plate: Non-starchy (low-GI) vegetables should fill half of the plate, with the remaining half divided into equal sections for a small serving of protein and a small serving of carbohydrates with a GI of 55 or less (see figure^7,9).

Her exercise program was based on recommendations from the American Association of Clinical Endocrinologists (AACE)¹⁰ and the US Department of Health and Human Services¹¹: cardiovascular/aerobic exercise (five 30-minute sessions per week), ranging in intensity from moderate (eg, brisk walking, bicycling, doubles tennis) to vigorous (jogging or running, swimming laps, singles tennis); and strength training (two 30-minute sessions per week), such as weight-lifting, push-ups, and sit-ups.

Discussion
Type 2 diabetes mellitus affects an estimated 25.8 million residents of the United States, including an estimated 8.3 million who have not yet been diagnosed.¹ According to the CDC,¹² prevalence of diabetes is greatest in black and Hispanic women and men.

The sixth leading cause of death in the US, diabetes is also the leading cause of blindness (ie, diabetic retinopathy), kidney disease requiring dialysis, and lower-limb amputation. Diabetes is closely associated with cardiovascular disease (CVD), the leading cause of death in the US.¹² Other diabetes-related health concerns include hypertension, peripheral diabetic neuropathy, dental disease, depression, delayed wound healing, and increased risk for infection.¹²

The standard criteria for a diagnosis of diabetes, according to the 2012 ADA Standards of Medical Care in Diabetes,¹³ are:

• A1C exceeding 6.5%, or
• A fasting blood glucose level at or exceeding 126 mg/dL, or

• A 2-hour plasma glucose at or exceeding 200 mg/dL during an oral glucose tolerance test, or

• A random blood glucose of 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.¹³

Treatment Goals
Goals for diabetic patients advocated by the National Diabetes Education Program (NDEP)¹ include maintaining blood pressure below 130/80 mm Hg, lowering LDL-C to below 100 mg/dL (and below 70 mg/dL in patients at risk for CVD), reducing triglyceride levels to below 150 mg/dL, and raising HDL-C above 40 mg/dL in women and above 50 mg/dL in men. Achieving these levels can reduce the diabetic patient’s risk for CVD and microvascular complications by 50%.¹

Medical Nutrition Therapy
The NDEP and other entities^1,14 refer to medical nutrition therapy as an integral component of diabetic management. This individualized meal plan, developed by a registered dietitian, is based on the patient’s nutritional status and preferences. To optimize the case patient’s glycemic control,¹⁰ a low-GI diet was selected.

As the ADA⁹ and Solomon et al¹⁵ have explained, this diet is based on foods that produce a reduced glucose response during the two hours after consumption. According to one literature review,¹⁶ use of a low-GI diet led a reduction in A1C of 0.43 percentage points. When combined with appropriate exercise, the low-GI diet can alleviate hypertension and postprandial hyperinsulinemia,^15,17 as well as levels of C-reactive protein, an inflammatory marker that in high concentrations is associated with increased risk for CVD.¹⁸

The Role of Exercise
The ADA 2012 standards¹³ recommend a minimum of 150 minutes per week of moderate physical activity. The benefits of exercise in diabetic patients include improved control of blood glucose and reduction of risk for heart disease and other illnesses.^3,11 Patients should be under the care of a provider who can help develop an appropriate, individualized plan.^3,11

According to ADA recommendations,¹³ the patient’s lipid levels, blood pressure, and smoking status should be evaluated, with assessment for the presence of CVD in at-risk patients. For asymptomatic diabetic patients, the American College of Cardiology/American Heart Association recommend an ECG stress test before an exercise program is undertaken.^19,20 Exercise is contraindicated in those with decompensated congestive heart failure, complex ventricular arrhythmias, unstable angina, significant aortic stenosis, or aortic aneurysm.¹⁹

Because initiating an exercise program incurs a slight risk for injury, patients should start gradually, warming up before each session and cooling down afterward.^11,19 Diabetic patients should also wear proper shoes for maximum foot protection. They must also be instructed to watch for signs of hypoglycemia during physical activity and be prepared to treat it.^11,13

Patient Outcome
After one year on her prescribed treatment regimen, the patient’s A1C was measured at 6.3%, and her LDL-C was 124 mg/dL. Another year later, her A1C was further reduced to 5.9%, and her LDL-C to 77.2 mg/dL. By then, she had lost 15 lb (BMI, 28.2) and perceived her current maintenance plan as enjoyable and manageable, long-term: She was exercising every day possible, with seven sessions of at least 30 minutes, and maintaining a diet of low-GI foods. The patient was committed to following up with her clinician for glucose monitoring every three months.

Conclusion
As illustrated in this patient’s case, the best plan for management of diabetes in its early stages is one that is realistic for the patient and that will prevent diabetic complications for as long as possible.

References
1. US Department of Health and Human Services, National Diabetes Education Program. Guiding Principles for Diabetes Care for Healthcare Professionals (2009). www.ndep.nih.gov/media/guid prin_hc_eng.pdf. Accessed January 24, 2013.

2. National Diabetes Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Insulin resistance and prediabetes (2011). http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance. Accessed January 25, 2013.

3. Hayes C, Kriska A. Role of physical activity in diabetes management and prevention. J Am Diet Assoc. 2008;108(4 suppl 1):S19-S23.

4. American Diabetes Association. Food and fitness: weight loss (2011). www.diabetes.org/food-and-fitness/fitness/weight-loss. Accessed January 25, 2013.

5. US Department of Health and Human Services, NIH. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 reference card, 2003). www.nhlbi.nih.gov/guidelines/hyper tension/phycard.pdf. Accessed January 24, 2013.

6. Ma Y, Olendzki BC, Merriam PA, et al. A randomized clinical trial comparing low-glycemic index versus ADA dietary education among individuals with type 2 diabetes. Nutrition. 2008;24(1):45-56.

7. American Diabetes Association. Glycemic index of foods (2013). www.diabetes.org/food-and-fit ness/food/planning-meals/the-glycemic-index-of-foods.html. Accessed January 25, 2013.

8. Pariser G, Ann Demeuro M, Gillette P, Stephen W. Outcomes of an education and exercise program for adults with type 2 diabetes, and comorbidities that limit their mobility: a preliminary project report. Cardiopulm Phys Ther J. 2010;21(2):5-12.

9. American Diabetes Association. Food and fitness: create your plate (2013). www.diabetes.org/food-and-fitness/food/planning-meals/create-your-plate. Accessed January 24, 2013.

10. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 suppl 2:1-53.

11. CDC. 2008 Physical Activity Guidelines. www.health.gov/PAGuidelines/pdf/paguide.pdf. Accessed January 24, 2013.

12. CDC. 2011 National Diabetes Fact Sheet. www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed January 25, 2013.

13. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 suppl 1:S11-S63.

14. Franz MJ, Powers MA, Leontos C, et al. The evidence for medical nutrition therapy for type 1 and type 2 diabetes in adults. J Am Diet Assoc. 2010;110(12):1852-1889.

15. Solomon TP, Haus JM, Kelly KR, et al. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am J Clin Nutr. 2010;92(6):1359-1368.

16. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2003;26(8):2261-2267.

17. Solomon TP, Haus JM, Kelly KR, et al. Randomized trial on the effects of a 7-d low–glycemic diet and exercise intervention on insulin resistance in older obese humans. Am J Clin Nutr. 2009;90(5):1222-1229.

18. Wolever TM, Gibbs AL, Mehling C, et al. The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low–glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein. Am J Clin Nutr. 2008;87(1):114-125.

19. Metkus TS, Baughman KL, Thompson PD. Exercise prescription and primary prevention of cardiovascular disease. Circulation. 2010;121(23):2601-2604.

20. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106(14);1883-1892.

Nearly 26 million US adults are estimated to have type 2 diabetes, including at least eight million who are unaware they have the disease.¹ An additional 80 million adults are affected by prediabetes, with above-average glucose levels that do not yet meet American Diabetes Association (ADA) criteria for type 2 diabetes.^1,2

In this context, the primary care provider is likely to encounter patients with a diagnosis of type 2 diabetes in its early stages. Which patients can be considered candidates for conservative management—that is, lifestyle modification—before antidiabetic medications are initiated?

Case Patient
A black woman, age 44, presented for a routine physical examination. She said she had been in good health until three months earlier, when she began to experience weakness and fatigue. She complained of increased thirst and frequent urination, requiring her to get up three or four times each night. She had increased her average fluid intake to nine glasses a day from the usual four. Despite a good appetite, she had lost about 7 lb over the previous three months.

The patient’s previous medical history was significant for four cesarean deliveries, gestational diabetes during all four pregnancies, hemorrhoids, constipation, keloid formation, and hyperlipidemia. Her family history was significant for diabetes (paternal side) and hyperlipidemia.

Findings from the patient’s physical exam included weight, 217 lb; height, 5’11”; BMI, 30.3; pulse, 80 beats/min and regular; and blood pressure, 138/78 mm Hg. With the exception of obesity and elevated systolic blood pressure, her physical exam findings were within normal limits.

Laboratory testing yielded the following results: urinalysis, 3+ glucose, negative for ketones and protein; fasting blood glucose, 145 mg/dL; hemoglobin A1C, 6.9%; total cholesterol, 230 mg/dL; HDL cholesterol (HDL-C), 21 mg/dL; LDL cholesterol (LDL-C), 144 mg/dL; and triglycerides, 400 mg/dL.

The patient’s history of gestational diabetes, her acknowledged sedentary lifestyle, body weight currently exceeding her ideal weight by 50 lb, and family history positive for diabetes put her at increased risk for diabetes. Also of concern was her elevated systolic blood pressure.

The patient’s A1C of 6.9% indicated that during the previous two months, her average blood glucose had been in excess of 125 mg/dL. A diagnosis of type 2 diabetes was made, based on the patient’s elevated fasting blood glucose and A1C, and the aforementioned symptoms of weight loss, fatigue, polydypsia, and polyuria. 

Because the patient was perceived as self-reliant and responsible, it was recommended that she be treated conservatively with a broad lifestyle modification regimen. Goals were to reduce all of her diabetes indicators, including weight,^3,4 blood pressure,⁵ and A1C, with an improved lipids profile—all, if possible, without the use of medication. The regimen comprised a low–glycemic index (GI) diet^6,7 to reduce her glucose level, and aerobic exercise and strength training⁸ to improve her cardiovascular health. With resulting weight loss and reduced salt intake,^3-5 it was expected that the patient would see reductions in her total cholesterol, LDL-C, and systolic blood pressure.

The patient’s management team recommended a daily plan of four small meals and one or two small snacks. She was advised to control portions by visually dividing her plate: Non-starchy (low-GI) vegetables should fill half of the plate, with the remaining half divided into equal sections for a small serving of protein and a small serving of carbohydrates with a GI of 55 or less (see figure^7,9).

Her exercise program was based on recommendations from the American Association of Clinical Endocrinologists (AACE)¹⁰ and the US Department of Health and Human Services¹¹: cardiovascular/aerobic exercise (five 30-minute sessions per week), ranging in intensity from moderate (eg, brisk walking, bicycling, doubles tennis) to vigorous (jogging or running, swimming laps, singles tennis); and strength training (two 30-minute sessions per week), such as weight-lifting, push-ups, and sit-ups.

Discussion
Type 2 diabetes mellitus affects an estimated 25.8 million residents of the United States, including an estimated 8.3 million who have not yet been diagnosed.¹ According to the CDC,¹² prevalence of diabetes is greatest in black and Hispanic women and men.

The sixth leading cause of death in the US, diabetes is also the leading cause of blindness (ie, diabetic retinopathy), kidney disease requiring dialysis, and lower-limb amputation. Diabetes is closely associated with cardiovascular disease (CVD), the leading cause of death in the US.¹² Other diabetes-related health concerns include hypertension, peripheral diabetic neuropathy, dental disease, depression, delayed wound healing, and increased risk for infection.¹²

The standard criteria for a diagnosis of diabetes, according to the 2012 ADA Standards of Medical Care in Diabetes,¹³ are:

• A1C exceeding 6.5%, or
• A fasting blood glucose level at or exceeding 126 mg/dL, or

• A 2-hour plasma glucose at or exceeding 200 mg/dL during an oral glucose tolerance test, or

• A random blood glucose of 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.¹³

Treatment Goals
Goals for diabetic patients advocated by the National Diabetes Education Program (NDEP)¹ include maintaining blood pressure below 130/80 mm Hg, lowering LDL-C to below 100 mg/dL (and below 70 mg/dL in patients at risk for CVD), reducing triglyceride levels to below 150 mg/dL, and raising HDL-C above 40 mg/dL in women and above 50 mg/dL in men. Achieving these levels can reduce the diabetic patient’s risk for CVD and microvascular complications by 50%.¹

Medical Nutrition Therapy
The NDEP and other entities^1,14 refer to medical nutrition therapy as an integral component of diabetic management. This individualized meal plan, developed by a registered dietitian, is based on the patient’s nutritional status and preferences. To optimize the case patient’s glycemic control,¹⁰ a low-GI diet was selected.

As the ADA⁹ and Solomon et al¹⁵ have explained, this diet is based on foods that produce a reduced glucose response during the two hours after consumption. According to one literature review,¹⁶ use of a low-GI diet led a reduction in A1C of 0.43 percentage points. When combined with appropriate exercise, the low-GI diet can alleviate hypertension and postprandial hyperinsulinemia,^15,17 as well as levels of C-reactive protein, an inflammatory marker that in high concentrations is associated with increased risk for CVD.¹⁸

The Role of Exercise
The ADA 2012 standards¹³ recommend a minimum of 150 minutes per week of moderate physical activity. The benefits of exercise in diabetic patients include improved control of blood glucose and reduction of risk for heart disease and other illnesses.^3,11 Patients should be under the care of a provider who can help develop an appropriate, individualized plan.^3,11

According to ADA recommendations,¹³ the patient’s lipid levels, blood pressure, and smoking status should be evaluated, with assessment for the presence of CVD in at-risk patients. For asymptomatic diabetic patients, the American College of Cardiology/American Heart Association recommend an ECG stress test before an exercise program is undertaken.^19,20 Exercise is contraindicated in those with decompensated congestive heart failure, complex ventricular arrhythmias, unstable angina, significant aortic stenosis, or aortic aneurysm.¹⁹

Because initiating an exercise program incurs a slight risk for injury, patients should start gradually, warming up before each session and cooling down afterward.^11,19 Diabetic patients should also wear proper shoes for maximum foot protection. They must also be instructed to watch for signs of hypoglycemia during physical activity and be prepared to treat it.^11,13

Patient Outcome
After one year on her prescribed treatment regimen, the patient’s A1C was measured at 6.3%, and her LDL-C was 124 mg/dL. Another year later, her A1C was further reduced to 5.9%, and her LDL-C to 77.2 mg/dL. By then, she had lost 15 lb (BMI, 28.2) and perceived her current maintenance plan as enjoyable and manageable, long-term: She was exercising every day possible, with seven sessions of at least 30 minutes, and maintaining a diet of low-GI foods. The patient was committed to following up with her clinician for glucose monitoring every three months.

Conclusion
As illustrated in this patient’s case, the best plan for management of diabetes in its early stages is one that is realistic for the patient and that will prevent diabetic complications for as long as possible.

References
1. US Department of Health and Human Services, National Diabetes Education Program. Guiding Principles for Diabetes Care for Healthcare Professionals (2009). www.ndep.nih.gov/media/guid prin_hc_eng.pdf. Accessed January 24, 2013.

2. National Diabetes Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Insulin resistance and prediabetes (2011). http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance. Accessed January 25, 2013.

3. Hayes C, Kriska A. Role of physical activity in diabetes management and prevention. J Am Diet Assoc. 2008;108(4 suppl 1):S19-S23.

4. American Diabetes Association. Food and fitness: weight loss (2011). www.diabetes.org/food-and-fitness/fitness/weight-loss. Accessed January 25, 2013.

5. US Department of Health and Human Services, NIH. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 reference card, 2003). www.nhlbi.nih.gov/guidelines/hyper tension/phycard.pdf. Accessed January 24, 2013.

6. Ma Y, Olendzki BC, Merriam PA, et al. A randomized clinical trial comparing low-glycemic index versus ADA dietary education among individuals with type 2 diabetes. Nutrition. 2008;24(1):45-56.

7. American Diabetes Association. Glycemic index of foods (2013). www.diabetes.org/food-and-fit ness/food/planning-meals/the-glycemic-index-of-foods.html. Accessed January 25, 2013.

8. Pariser G, Ann Demeuro M, Gillette P, Stephen W. Outcomes of an education and exercise program for adults with type 2 diabetes, and comorbidities that limit their mobility: a preliminary project report. Cardiopulm Phys Ther J. 2010;21(2):5-12.

9. American Diabetes Association. Food and fitness: create your plate (2013). www.diabetes.org/food-and-fitness/food/planning-meals/create-your-plate. Accessed January 24, 2013.

10. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 suppl 2:1-53.

11. CDC. 2008 Physical Activity Guidelines. www.health.gov/PAGuidelines/pdf/paguide.pdf. Accessed January 24, 2013.

12. CDC. 2011 National Diabetes Fact Sheet. www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed January 25, 2013.

13. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 suppl 1:S11-S63.

14. Franz MJ, Powers MA, Leontos C, et al. The evidence for medical nutrition therapy for type 1 and type 2 diabetes in adults. J Am Diet Assoc. 2010;110(12):1852-1889.

15. Solomon TP, Haus JM, Kelly KR, et al. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am J Clin Nutr. 2010;92(6):1359-1368.

16. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2003;26(8):2261-2267.

17. Solomon TP, Haus JM, Kelly KR, et al. Randomized trial on the effects of a 7-d low–glycemic diet and exercise intervention on insulin resistance in older obese humans. Am J Clin Nutr. 2009;90(5):1222-1229.

18. Wolever TM, Gibbs AL, Mehling C, et al. The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low–glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein. Am J Clin Nutr. 2008;87(1):114-125.

19. Metkus TS, Baughman KL, Thompson PD. Exercise prescription and primary prevention of cardiovascular disease. Circulation. 2010;121(23):2601-2604.

20. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106(14);1883-1892.

Nearly 26 million US adults are estimated to have type 2 diabetes, including at least eight million who are unaware they have the disease.¹ An additional 80 million adults are affected by prediabetes, with above-average glucose levels that do not yet meet American Diabetes Association (ADA) criteria for type 2 diabetes.^1,2

In this context, the primary care provider is likely to encounter patients with a diagnosis of type 2 diabetes in its early stages. Which patients can be considered candidates for conservative management—that is, lifestyle modification—before antidiabetic medications are initiated?

Case Patient
A black woman, age 44, presented for a routine physical examination. She said she had been in good health until three months earlier, when she began to experience weakness and fatigue. She complained of increased thirst and frequent urination, requiring her to get up three or four times each night. She had increased her average fluid intake to nine glasses a day from the usual four. Despite a good appetite, she had lost about 7 lb over the previous three months.

The patient’s previous medical history was significant for four cesarean deliveries, gestational diabetes during all four pregnancies, hemorrhoids, constipation, keloid formation, and hyperlipidemia. Her family history was significant for diabetes (paternal side) and hyperlipidemia.

Findings from the patient’s physical exam included weight, 217 lb; height, 5’11”; BMI, 30.3; pulse, 80 beats/min and regular; and blood pressure, 138/78 mm Hg. With the exception of obesity and elevated systolic blood pressure, her physical exam findings were within normal limits.

Laboratory testing yielded the following results: urinalysis, 3+ glucose, negative for ketones and protein; fasting blood glucose, 145 mg/dL; hemoglobin A1C, 6.9%; total cholesterol, 230 mg/dL; HDL cholesterol (HDL-C), 21 mg/dL; LDL cholesterol (LDL-C), 144 mg/dL; and triglycerides, 400 mg/dL.

The patient’s history of gestational diabetes, her acknowledged sedentary lifestyle, body weight currently exceeding her ideal weight by 50 lb, and family history positive for diabetes put her at increased risk for diabetes. Also of concern was her elevated systolic blood pressure.

The patient’s A1C of 6.9% indicated that during the previous two months, her average blood glucose had been in excess of 125 mg/dL. A diagnosis of type 2 diabetes was made, based on the patient’s elevated fasting blood glucose and A1C, and the aforementioned symptoms of weight loss, fatigue, polydypsia, and polyuria. 

Because the patient was perceived as self-reliant and responsible, it was recommended that she be treated conservatively with a broad lifestyle modification regimen. Goals were to reduce all of her diabetes indicators, including weight,^3,4 blood pressure,⁵ and A1C, with an improved lipids profile—all, if possible, without the use of medication. The regimen comprised a low–glycemic index (GI) diet^6,7 to reduce her glucose level, and aerobic exercise and strength training⁸ to improve her cardiovascular health. With resulting weight loss and reduced salt intake,^3-5 it was expected that the patient would see reductions in her total cholesterol, LDL-C, and systolic blood pressure.

The patient’s management team recommended a daily plan of four small meals and one or two small snacks. She was advised to control portions by visually dividing her plate: Non-starchy (low-GI) vegetables should fill half of the plate, with the remaining half divided into equal sections for a small serving of protein and a small serving of carbohydrates with a GI of 55 or less (see figure^7,9).

Her exercise program was based on recommendations from the American Association of Clinical Endocrinologists (AACE)¹⁰ and the US Department of Health and Human Services¹¹: cardiovascular/aerobic exercise (five 30-minute sessions per week), ranging in intensity from moderate (eg, brisk walking, bicycling, doubles tennis) to vigorous (jogging or running, swimming laps, singles tennis); and strength training (two 30-minute sessions per week), such as weight-lifting, push-ups, and sit-ups.

Discussion
Type 2 diabetes mellitus affects an estimated 25.8 million residents of the United States, including an estimated 8.3 million who have not yet been diagnosed.¹ According to the CDC,¹² prevalence of diabetes is greatest in black and Hispanic women and men.

The sixth leading cause of death in the US, diabetes is also the leading cause of blindness (ie, diabetic retinopathy), kidney disease requiring dialysis, and lower-limb amputation. Diabetes is closely associated with cardiovascular disease (CVD), the leading cause of death in the US.¹² Other diabetes-related health concerns include hypertension, peripheral diabetic neuropathy, dental disease, depression, delayed wound healing, and increased risk for infection.¹²

The standard criteria for a diagnosis of diabetes, according to the 2012 ADA Standards of Medical Care in Diabetes,¹³ are:

• A1C exceeding 6.5%, or
• A fasting blood glucose level at or exceeding 126 mg/dL, or

• A 2-hour plasma glucose at or exceeding 200 mg/dL during an oral glucose tolerance test, or

• A random blood glucose of 200 mg/dL or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.¹³

Treatment Goals
Goals for diabetic patients advocated by the National Diabetes Education Program (NDEP)¹ include maintaining blood pressure below 130/80 mm Hg, lowering LDL-C to below 100 mg/dL (and below 70 mg/dL in patients at risk for CVD), reducing triglyceride levels to below 150 mg/dL, and raising HDL-C above 40 mg/dL in women and above 50 mg/dL in men. Achieving these levels can reduce the diabetic patient’s risk for CVD and microvascular complications by 50%.¹

Medical Nutrition Therapy
The NDEP and other entities^1,14 refer to medical nutrition therapy as an integral component of diabetic management. This individualized meal plan, developed by a registered dietitian, is based on the patient’s nutritional status and preferences. To optimize the case patient’s glycemic control,¹⁰ a low-GI diet was selected.

As the ADA⁹ and Solomon et al¹⁵ have explained, this diet is based on foods that produce a reduced glucose response during the two hours after consumption. According to one literature review,¹⁶ use of a low-GI diet led a reduction in A1C of 0.43 percentage points. When combined with appropriate exercise, the low-GI diet can alleviate hypertension and postprandial hyperinsulinemia,^15,17 as well as levels of C-reactive protein, an inflammatory marker that in high concentrations is associated with increased risk for CVD.¹⁸

The Role of Exercise
The ADA 2012 standards¹³ recommend a minimum of 150 minutes per week of moderate physical activity. The benefits of exercise in diabetic patients include improved control of blood glucose and reduction of risk for heart disease and other illnesses.^3,11 Patients should be under the care of a provider who can help develop an appropriate, individualized plan.^3,11

According to ADA recommendations,¹³ the patient’s lipid levels, blood pressure, and smoking status should be evaluated, with assessment for the presence of CVD in at-risk patients. For asymptomatic diabetic patients, the American College of Cardiology/American Heart Association recommend an ECG stress test before an exercise program is undertaken.^19,20 Exercise is contraindicated in those with decompensated congestive heart failure, complex ventricular arrhythmias, unstable angina, significant aortic stenosis, or aortic aneurysm.¹⁹

Because initiating an exercise program incurs a slight risk for injury, patients should start gradually, warming up before each session and cooling down afterward.^11,19 Diabetic patients should also wear proper shoes for maximum foot protection. They must also be instructed to watch for signs of hypoglycemia during physical activity and be prepared to treat it.^11,13

Patient Outcome
After one year on her prescribed treatment regimen, the patient’s A1C was measured at 6.3%, and her LDL-C was 124 mg/dL. Another year later, her A1C was further reduced to 5.9%, and her LDL-C to 77.2 mg/dL. By then, she had lost 15 lb (BMI, 28.2) and perceived her current maintenance plan as enjoyable and manageable, long-term: She was exercising every day possible, with seven sessions of at least 30 minutes, and maintaining a diet of low-GI foods. The patient was committed to following up with her clinician for glucose monitoring every three months.

Conclusion
As illustrated in this patient’s case, the best plan for management of diabetes in its early stages is one that is realistic for the patient and that will prevent diabetic complications for as long as possible.

References
1. US Department of Health and Human Services, National Diabetes Education Program. Guiding Principles for Diabetes Care for Healthcare Professionals (2009). www.ndep.nih.gov/media/guid prin_hc_eng.pdf. Accessed January 24, 2013.

2. National Diabetes Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Insulin resistance and prediabetes (2011). http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance. Accessed January 25, 2013.

3. Hayes C, Kriska A. Role of physical activity in diabetes management and prevention. J Am Diet Assoc. 2008;108(4 suppl 1):S19-S23.

4. American Diabetes Association. Food and fitness: weight loss (2011). www.diabetes.org/food-and-fitness/fitness/weight-loss. Accessed January 25, 2013.

5. US Department of Health and Human Services, NIH. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7 reference card, 2003). www.nhlbi.nih.gov/guidelines/hyper tension/phycard.pdf. Accessed January 24, 2013.

6. Ma Y, Olendzki BC, Merriam PA, et al. A randomized clinical trial comparing low-glycemic index versus ADA dietary education among individuals with type 2 diabetes. Nutrition. 2008;24(1):45-56.

7. American Diabetes Association. Glycemic index of foods (2013). www.diabetes.org/food-and-fit ness/food/planning-meals/the-glycemic-index-of-foods.html. Accessed January 25, 2013.

8. Pariser G, Ann Demeuro M, Gillette P, Stephen W. Outcomes of an education and exercise program for adults with type 2 diabetes, and comorbidities that limit their mobility: a preliminary project report. Cardiopulm Phys Ther J. 2010;21(2):5-12.

9. American Diabetes Association. Food and fitness: create your plate (2013). www.diabetes.org/food-and-fitness/food/planning-meals/create-your-plate. Accessed January 24, 2013.

10. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 suppl 2:1-53.

11. CDC. 2008 Physical Activity Guidelines. www.health.gov/PAGuidelines/pdf/paguide.pdf. Accessed January 24, 2013.

12. CDC. 2011 National Diabetes Fact Sheet. www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed January 25, 2013.

13. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 suppl 1:S11-S63.

14. Franz MJ, Powers MA, Leontos C, et al. The evidence for medical nutrition therapy for type 1 and type 2 diabetes in adults. J Am Diet Assoc. 2010;110(12):1852-1889.

15. Solomon TP, Haus JM, Kelly KR, et al. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am J Clin Nutr. 2010;92(6):1359-1368.

16. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2003;26(8):2261-2267.

17. Solomon TP, Haus JM, Kelly KR, et al. Randomized trial on the effects of a 7-d low–glycemic diet and exercise intervention on insulin resistance in older obese humans. Am J Clin Nutr. 2009;90(5):1222-1229.

18. Wolever TM, Gibbs AL, Mehling C, et al. The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low–glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein. Am J Clin Nutr. 2008;87(1):114-125.

19. Metkus TS, Baughman KL, Thompson PD. Exercise prescription and primary prevention of cardiovascular disease. Circulation. 2010;121(23):2601-2604.

20. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106(14);1883-1892.

Dr. Abusief reports no financial relationships relevant to this article. Dr. Adamson reports that he receives research grants from LabCorp and Auxogyn, and is the founder and CEO of Advanced Reproductive Care.

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool [email protected]. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

We want to hear from you!  Tell us what you think.

Dr. Abusief reports no financial relationships relevant to this article. Dr. Adamson reports that he receives research grants from LabCorp and Auxogyn, and is the founder and CEO of Advanced Reproductive Care.

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool [email protected]. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

We want to hear from you!  Tell us what you think.

Dr. Abusief reports no financial relationships relevant to this article. Dr. Adamson reports that he receives research grants from LabCorp and Auxogyn, and is the founder and CEO of Advanced Reproductive Care.

Infertility is not just a woman’s issue; it is a couple’s issue. According to the Centers for Disease Control and Prevention, one-third of cases of infertility are caused by a reproductive problem for the woman, one-third are caused by a problem for the man, and one-third are due to problems for both partners or to unknown causes.¹

Here, we discuss three developments within the past 12 months related to the treatment of infertility:

• The International Federation of Gynecology and Obstetrics (FIGO) Committee on Reproductive Medicine—charged with developing evidence-based, cost-effective guidelines that would be accepted as standards for increasing access to quality reproductive medical care in all countries of the world—has developed The FIGO Fertility Tool Box™.
• Smoking cigarettes negatively affects a man’s and woman’s fertility, yet smoking’s contribution to infertility is under-recognized. The Practice Committee of the American Society for Reproductive Medicine culled the evidence, and published its review on the effects of smoking on fertility.
• Results of a large, population-wide cohort study shed light on the association of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with birth defects and whether underlying factors present in patients with infertility also may play a role.

FIGO offers Tools for managing infertility

Adamson GD. A quick guide to the FIGO Fertility Tool Box. The FIGO Fertility Tool Box. The International Federation of Gynecology and Obstetrics Web site. http://www.arcfertility.com/figo. Published 2013. Accessed January 21, 2013.

FIGO has as members 125 national ObGyn societies. The FIGO Committee on Reproductive Medicine’s mission is to create access to quality reproductive medical care and is focused on helping infertile women become pregnant and/or on alleviating the burden of infertility. The Committee has just released The FIGO Fertility Tool Box™ to further this goal.

Who should use the Tool Box?

Anybody who wants to help infertile people! It is designed for health-care workers and others who want to make a difference in the lives of infertile people. The Tool Box can be accessed electronically on both computers and cell phones at http://www.figo.org/news/resources/FIGO_Fertility_Tool_Box.

What’s in the Tool Box?

Seven Tools help you tackle the disease/ disability of infertility. Each Tool provides information on how to manage a particular aspect of infertility:

• Tool 1: The FIGO Fertility Daisy—why we should care about infertility
• Tool 2: Overcome personal barriers
• Tool 3: Overcome societal barriers
• Tool 4: Diagnose infertility
• Tool 5: Treat infertility
• Tool 6: Refer/resolve infertility
• Tool 7: Prevent infertility.

The Tools Pyramid ( FIGURE 1 ) contains these seven Tools.

FIGURE 1 The Tools Pyramid^™

How do the Tools work?

Each of the seven Tools consists of three levels:

Level 1: Basic Tools. The first level consists of 7 Basic Tools™, which contain information that is brief and succinct—just a simple statement or summary of the Daisy and each of the six Pyramids of Action. The Basic Tools are colored orange.

Level 2: Support Tools. The second level is Support Tools™, which provide more information and detail—enough so that you know what to do to take action. Support Tools are colored green.

Level 3: Reference Tools. The third level is Reference Tools™, which are lists of references that provide evidence for the information and recommended actions in the Basic and Support Tools. Reference Tools are colored white.

The Glossary provides definitions and explanations of abbreviations and acronyms and is colored white like the References. By coloring the levels icons this way, you can always tell whether you are using a Basic Tool, Support Tool, or Reference Tool.

The Levels Pyramid (FIGURE 2 ) shows how the Basic Tools, Support Tools, and Reference Tools relate to each other. You can choose your Tool and level by clicking on the icons from your computer or cellphone.

FIGURE 2 The Levels Pyramid^™

How do I know what to do?—The Actions Pyramids^™

With the exception of the Daisy (Tool 1), all Tools have the shape of a pyramid ( FIGURE 3 ). At the base of each pyramid are actions that can be taken in low-resource settings; that is, they are often simpler, elementary, involve fewer people and are low-cost interventions or opportunities. Overall, there are 64 total actions described in the seven Tools.

As you move higher in the pyramid, generally more resources are required to take actions that are usually more complex. You can think of it as a kind of ladder—as you climb higher it usually gets a bit more complex or complicated. Sometimes, however, it might also be easier higher up on the ladder, and the elementary aspects might be those most challenging.

If you are interested in helping a patient with infertility, you are encouraged to do whatever you can do at any level in any of the Tools in The Actions Pyramid. In the online version, you can click on the actions arrow or icons to click immediately to the action you wish to learn about and do.

FIGURE 3 The Actions Pyramid^™

Which Tool should I use?

The one you think will work best for you and will give you some results quickly. Doing something is better than doing nothing. There is no right or wrong way to make a start. Then, if you want to do more you can choose other Tools or individual aspects of other Tools to build on what you have already achieved. Or, if you want to be very systematic and are very committed you can start with Tool 1 and work your way through the entire Tool Box.

What if I can’t implement some of the recommendations?

Then drop it and move onto something that you can do or implement. No single component of the Tool Box is so essential to helping infertile couples that your efforts will fail if you can’t apply it. Using even one or two actions in one or two Tools will empower you to help many infertile individuals.

What if I want to change a Tool?

Just do it. The Tool Box is made to be changed so that it can be adapted to work in any type of health-care setting anywhere in the world. You know what works best in your situation. Just never stop caring and trying to help infertile people.

Does the Tool Box have a compliments and complaints section?

Yes, it is called the FIGO Committee on Reproductive Medicine. E-mail us at fertilitytool [email protected]. We would love to hear from you about what you like and what works in the Tool Box and what doesn’t. We hope to constantly improve The FIGO Fertility Tool Box to make it a better Tool to help you tackle the disease/disability of infertility.

Smoking, by either partner, active or passive, negatively affects reproductive health

Pfeifer S, Fritz M, Goldberg J, et al; the Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil Steril. 2012;98(6):1400–1406.

Approximately 30% of reproductive-age women and 35% of reproductive-age men smoke cigarettes. Although smoking has been linked to many adverse health effects, the substantial detrimental effects of cigarette smoking on fecundity and reproduction are under-recognized. In a recent publication, the Practice Committee of the American Society for Reproductive Medicine reviewed the effects of smoking on fertility.

Smoking’s ill effects on fertility

Conception delay

Smokers are at an increased risk for infertility and conception delay. Independent of other factors, smoking has a negative impact on fecundity, with a trend toward increased time to conception with increased number of cigarettes smoked.^2,3 The percentage of women experiencing conception delay for more than 12 months was shown to be 54% higher in smoking versus nonsmoking women in one study.³ These authors found that active smoking by either partner had an adverse effect on conception. Furthermore, the impact of passive smoking by either partner was found to be only slightly less than the impact found for active smoking by either partner.³

Ovarian follicular depletion

Basal levels of follicle-stimulating hormone (FSH) are significantly higher in smokers, with one study demonstrating a 66% increase in smoking versus nonsmoking women and a 39% increase in passive versus nonsmoking women.⁴ Chemicals in cigarette smoke appear to accelerate follicular depletion and loss of reproductive function, and menopause has been found to occur 1 to 4 years earlier in smoking versus nonsmoking women.²

Effects on sperm parameters

Poor function. Smoking has been found to reduce sperm density, motility, and possibly morphology. Sperm function tests appear to be 22% poorer in smokers versus nonsmokers, and the effects are dose-dependent.

No link to male infertility, yet. While evidence suggests an adverse effect on sperm function from smoking, available data do not conclusively demonstrate a reduction in male fertility due to smoking. This could be due to secondary confounding effects of partner status.²

Maternal smoking may decrease sperm counts in offspring, according to Storgaard and colleagues, who found that men whose mothers had smoked more than 10 cigarettes per day had lower sperm densities than men with nonsmoking mothers.⁵

Mutagenic potential

Tobacco smoke exposure may harm gametogenesis by adversely affecting chromosomes and damaging the meiotic spindle and has been associated with an increased risk of trisomy 21 offspring resulting from maternal nondisjunction.^6,7 Gene damage in sperm may be secondary to direct binding of tobacco smoke constituents or chemical byproducts to DNA, creating premutational lesions or “adducts.” These mutagenic adducts have been found in greater numbers in embryos from smokers versus nonsmokers, suggesting a mechanism for the transmission of adversely modified DNA from parental smoking.²

Early pregnancy effects

Smoking increases the risk of spontaneous miscarriage in both natural and assisted conceptions and has been linked to an increased risk for bacterial vaginosis, which in turn increases the risk for second trimester miscarriage and preterm labor.² Studies also have identified an increased risk of ectopic pregnancy in smokers, including one study demonstrating an odds ratio (OR) for ectopic pregnancy of 3.5 (95% confidence interval [CI], 1.4–8.6) in women who smoked more than 20 cigarettes per day versus nonsmokers.⁶

Assisted reproductive therapies rendered less effective

Studies of IVF have demonstrated that smokers versus nonsmokers have an increased gonadotropin requirement for ovarian stimulation, lower peak estradiol levels, elevated testosterone levels, fewer oocytes retrieved, higher numbers of cancelled cycles, thicker zone pellucida, lower implantation rates, and an increased rate of failed fertilization.² In order to achieve conception, smokers require nearly twice the number of IVF cycles versus nonsmokers.² Authors of a 5-year, prospective study controlling for potential confounders found that if a woman ever smoked in her lifetime, her risk of failing to conceive with assisted reproductive technologies (ART) more than doubled (relative risk, 2.5; 95% CI, 1.38–4.55). Each year of smoking was associated with a 9% increase in the risk of unsuccessful ART cycles (95% CI, 1.02–1.15;
P <.01).⁸

We have an important role in helping patients quit

A study involving smoking cessation in infertile women found that simple interventions, such as counseling, education, and encouragement during each clinic visit, were more successful than merely providing educational materials and Web site addresses. The rates of smoking cessation increased from 4% at baseline to 24% after 12 months.⁹

The Public Health Service and National Cancer Institute offer validated, office-based intervention guidelines for smoking cessation, including a five-step approach² :

1. Ask about smoking at every opportunity
2. Advise all smokers to stop
3. Assist willingness to stop
4. Assist patients in stopping (including through the use of pharmaceuticals and carbon monoxide handheld monitors)
5. Arrange follow-up visits.

The use of adjunctive medical therapies, including nicotine replacement therapy and/or buproprion, has resulted in a twofold increase in the proportion of nonpregnant women who quit smoking.² These medical therapies may be useful if behavioral approaches alone fail—although their use has not been studied in infertile women. Smoking cessation rates appear to be higher in infertile versus pregnant women, yet only 18% of women referred for infertility care have received advice on smoking cessation from their referring provider.⁹

The safety of assisted reproductive technologies

Davies ML, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803–1813.

Since the birth of Louise Brown, the first baby born after being conceived with in vitro fertilization (IVF) in 1978, IVF has become a pillar in the treatment of infertility. Although recognized as a highly effective treatment, the safety of IVF and its related technologies, such as intracytoplasmic sperm injection (ICSI), has been questioned. Studies have linked the use of assisted reproduction, including IVF and ICSI, with an increased risk of birth defects.^10-15 Findings, however, were limited by small sample sizes and lack of appropriate controls. Furthermore, it has been unclear if this increased risk is due to factors related to treatment or to an underlying factor present in patients with infertility. It also has been unclear whether there is a differential in risk according to the type of ART used. In a large population-wide cohort study, Davies and colleagues linked a census of treatment with ART in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of 400 g and registries of birth defects.

The authors compared the risk of birth defects in pregnancies among women who had conceived with the use of ART, women with spontaneous pregnancies who had had a previous birth after ART treatment, women with a diagnosis of infertility who had conceived without ART, and pregnancies in women without infertility. Births and pregnancy terminations secondary to birth defects were studied to assess the birth defect risk from pregnancy to a child’s fifth birthday.

Details of the trial

A total of 308,974 births were included in the analysis. Births in women who conceived with the use of ART were associated with a significant increase in risk of birth defects (8.3%) compared with births conceived spontaneously in fertile women (8.3% vs 5.8%, respectively; unadjusted OR, 1.47; 95% CI, 1.33-1.62). This effect remained significant after multivariate adjustment (adjusted OR, 1.28; 95% CI, 1.16-1.41).

While there was no significant association between ART and the risk of specific syndromes such as Down’s, Turner’s, Edward’s, and others, there was a significantly increased adjusted OR for any defect and multiple defects in births conceived with ART versus those conceived spontaneously in fertile women.

The OR for birth defects associated with IVF was 1.26 (95% CI, 1.07-1.48) in unadjusted analyses and 1.07 (95% CI, 0.9-1.26) after multivariate adjustment. The OR for birth defects associated with IVF with ICSI were 1.77 (95% CI, 1.47-2.12) in unadjusted and 1.57 (95% CI, 1.30-1.90) after multivariate analysis. Compared with ICSI, IVF was associated with a reduced risk of any birth defect (OR, 0.68; 95% CI, 0.53-0.87).

Births after gamete intrafallopian transfer, intrauterine insemination, or the use of clomiphene citrate at home were associated with significantly increased risks of any birth defect in adjusted analyses. Births after conception with donor insemination and clinically supervised ovulation induction were not associated with an increased risk of birth defects. Births occurring after spontaneous conception in women with a history of a previous birth with ART were also associated with an increased risk of birth defects, even after adjustment for confounders (adjusted OR, 1.25; 95% CI, 1.01-1.56). Births occurring after spontaneous conception in women with a history of infertility without previous ART treatment were also significantly associated with a small increased risk in birth defects (OR, 1.29; 95% CI, 0.99-1.68).

ICSI and birth-defect association persisted

In this large observational study, the authors confirmed findings from previous studies^11,12,16-18 that the number of birth defects found in pregnancies conceived with ART are higher than the number found in pregnancies conceived spontaneously. In this study, after multivariate adjustment, the association between IVF and an increased risk of birth defects was found to be no longer significant, but the risk remained elevated after ART with ICSI. These findings are similar to results in previous studies.^18,19 The increased risk may be secondary to the ICSI procedure itself^19,20 or to underlying male infertility factors leading to the use of ICSI.¹⁴

Birth defects appeared to be highest in fresh embryo cycles of ICSI versus IVF and lowest in frozen-embryo cycles. A reduction in birth defects with cryopreservation may be secondary to a reduced likelihood that cryopreserved embryos would survive the thawing process as well as the temporal separation of the developing embryo from a hormonally stimulated cycle.^21-23 Treatment with ART was associated with an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy. The observation of an increased risk of cerebral palsy with ART treatment is consistent with findings from a previous study. Strömberg and colleagues found that the risk of cerebral palsy was increased by a factor of 3.7 among multiples conceived with IVF and 2.8 among singletons conceived with IVF.²⁴

Davies and colleagues also observed that the risk of a birth defect was increased among women with a history of infertility who were able to conceive without ART,²⁵ a finding observed in a previous large Danish registry.¹⁵

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