Christine Kilgore

New federal guidelines on food allergy recommend "prompt and rapid" treatment of food-induced anaphylaxis with intramuscular epinephrine as first-line therapy.

And in cases of a suboptimal response to epinephrine – or if symptoms progress – "repeat epinephrine dosing remains first-line therapy over adjunctive treatments," the guidelines say.

© Julian Rovagnati/Fotolia.com

The "consistency and strength" of the recommendation for prompt treatment with IM epinephrine may come as a surprise to some emergency physicians who "reserve treatment with epinephrine until patients are in shock, which is an extreme and late manifestation" of anaphylaxis, said Dr. Carlos A. Camargo Jr., an emergency physician who served on the multidisciplinary expert panel that developed the guidelines for the National Institute of Allergy and Infectious Diseases.

"Earlier diagnosis of anaphylaxis and earlier treatment with epinephrine would benefit patients," said Dr. Camargo of Massachusetts General Hospital and Harvard Medical School, both in Boston. "The guidelines strongly encourage earlier use of IM epinephrine for food-induced anaphylaxis."

Studies suggest that almost half of food-related allergic reactions in the emergency department involve multiple organ systems and therefore qualify as anaphylaxis, he said in an interview.

The guidelines, published in the December issue of the Journal of Allergy and Clinical Immunology, were based on a systematic literature review combined with consensus expert opinion, and were designed to standardize the diagnosis and management of food allergies across clinical settings and disciplines (J. Allergy Clin. Immunol. 2010;126:1105-18).

Expert opinion played a prominent role in the development of the guidelines – particularly in the section on managing acute allergic reactions to food – because there have been few, if any, controlled studies on food-induced anaphylaxis management, the 25-member expert panel said in the report.

Anaphylaxis, whether food induced or not, is significantly underrecognized and undertreated, they wrote. One possible reason, the panel said, is the "failure to appreciate that anaphylaxis can present without obvious cutaneous symptoms, which happens in 10%-20% of cases, or without overt shock."

Food-induced anaphylaxis can occur within minutes to several hours after a defined exposure to a food allergen. Although it can sometimes take a milder course and resolve spontaneously, it can also be fatal. Deaths from food-induced anaphylaxis have been reported within 30 minutes to 2 hours of exposure, and are associated with delayed use of epinephrine or improper epinephrine dosing, the panel said.

The guidelines, which include guidance and dosing information for epinephrine and various adjunctive treatments – from inhaled bronchodilators and antihistamines to vasopressors and glucagons – caution specifically against the use of H1 and H2 antihistamines for anaphylaxis in anything but an adjunctive role.

Antihistamines such as diphenhydramine are commonly used to treat anaphylaxis, but the report noted that data demonstrating their effectiveness are lacking. Similarly, "there is no persuasive evidence for the use of corticosteroids in acute food-related allergic reactions," Dr. Camargo said.

[Perspective: NIH Guidelines Offer Roadmap for Managing Food Allergies]

Epinephrine has an onset of action within minutes but is rapidly metabolized. Repeated doses of epinephrine may therefore be required after 5-15 minutes, the guidelines say. Among individuals who require epinephrine for anaphylaxis, approximately 10%-20% will require more than one dose, Dr. Camargo emphasized.

The expert panel acknowledged in its report that some level of decision making regarding the risk-benefit ratio of epinephrine "may be warranted" for some patients, but it emphasized that severe adverse effects are rare with epinephrine and are more likely to occur when the drug is given in overdose than in other circumstances.

"Because the risk of death or serious disability from anaphylaxis itself usually outweighs other concerns, existing evidence clearly favors the benefit of epinephrine administration in most situations," the guidelines state.

IM injection of epinephrine should be quickly followed by placement of the patient in a recumbent position (if tolerated, and with lower extremities elevated), the provision of supplemental oxygen, and the administration of intravenous fluid, the panel noted.

Not enough is known, the panel noted, about the true incidence of biphasic and protracted reactions related to food-induced anaphylaxis and how to best prevent or treat these reactions.

Another "knowledge gap" concerns the relative benefits of certain alternative routes of epinephrine administration, such as sublingual administration.

And although little is known about the most effective methods for educating and protecting patients at risk for food-induced anaphylaxis, the guidelines recommend a thorough discharge plan following treatment for food-induced anaphylaxis – one that includes a plan for arranging further evaluation, an anaphylaxis emergency action plan, and an epinephrine auto-injector (two doses) with instructions and a plan for monitoring auto-injector expiration dates.

Management of food-induced anaphylaxis should also include observation for 4-6 hours or longer, based on the severity of the reaction, according to the guidelines.

"Practically speaking, the key is for the patient to be under some type of observation, not necessarily in the emergency department but somewhere with very quick access to emergency care," Dr. Camargo said.

The NIAID-sponsored guidelines were approved by the American College of Emergency Physicians, which had representation on the project’s coordinating committee.

To address potential conflicts of interest, members of the coordinating committee and expert panel submitted voluntary written statements on their relevant and significant financial interests for the NIAID to review. Expert panel members with perceived conflicts of interest were asked to remove themselves from voting on any recommendations relevant to the conflicted topic.

Dr. Camargo reported to the NIAID that he has consulted for and has received funding/grant support from Dey and Novartis, as well as funding/grant support from a variety of government agencies and not-for-profit research foundations.

The complete guidelines, as well as a summary of the expert panel’s report, are available to view or download on the NIAID food allergy guidelines Web site.

New federal guidelines on food allergy recommend "prompt and rapid" treatment of food-induced anaphylaxis with intramuscular epinephrine as first-line therapy.

And in cases of a suboptimal response to epinephrine – or if symptoms progress – "repeat epinephrine dosing remains first-line therapy over adjunctive treatments," the guidelines say.

© Julian Rovagnati/Fotolia.com

The "consistency and strength" of the recommendation for prompt treatment with IM epinephrine may come as a surprise to some emergency physicians who "reserve treatment with epinephrine until patients are in shock, which is an extreme and late manifestation" of anaphylaxis, said Dr. Carlos A. Camargo Jr., an emergency physician who served on the multidisciplinary expert panel that developed the guidelines for the National Institute of Allergy and Infectious Diseases.

"Earlier diagnosis of anaphylaxis and earlier treatment with epinephrine would benefit patients," said Dr. Camargo of Massachusetts General Hospital and Harvard Medical School, both in Boston. "The guidelines strongly encourage earlier use of IM epinephrine for food-induced anaphylaxis."

Studies suggest that almost half of food-related allergic reactions in the emergency department involve multiple organ systems and therefore qualify as anaphylaxis, he said in an interview.

The guidelines, published in the December issue of the Journal of Allergy and Clinical Immunology, were based on a systematic literature review combined with consensus expert opinion, and were designed to standardize the diagnosis and management of food allergies across clinical settings and disciplines (J. Allergy Clin. Immunol. 2010;126:1105-18).

Expert opinion played a prominent role in the development of the guidelines – particularly in the section on managing acute allergic reactions to food – because there have been few, if any, controlled studies on food-induced anaphylaxis management, the 25-member expert panel said in the report.

Anaphylaxis, whether food induced or not, is significantly underrecognized and undertreated, they wrote. One possible reason, the panel said, is the "failure to appreciate that anaphylaxis can present without obvious cutaneous symptoms, which happens in 10%-20% of cases, or without overt shock."

Food-induced anaphylaxis can occur within minutes to several hours after a defined exposure to a food allergen. Although it can sometimes take a milder course and resolve spontaneously, it can also be fatal. Deaths from food-induced anaphylaxis have been reported within 30 minutes to 2 hours of exposure, and are associated with delayed use of epinephrine or improper epinephrine dosing, the panel said.

The guidelines, which include guidance and dosing information for epinephrine and various adjunctive treatments – from inhaled bronchodilators and antihistamines to vasopressors and glucagons – caution specifically against the use of H1 and H2 antihistamines for anaphylaxis in anything but an adjunctive role.

Antihistamines such as diphenhydramine are commonly used to treat anaphylaxis, but the report noted that data demonstrating their effectiveness are lacking. Similarly, "there is no persuasive evidence for the use of corticosteroids in acute food-related allergic reactions," Dr. Camargo said.

[Perspective: NIH Guidelines Offer Roadmap for Managing Food Allergies]

Epinephrine has an onset of action within minutes but is rapidly metabolized. Repeated doses of epinephrine may therefore be required after 5-15 minutes, the guidelines say. Among individuals who require epinephrine for anaphylaxis, approximately 10%-20% will require more than one dose, Dr. Camargo emphasized.

The expert panel acknowledged in its report that some level of decision making regarding the risk-benefit ratio of epinephrine "may be warranted" for some patients, but it emphasized that severe adverse effects are rare with epinephrine and are more likely to occur when the drug is given in overdose than in other circumstances.

"Because the risk of death or serious disability from anaphylaxis itself usually outweighs other concerns, existing evidence clearly favors the benefit of epinephrine administration in most situations," the guidelines state.

IM injection of epinephrine should be quickly followed by placement of the patient in a recumbent position (if tolerated, and with lower extremities elevated), the provision of supplemental oxygen, and the administration of intravenous fluid, the panel noted.

Not enough is known, the panel noted, about the true incidence of biphasic and protracted reactions related to food-induced anaphylaxis and how to best prevent or treat these reactions.

Another "knowledge gap" concerns the relative benefits of certain alternative routes of epinephrine administration, such as sublingual administration.

And although little is known about the most effective methods for educating and protecting patients at risk for food-induced anaphylaxis, the guidelines recommend a thorough discharge plan following treatment for food-induced anaphylaxis – one that includes a plan for arranging further evaluation, an anaphylaxis emergency action plan, and an epinephrine auto-injector (two doses) with instructions and a plan for monitoring auto-injector expiration dates.

Management of food-induced anaphylaxis should also include observation for 4-6 hours or longer, based on the severity of the reaction, according to the guidelines.

"Practically speaking, the key is for the patient to be under some type of observation, not necessarily in the emergency department but somewhere with very quick access to emergency care," Dr. Camargo said.

The NIAID-sponsored guidelines were approved by the American College of Emergency Physicians, which had representation on the project’s coordinating committee.

To address potential conflicts of interest, members of the coordinating committee and expert panel submitted voluntary written statements on their relevant and significant financial interests for the NIAID to review. Expert panel members with perceived conflicts of interest were asked to remove themselves from voting on any recommendations relevant to the conflicted topic.

Dr. Camargo reported to the NIAID that he has consulted for and has received funding/grant support from Dey and Novartis, as well as funding/grant support from a variety of government agencies and not-for-profit research foundations.

The complete guidelines, as well as a summary of the expert panel’s report, are available to view or download on the NIAID food allergy guidelines Web site.

New federal guidelines on food allergy recommend "prompt and rapid" treatment of food-induced anaphylaxis with intramuscular epinephrine as first-line therapy.

And in cases of a suboptimal response to epinephrine – or if symptoms progress – "repeat epinephrine dosing remains first-line therapy over adjunctive treatments," the guidelines say.

© Julian Rovagnati/Fotolia.com

The "consistency and strength" of the recommendation for prompt treatment with IM epinephrine may come as a surprise to some emergency physicians who "reserve treatment with epinephrine until patients are in shock, which is an extreme and late manifestation" of anaphylaxis, said Dr. Carlos A. Camargo Jr., an emergency physician who served on the multidisciplinary expert panel that developed the guidelines for the National Institute of Allergy and Infectious Diseases.

"Earlier diagnosis of anaphylaxis and earlier treatment with epinephrine would benefit patients," said Dr. Camargo of Massachusetts General Hospital and Harvard Medical School, both in Boston. "The guidelines strongly encourage earlier use of IM epinephrine for food-induced anaphylaxis."

Studies suggest that almost half of food-related allergic reactions in the emergency department involve multiple organ systems and therefore qualify as anaphylaxis, he said in an interview.

The guidelines, published in the December issue of the Journal of Allergy and Clinical Immunology, were based on a systematic literature review combined with consensus expert opinion, and were designed to standardize the diagnosis and management of food allergies across clinical settings and disciplines (J. Allergy Clin. Immunol. 2010;126:1105-18).

Expert opinion played a prominent role in the development of the guidelines – particularly in the section on managing acute allergic reactions to food – because there have been few, if any, controlled studies on food-induced anaphylaxis management, the 25-member expert panel said in the report.

Anaphylaxis, whether food induced or not, is significantly underrecognized and undertreated, they wrote. One possible reason, the panel said, is the "failure to appreciate that anaphylaxis can present without obvious cutaneous symptoms, which happens in 10%-20% of cases, or without overt shock."

Food-induced anaphylaxis can occur within minutes to several hours after a defined exposure to a food allergen. Although it can sometimes take a milder course and resolve spontaneously, it can also be fatal. Deaths from food-induced anaphylaxis have been reported within 30 minutes to 2 hours of exposure, and are associated with delayed use of epinephrine or improper epinephrine dosing, the panel said.

The guidelines, which include guidance and dosing information for epinephrine and various adjunctive treatments – from inhaled bronchodilators and antihistamines to vasopressors and glucagons – caution specifically against the use of H1 and H2 antihistamines for anaphylaxis in anything but an adjunctive role.

Antihistamines such as diphenhydramine are commonly used to treat anaphylaxis, but the report noted that data demonstrating their effectiveness are lacking. Similarly, "there is no persuasive evidence for the use of corticosteroids in acute food-related allergic reactions," Dr. Camargo said.

[Perspective: NIH Guidelines Offer Roadmap for Managing Food Allergies]

Epinephrine has an onset of action within minutes but is rapidly metabolized. Repeated doses of epinephrine may therefore be required after 5-15 minutes, the guidelines say. Among individuals who require epinephrine for anaphylaxis, approximately 10%-20% will require more than one dose, Dr. Camargo emphasized.

The expert panel acknowledged in its report that some level of decision making regarding the risk-benefit ratio of epinephrine "may be warranted" for some patients, but it emphasized that severe adverse effects are rare with epinephrine and are more likely to occur when the drug is given in overdose than in other circumstances.

"Because the risk of death or serious disability from anaphylaxis itself usually outweighs other concerns, existing evidence clearly favors the benefit of epinephrine administration in most situations," the guidelines state.

IM injection of epinephrine should be quickly followed by placement of the patient in a recumbent position (if tolerated, and with lower extremities elevated), the provision of supplemental oxygen, and the administration of intravenous fluid, the panel noted.

Not enough is known, the panel noted, about the true incidence of biphasic and protracted reactions related to food-induced anaphylaxis and how to best prevent or treat these reactions.

Another "knowledge gap" concerns the relative benefits of certain alternative routes of epinephrine administration, such as sublingual administration.

And although little is known about the most effective methods for educating and protecting patients at risk for food-induced anaphylaxis, the guidelines recommend a thorough discharge plan following treatment for food-induced anaphylaxis – one that includes a plan for arranging further evaluation, an anaphylaxis emergency action plan, and an epinephrine auto-injector (two doses) with instructions and a plan for monitoring auto-injector expiration dates.

Management of food-induced anaphylaxis should also include observation for 4-6 hours or longer, based on the severity of the reaction, according to the guidelines.

"Practically speaking, the key is for the patient to be under some type of observation, not necessarily in the emergency department but somewhere with very quick access to emergency care," Dr. Camargo said.

The NIAID-sponsored guidelines were approved by the American College of Emergency Physicians, which had representation on the project’s coordinating committee.

To address potential conflicts of interest, members of the coordinating committee and expert panel submitted voluntary written statements on their relevant and significant financial interests for the NIAID to review. Expert panel members with perceived conflicts of interest were asked to remove themselves from voting on any recommendations relevant to the conflicted topic.

Dr. Camargo reported to the NIAID that he has consulted for and has received funding/grant support from Dey and Novartis, as well as funding/grant support from a variety of government agencies and not-for-profit research foundations.

The complete guidelines, as well as a summary of the expert panel’s report, are available to view or download on the NIAID food allergy guidelines Web site.

Discussing the risks of the human papillomavirus and vaccinating teenage and young adult patients is no easy feat, but many gynecologic practices will find they can do it – and be “in the black” financially” – if they just appoint an office “vaccine advocate” to take charge of instituting national vaccination recommendations.

So says Dr. Stanley A. Gall, professor of obstetrics and gynecology at the University of Louisville (Ky.) and the American College of Obstetricians and Gynecologists' liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, he and other experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil (the first of two HPV vaccines) was licensed.

Pediatricians are vaccine experts and are used to low fees for vaccine administration, but in the case of HPV vaccine, they're challenged by their key age group: the 11- to 12-year-olds for whom the vaccine is recommended as part of the regular immunization schedule.

A recent survey of more than 1,500 parents showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010;125:654-9).

Ob.gyns., on the other hand, are better positioned to discuss HPV infection as a sexually transmitted disease, but for many, vaccination requires a true “paradigm shift” in terms of practice values and resources.

HPV vaccination is recommended by ACIP on a “catch-up” basis for young women aged 13–26 years. Most private insurers cover vaccination, sources said, although coverage through some insurers diminishes in the 19- to 26-year age bracket. The public sector, Dr. Gall said, is now “catching up” with the private sector in covering HPV vaccination.

“Practices need to look at the reimbursement they're getting [or would get] from a handful of their insurers, and find out if they're in the black or the red,” said Dr. Gall, a member of ACIP's working group on HPV. “A lot of times, offices find that even though the amounts are small, they can make money.”

Success with HPV vaccine administration – as well as the administration of other vaccines – often comes with the appointment of a nurse or other practice member who “feels passionate” about the value of vaccination and can take charge of ordering and properly storing vaccines as well as teaching staff about proper vaccination indications, schedules, and techniques, said Dr. Gall.

“The physician shouldn't even have to think about it,” he said, noting that practices must institute standing orders for vaccines to be delivered in the physician's absence. “Take it out of their hands and make it a routine in the office.”

Even though the ob.gyn. practice staff may be more likely than pediatricians to find patients and parents more appreciative of HPV risks, it is still important to understand and anticipate the common reasons for refusal of the vaccine, Dr. Gall and other experts told this news organization.

For one, “there isn't as immediate a preventive effect” to appreciate compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both [teens] and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “Why Now” Factor. HPV infection is the most commonly occurring STD. About 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

It is important to emphasize, however, that vaccination is not about sexual readiness or sexual activity but about preventing cervical cancer – and, sources said, it's important to give numbers.

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, explains that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%–90% HPV vaccination rate in female patients.

Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, advises telling patients and parents that “studies show without a doubt that when you vaccinate at a younger age, you get much higher immunity levels.”

And Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco, advises telling patients that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe by parents.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents who are concerned about safety to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the Web site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of Efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can [say] that, as with any new vaccine, we [don't know] how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7 and a half years, and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine Differences. The most important facts for parents and/or older patients to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, said Dr. Gall.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV−16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Block has done research for both manufacturers and is on the speakers bureau for Gardasil (Merck's HPV vaccine). Dr. Pichichero has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively. Dr. Gall said he was working on clinical trials and is a speaker for GSK and Merck. The other physicians reported no disclosures.

Tell patients studies show 'that when you vaccinate at a younger age, you get much higher immunity levels.'

Source DR. PICHICHERO

Tell patients that at least 10,000 women die each year of cervical cancer, and HPV causes cervical cancer.

Source ©BVDC/Fotolia.com

Emphasize vaccination is not about sexual activity, but about preventing cervical cancer.

Source DR. BOCCHINI

Discussing the risks of the human papillomavirus and vaccinating teenage and young adult patients is no easy feat, but many gynecologic practices will find they can do it – and be “in the black” financially” – if they just appoint an office “vaccine advocate” to take charge of instituting national vaccination recommendations.

So says Dr. Stanley A. Gall, professor of obstetrics and gynecology at the University of Louisville (Ky.) and the American College of Obstetricians and Gynecologists' liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, he and other experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil (the first of two HPV vaccines) was licensed.

Pediatricians are vaccine experts and are used to low fees for vaccine administration, but in the case of HPV vaccine, they're challenged by their key age group: the 11- to 12-year-olds for whom the vaccine is recommended as part of the regular immunization schedule.

A recent survey of more than 1,500 parents showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010;125:654-9).

Ob.gyns., on the other hand, are better positioned to discuss HPV infection as a sexually transmitted disease, but for many, vaccination requires a true “paradigm shift” in terms of practice values and resources.

HPV vaccination is recommended by ACIP on a “catch-up” basis for young women aged 13–26 years. Most private insurers cover vaccination, sources said, although coverage through some insurers diminishes in the 19- to 26-year age bracket. The public sector, Dr. Gall said, is now “catching up” with the private sector in covering HPV vaccination.

“Practices need to look at the reimbursement they're getting [or would get] from a handful of their insurers, and find out if they're in the black or the red,” said Dr. Gall, a member of ACIP's working group on HPV. “A lot of times, offices find that even though the amounts are small, they can make money.”

Success with HPV vaccine administration – as well as the administration of other vaccines – often comes with the appointment of a nurse or other practice member who “feels passionate” about the value of vaccination and can take charge of ordering and properly storing vaccines as well as teaching staff about proper vaccination indications, schedules, and techniques, said Dr. Gall.

“The physician shouldn't even have to think about it,” he said, noting that practices must institute standing orders for vaccines to be delivered in the physician's absence. “Take it out of their hands and make it a routine in the office.”

Even though the ob.gyn. practice staff may be more likely than pediatricians to find patients and parents more appreciative of HPV risks, it is still important to understand and anticipate the common reasons for refusal of the vaccine, Dr. Gall and other experts told this news organization.

For one, “there isn't as immediate a preventive effect” to appreciate compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both [teens] and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “Why Now” Factor. HPV infection is the most commonly occurring STD. About 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

It is important to emphasize, however, that vaccination is not about sexual readiness or sexual activity but about preventing cervical cancer – and, sources said, it's important to give numbers.

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, explains that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%–90% HPV vaccination rate in female patients.

Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, advises telling patients and parents that “studies show without a doubt that when you vaccinate at a younger age, you get much higher immunity levels.”

And Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco, advises telling patients that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe by parents.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents who are concerned about safety to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the Web site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of Efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can [say] that, as with any new vaccine, we [don't know] how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7 and a half years, and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine Differences. The most important facts for parents and/or older patients to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, said Dr. Gall.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV−16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Block has done research for both manufacturers and is on the speakers bureau for Gardasil (Merck's HPV vaccine). Dr. Pichichero has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively. Dr. Gall said he was working on clinical trials and is a speaker for GSK and Merck. The other physicians reported no disclosures.

Tell patients studies show 'that when you vaccinate at a younger age, you get much higher immunity levels.'

Source DR. PICHICHERO

Tell patients that at least 10,000 women die each year of cervical cancer, and HPV causes cervical cancer.

Source ©BVDC/Fotolia.com

Emphasize vaccination is not about sexual activity, but about preventing cervical cancer.

Source DR. BOCCHINI

Discussing the risks of the human papillomavirus and vaccinating teenage and young adult patients is no easy feat, but many gynecologic practices will find they can do it – and be “in the black” financially” – if they just appoint an office “vaccine advocate” to take charge of instituting national vaccination recommendations.

So says Dr. Stanley A. Gall, professor of obstetrics and gynecology at the University of Louisville (Ky.) and the American College of Obstetricians and Gynecologists' liaison to the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, he and other experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil (the first of two HPV vaccines) was licensed.

Pediatricians are vaccine experts and are used to low fees for vaccine administration, but in the case of HPV vaccine, they're challenged by their key age group: the 11- to 12-year-olds for whom the vaccine is recommended as part of the regular immunization schedule.

A recent survey of more than 1,500 parents showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010;125:654-9).

Ob.gyns., on the other hand, are better positioned to discuss HPV infection as a sexually transmitted disease, but for many, vaccination requires a true “paradigm shift” in terms of practice values and resources.

HPV vaccination is recommended by ACIP on a “catch-up” basis for young women aged 13–26 years. Most private insurers cover vaccination, sources said, although coverage through some insurers diminishes in the 19- to 26-year age bracket. The public sector, Dr. Gall said, is now “catching up” with the private sector in covering HPV vaccination.

“Practices need to look at the reimbursement they're getting [or would get] from a handful of their insurers, and find out if they're in the black or the red,” said Dr. Gall, a member of ACIP's working group on HPV. “A lot of times, offices find that even though the amounts are small, they can make money.”

Success with HPV vaccine administration – as well as the administration of other vaccines – often comes with the appointment of a nurse or other practice member who “feels passionate” about the value of vaccination and can take charge of ordering and properly storing vaccines as well as teaching staff about proper vaccination indications, schedules, and techniques, said Dr. Gall.

“The physician shouldn't even have to think about it,” he said, noting that practices must institute standing orders for vaccines to be delivered in the physician's absence. “Take it out of their hands and make it a routine in the office.”

Even though the ob.gyn. practice staff may be more likely than pediatricians to find patients and parents more appreciative of HPV risks, it is still important to understand and anticipate the common reasons for refusal of the vaccine, Dr. Gall and other experts told this news organization.

For one, “there isn't as immediate a preventive effect” to appreciate compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both [teens] and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “Why Now” Factor. HPV infection is the most commonly occurring STD. About 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

It is important to emphasize, however, that vaccination is not about sexual readiness or sexual activity but about preventing cervical cancer – and, sources said, it's important to give numbers.

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, explains that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%–90% HPV vaccination rate in female patients.

Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, advises telling patients and parents that “studies show without a doubt that when you vaccinate at a younger age, you get much higher immunity levels.”

And Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco, advises telling patients that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe by parents.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents who are concerned about safety to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the Web site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of Efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can [say] that, as with any new vaccine, we [don't know] how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7 and a half years, and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine Differences. The most important facts for parents and/or older patients to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, said Dr. Gall.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV−16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Block has done research for both manufacturers and is on the speakers bureau for Gardasil (Merck's HPV vaccine). Dr. Pichichero has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively. Dr. Gall said he was working on clinical trials and is a speaker for GSK and Merck. The other physicians reported no disclosures.

Tell patients studies show 'that when you vaccinate at a younger age, you get much higher immunity levels.'

Source DR. PICHICHERO

Tell patients that at least 10,000 women die each year of cervical cancer, and HPV causes cervical cancer.

Source ©BVDC/Fotolia.com

Emphasize vaccination is not about sexual activity, but about preventing cervical cancer.

Source DR. BOCCHINI

Major Finding: Treatment with atopaxar, a PAR-1 thrombin receptor antagonist, resulted in a rate of bleeding of 3.1% in patients with acute coronary syndromes, compared with 2.2% among patients who received placebo, a statistically nonsignificant difference.

Data Source: LANCELOT ACS, a prospective, randomized, double-blinded, placebo-controlled study of 603 patients with acute coronary syndromes.

Disclosures: The study was funded by Eisai Inc. Dr. O'Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly and Daiichi Sankyo.

WASHINGTON — Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial's lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y₁₂ inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O'Donoghue of Brigham and Women's Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition … without a significant increase in bleeding in patients with ACS,” Dr. O'Donoghue reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O'Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O'Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

Major Finding: Treatment with atopaxar, a PAR-1 thrombin receptor antagonist, resulted in a rate of bleeding of 3.1% in patients with acute coronary syndromes, compared with 2.2% among patients who received placebo, a statistically nonsignificant difference.

Data Source: LANCELOT ACS, a prospective, randomized, double-blinded, placebo-controlled study of 603 patients with acute coronary syndromes.

Disclosures: The study was funded by Eisai Inc. Dr. O'Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly and Daiichi Sankyo.

WASHINGTON — Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial's lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y₁₂ inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O'Donoghue of Brigham and Women's Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition … without a significant increase in bleeding in patients with ACS,” Dr. O'Donoghue reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O'Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O'Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

Major Finding: Treatment with atopaxar, a PAR-1 thrombin receptor antagonist, resulted in a rate of bleeding of 3.1% in patients with acute coronary syndromes, compared with 2.2% among patients who received placebo, a statistically nonsignificant difference.

Data Source: LANCELOT ACS, a prospective, randomized, double-blinded, placebo-controlled study of 603 patients with acute coronary syndromes.

Disclosures: The study was funded by Eisai Inc. Dr. O'Donoghue disclosed that she has received research support from Eisai and GlaxoSmithKline, and that she is a consultant for Eli Lilly and Daiichi Sankyo.

WASHINGTON — Treatment with the investigational antiplatelet agent atopaxar did not significantly increase bleeding in patients with acute coronary syndromes in a randomized trial, making protease-activated receptor-1 blockade “a promising target” for ACS treatment, the trial's lead investigator reported.

Drugs that inhibit platelet activation, such as aspirin and P2Y₁₂ inhibitors (clopidogrel, for instance), are the mainstay of therapy for patients with ACS, but these drugs do not inhibit the thrombin receptor as atopaxar does. “Thrombin is known to be the most potent platelet agonist,” explained Dr. Michelle O'Donoghue of Brigham and Women's Hospital in Boston.

Thrombin acts primarily via the PAR-1 receptor, which has led investigators to wonder whether PAR-1 receptor blockage – in addition to the current antiplatelet therapy – can move clinicians closer to the goal of reducing major adverse cardiac events without increasing the incidence of clinically significant bleeding.

Results from the LANCELOT ACS trial show that the PAR-1 antagonist atopaxar “achieves potent and rapid platelet inhibition … without a significant increase in bleeding in patients with ACS,” Dr. O'Donoghue reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

In the multicenter, double-blind study, 603 patients with unstable angina or non–ST-elevation myocardial infarction (NSTEMI) were randomized within 72 hours of symptom onset to receive either placebo or a 400-mg loading dose of atopaxar followed by a daily maintenance dose of 50 mg, 100 mg, or 200 mg for 12 weeks. The patients were followed for 4 weeks and, with few exceptions, were treated with aspirin or dual antiplatelet therapy in addition to atopaxar or the placebo drug.

The average rate of bleeding across the three atopaxar groups was 3.1% according to the CURE bleeding classification (1.8% CURE major and 1.3% CURE minor), compared with 2.2% in placebo group (all CURE minor). There was “no evidence of any dose-dependent trend,” Dr. O'Donoghue said.

The study, funded by Eisai Inc., was not powered for efficacy – the primary objective was to establish safety and tolerability – but “numerically, there was a lower incidence of cardiovascular death, MI, or stroke in the active combined group as compared with placebo,” Dr. O'Donoghue said. This difference was not statistically significant, but it shows “favorable trends for efficacy,” she said.

The incidence of Holter-detected ischemia at 48 hours following a 400-mg loading dose also was significantly lower in the atopaxar groups, compared with placebo.

“There was a significant 33% relative risk reduction [in the atopaxar groups combined],” she said. “This is the first time an oral antiplatelet drug was shown to reduce Holter-detected ischemia.”

Overall, the drug was well tolerated, but dose-dependent transaminitis and relative QTc prolongation were observed with the higher doses of atopaxar.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still “a million dollar question,” said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did “not believe the vaccine is effective in preventing the disease” (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

“If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet” from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

“If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message,” said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

“Parents have never heard this type of approach used with a vaccine before,” he said.

It is important to tailor one's approach to the fact that “there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines,” said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

“We can do better at being straightforward in addressing the issues of HPV, with both children and their parents,” he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

▸ The “why now” factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

“But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response … and at an age that is prior to the risk,” said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

“Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgment that their daughter is about to become sexually active, whether or not that's true,” said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, “studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels.”

Kaiser's Dr. Wibbelsman said he tells parents that at least “10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer.”

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that “numbers give parents something concrete to hang their hats on.” He tells many parents that “the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination,” and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

“We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children,” said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. “You have to test the waters, the comfort level of the child … but whenever possible, I lay all this out.”

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. “Without a doubt, it's a malpractice risk,” he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

▸ Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

“I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine,” said Dr. Freed. “Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer.”

Others said they refer parents to the CDC's Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding “no pattern or clustering … to suggest they were caused by the HPV vaccination,” the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

▸ Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8–10 years at this point, with no “breakthrough cases” of HPV infection, sources said.

“We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer,” said Dr. Bocchini. If needed in the future, a booster dose will become available.

▸ Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and −11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. “There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer,” not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and −18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their “National Advisory Boards for periodic 1-day consulting.” Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one's approach to the fact that "there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, clinicians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and clinicians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that's true," said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser's Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it's a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC's Web site for vaccine safety profiles. "This way, it's not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP's HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one's approach to the fact that "there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, clinicians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and clinicians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that's true," said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser's Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it's a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC's Web site for vaccine safety profiles. "This way, it's not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP's HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics' committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying 'It's time to receive your HPV vaccine,' there's often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying 'It's time to discuss the possibility of your daughter receiving the HPV vaccine,' immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one's approach to the fact that "there isn't as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, clinicians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, 'I want to have this discussion 2 years from now,' I think it's our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics' committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and clinicians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC's Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren't ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that's true," said Dr. Pichichero.

That's why it's important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser's Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child's chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it's a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents' changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC's Web site for vaccine safety profiles. "This way, it's not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP's HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can't say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we're seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several physicians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

Discussing the risks of the human papillomavirus and the value of HPV vaccination is no easy feat for physicians who are seeing preteen and teenage girls and trying to institute national vaccination recommendations.

Especially in the 11- to 12-year-old population – the age group for whom the vaccine is recommended as part of the regular immunization schedule – how to best address HPV risk is still "a million dollar question," said Dr. Charles Wibbelsman, a pediatrician who is chief of adolescent medicine at Kaiser Permanente in San Francisco and a former member of the American Academy of Pediatrics’ committee on adolescents.

Uptake of the vaccine has been slower and lower than it has been for other vaccines, experts say, and both surveys and interviews with physicians around the country indicate that physicians face a host of moral, ethical, and safety concerns from parents, even though almost 5 years have passed since Gardasil – the first of two HPV vaccines – was licensed.

A survey of more than 1,500 parents published last April, for instance, showed that the HPV vaccine was the most commonly refused pediatric vaccine. Almost 80% of the parents who refused said they believed there had not been enough research on it, 51% said it challenged their belief systems, 59% said they believed their children were at low risk for contracting the sexually transmitted disease, and 37% said they did "not believe the vaccine is effective in preventing the disease" (Pediatrics 2010:125:654-9).

Physicians who spoke with this news organization said that understanding and anticipating these common reasons for refusal of the vaccine are key to an efficient and meaningful discussion of HPV risks. So is the use of affirmative, matter-of-fact statements about HPV vaccination.

"If you approach it by saying ‘It’s time to receive your HPV vaccine,’ there’s often no need to go any further, other than providing parents with the appropriate information pamphlet" from the Centers for Disease Control and Prevention, said Dr. Michael E. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute and a pediatrician in private practice in that city.

"If you start out, on the other hand, by saying ‘It’s time to discuss the possibility of your daughter receiving the HPV vaccine,’ immediately that sends a very different message," said Dr. Pichichero, who has served as a consultant for both Merck and GlaxoSmithKline, the manufacturers of Gardasil and Cervarix, respectively.

"Parents have never heard this type of approach used with a vaccine before," he said.

It is important to tailor one’s approach to the fact that "there isn’t as immediate a preventive effect that parents can appreciate, compared with other vaccines," said Dr. Gary L. Freed, immediate past chairman of the National Vaccine Advisory Committee and director of the division of general pediatrics and the child health evaluation and research unit at the University of Michigan in Ann Arbor.

"We can do better at being straightforward in addressing the issues of HPV, with both children and their parents," he said.

The following are some of the suggestions offered and experiences shared by these physicians and others:

• The "Why Now" Factor. As with other sensitive issues, pediatricians have to tailor the depth of discussion about HPV infection to the maturity of the child and values of the family.

"But when a parent [of an 11- to 12-year-old] says, ‘I want to have this discussion 2 years from now,’ I think it’s our responsibility to share data about the risk, and to convey the fact that we want to provide universal protection at an age when we know the child will respond effectively to the vaccine by developing a strong immune response ... and at an age that is prior to the risk," said Dr. Joseph Bocchini, immediate past chairman of the American Academy of Pediatrics’ committee on infectious diseases and chairman of the department of pediatrics at the Louisiana State University Health Sciences Center in Shreveport.

Both parents and pediatricians underestimate the likelihood that their child or patient is sexually active or about to become sexually active, said Dr. Bocchini, who also serves on the HPV working group of the CDC’s Advisory Committee on Immunization Practices (ACIP).

In all, 20% of adolescents are infected with HPV within 2 years of the onset of sexual activity, he said, which for the majority of girls occurs during their teenage years.

Although physicians should not shy away from discussing HPV infection as a sexually transmitted disease – indeed, it is the most commonly occurring STD – they should nevertheless take care to emphasize the overall goal of vaccination: the prevention of cervical cancer.

"Most mothers aren’t ready to deal with the possibility of their daughter becoming sexually active, so they tie together the vaccine with more or less an acknowledgement that their daughter is about to become sexually active, whether or not that’s true," said Dr. Pichichero.

That’s why it’s important, he and others said, to emphasize that vaccination is not about sexual readiness, but about preventing cervical cancer. Providing the vaccine has not been shown in any way to increase sexual activity, he and other physicians said. And, Dr. Pichichero added, "studies show, without a doubt, that when you vaccinate at a younger age, you get much higher immunity levels."

Kaiser’s Dr. Wibbelsman said he tells parents that at least "10,000 women die each year of cervical cancer and countless others have cervical cancer, and that HPV causes cervical cancer."

Dr. Stan Block, who practices in a six-pediatrician group in Bardstown, Ky., with a large adolescent population, said that "numbers give parents something concrete to hang their hats on." He tells many parents that "the lifetime risk of getting cervical, anal, vaginal, or vulvar precancer or cancer goes from about 1 in 20 without vaccination to 1 in 50 with vaccination," and that the risk of venereal warts similarly drops from 1 in 10 without vaccination with Gardasil to about 1 in 100 with vaccination.

"We explain that even precancerous lesions can have serious consequences, like surgery and the inability to have children," said Dr. Block, who estimates that his practice has an 85%-90% HPV vaccination rate in female patients. "You have to test the waters, the comfort level of the child ... but whenever possible, I lay all this out."

When parents refuse the vaccine, he either tells them that he is documenting the refusal in their child’s chart or asks them to sign a form to document that they acknowledge the risk of refusing vaccination. "Without a doubt, it’s a malpractice risk," he said. Sometimes, he added, such a statement or request results in parents’ changing their minds.

• Safety. At least several studies have shown that the vaccine would receive greater acceptance if it was perceived to be safe.

"I tell parents that the vaccine has now been received by literally hundreds of thousands in this country, and that there are no serious adverse events associated with the vaccine," said Dr. Freed. "Then I say that in the same time period, there likely have been at least several thousand young women who have been infected with HPV who will develop precancerous cervical lesions and may go on to develop cervical cancer."

Others said they refer parents to the CDC’s Web site for vaccine safety profiles (www.cdc.gov/vaccinesafety/vaccines/hpv). "This way, it’s not me talking, and not the manufacturer, but a body with a lot of credibility," said Dr. Stanley Gall, professor of ob.gyn at the University of Louisville (Ky.) and a member of ACIP’s HPV working group.

According to the CDC Web site, approximately 32 million doses of Gardasil were distributed in the United States from the time the vaccine was licensed in 2006 until September 2010. All serious adverse event reports that were made to the Vaccine Adverse Event Reporting System have been fully investigated, with staff finding "no pattern or clustering ... to suggest they were caused by the HPV vaccination," the site says.

Syncope and fainting are common in preteens and teens after injections, the CDC notes, making the recommended 15-minute postvaccination observation period extremely important. Patients should lie down or sit for this period of time.

• Duration of efficacy. Manufacturers have tracked vaccine recipients for up to 8-10 years at this point, with no "breakthrough cases" of HPV infection, sources said.

"We can tell parents that – as with any new vaccine – we can’t say how long efficacy will last, but that we do know the vaccine is highly immunogenic, that we’re seeing no breakthrough cases in the recipients being followed, and that we know protection will last at least 7.5 years and likely significantly longer," said Dr. Bocchini. If needed in the future, a booster dose will become available.

• Vaccine differences. The most important facts for parents to know, several pediatricians said, is that both Gardasil and Cervarix protect against the two strains of HPV (types 16 and 18) that are believed to cause 70% of all cervical cancers, and that Gardasil also protects against HPV-6 and -11, the most common cause of genital warts.

Parents and older teens should know the value of protecting against genital warts, they said. "There are about a million new cases of genital warts each year in this country, and the amount of money spent treating them is equivalent to the amount of money spent treating cervical cancer," not to mention the fact that genital warts cause significant anguish, Dr. Gall said.

Dr. Pichichero, however, said that Cervarix contains a novel adjuvant that is believed to be responsible for its ability to generate a greater antibody response to HPV-16 and -18, compared with Gardasil. Higher antibody titers may translate into a longer duration of protection, he said.

Cervarix also has been shown, he said, to afford some level of cross-protection against other HPV strains that are responsible for a small yet significant proportion of cervical cancer cases. Although such differences should be weighed in the long term, right now it seems that parents are more concerned about safety and experience with the vaccines, and physicians should focus on this, he said.

Dr. Pichichero said he has served as a consultant to Merck and GlaxoSmithKline on their "National Advisory Boards for periodic 1-day consulting." Dr. Block said he has done research for both companies and is on the speakers bureau for Gardasil. Dr. Gall said he was working on clinical trials and is a speaker for GlaxoSmithKline and Merck. The other physicians reported no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

WASHINGTON – Aan investigational paclitaxel-coated balloon catheter resulted in significant reductions in late lumen loss at 6 months compared with standard balloon angioplasty in a randomized study of 101 patients with femoropopliteal disease.

Tthe LEVANT I study randomized1patients to angioplasty – with or without stenting – using a regular angioplasty balloon catheter or the Moxy (Lutonix) paclitaxel-coated balloon catheter.

Six-month late lumen loss, the primary end point, was 0.46 mm in the paclitaxel-coated balloon group and 1.09 in the traditional angioplasty group, a statistically significant difference, reported Dr. Dierk Scheinert of the Heart Center Leipzig/Park Hospital, Germany.

Late lumen loss was reduced with the paclitaxel-coated balloon catheter in both the stented and nonstented patients. There also was a trend toward lower target lesion revascularization among patients who received treatment with the Moxy balloon catheter.

The paclitaxel-coated balloon catheter appears to have a “strong biologic effect … on the inhibition of neointimal hyperplasia,” Dr. Scheinert said at the meeting, sponsored by the Cardiovascular Research Foundation.

The study suggests that a shorter duration of antiplatelet therapy is feasible in the peripheral vasculature when such treatment is employed, he noted. Patients who were not stented were prescribed 1 month of a dual-antiplatelet regimen. Those who were stented were prescribed 3 months of the regimen.

The Moxy device is designed so that paclitaxel is retained during transit of the balloon catheter and is delivered during the 30- to 60-second inflation time. A larger and longer prospective randomized trial to look at primary patency of the target lesion and various clinical end points – LEVANT II – was pending approval, Dr. Scheinert said.

The trial was sponsored by Lutonix Inc., maker of the Moxy catheter. Dr. Scheinert had no disclosures.

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons that are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

Last month, after Dr. Edwards' wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF, committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Prof. Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced a succession of developments that improved the success rates of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis in 1990 and the development of intracytoplasmic sperm injection in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren't able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

In comments made after the Nobel Prize announcement, Prof. Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world's master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nat. Med. 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown's birth. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va. By the end of 1983, 150 IVF babies had been born worldwide. Through continual improvements in clinical IVF, the number of live births worldwide soared, to 1 million in 2000.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF skyrocketed. Reproductive specialty organizations set standards for maximal embryo transfers. The efforts have paid off in terms of triplet and higher-order multiple births, but twin pregnancies continue to rise.

Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City.

To resolve this dilemma, many in the field are pinning their hopes on embryo selection – finding the healthiest, most viable embryos, those most likely to implant. “Without question,” said Dr. Rosenwaks, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Robert G. Edwards in 1998 with 'test-tube babies' Jack and Sophie Emery.

Source ©AP Photo/Alastair Grant