Obstetrics

MINNEAPOLIS – Prenatal exposure to traffic-related toxins may increase the risk for Wilms tumor, the most common form of childhood kidney cancer, the results of a study suggest.

Furthermore, findings suggest that different toxins may be potent at different pregnancy periods, Anshu Shrestha reported in a poster presentation at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The main culprits – formaldehyde, lead, and chromium VI – all have been shown to increase the risk of kidney cancer in adults, but little is known about their relationship to childhood renal cancers.

Wilms tumor occurs in 1 in 200,000-250,000 children, typically striking at about 3 years and rarely developing after age 8 years. The cure rate is about 90%, if the tumor has not metastasized.

The population-based, case-control study included 84 children in the California Cancer Registry who were aged 5 years and younger at the time of diagnosis with Wilms tumor, and 25,222 controls who were randomly selected from a birth registry and matched by birth year. Cases and controls lived within a 5-mile radius of a California Air Resources Board monitoring site, which measures 24-hour averages of air toxic concentrations every 12 days. Trimester-specific averages were calculated for 20 air toxins that were selected for carcinogenic property and sufficient sample size. Logistic regression analysis was adjusted for birth year, maternal age, maternal race/ethnicity and census-based socioeconomic status.

Third-trimester exposure to formaldehyde increased the risk of Wilms tumor by nearly 1.5-fold (odds ratio, 1.43), said Ms. Shrestha, an epidemiology doctoral student at the school of public health, University of California, Los Angeles.

Exposure to chromium VI in the first trimester and to lead in the second trimester also increased the odds of Wilms tumor, although to a lesser degree (OR, 1.10 and 1.27).

Positive associations were suggested for first-trimester exposure to lead, selenium, and benzene, but not for 1,3-butadiene, styrene, and ortho-dichlorobenzene.

Ms. Shrestha said that the data are preliminary and require more work to confirm that they are not due to chance alone.

Nearly half (47.6%) of the cases were Hispanic, 52.4% lived at the two lowest socioeconomic levels, and 55% had mothers aged 20-29 years at the time of their birth. Only 10.7% of cases lived at the highest socioeconomic level (defined by a combination of seven census indicators, including education and median household income).

The study was supported by grants from the National Institute of Environmental Health Sciences. Ms. Shrestha did not provide conflict of interest information.

MINNEAPOLIS – Prenatal exposure to traffic-related toxins may increase the risk for Wilms tumor, the most common form of childhood kidney cancer, the results of a study suggest.

Furthermore, findings suggest that different toxins may be potent at different pregnancy periods, Anshu Shrestha reported in a poster presentation at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The main culprits – formaldehyde, lead, and chromium VI – all have been shown to increase the risk of kidney cancer in adults, but little is known about their relationship to childhood renal cancers.

Wilms tumor occurs in 1 in 200,000-250,000 children, typically striking at about 3 years and rarely developing after age 8 years. The cure rate is about 90%, if the tumor has not metastasized.

The population-based, case-control study included 84 children in the California Cancer Registry who were aged 5 years and younger at the time of diagnosis with Wilms tumor, and 25,222 controls who were randomly selected from a birth registry and matched by birth year. Cases and controls lived within a 5-mile radius of a California Air Resources Board monitoring site, which measures 24-hour averages of air toxic concentrations every 12 days. Trimester-specific averages were calculated for 20 air toxins that were selected for carcinogenic property and sufficient sample size. Logistic regression analysis was adjusted for birth year, maternal age, maternal race/ethnicity and census-based socioeconomic status.

Third-trimester exposure to formaldehyde increased the risk of Wilms tumor by nearly 1.5-fold (odds ratio, 1.43), said Ms. Shrestha, an epidemiology doctoral student at the school of public health, University of California, Los Angeles.

Exposure to chromium VI in the first trimester and to lead in the second trimester also increased the odds of Wilms tumor, although to a lesser degree (OR, 1.10 and 1.27).

Positive associations were suggested for first-trimester exposure to lead, selenium, and benzene, but not for 1,3-butadiene, styrene, and ortho-dichlorobenzene.

Ms. Shrestha said that the data are preliminary and require more work to confirm that they are not due to chance alone.

Nearly half (47.6%) of the cases were Hispanic, 52.4% lived at the two lowest socioeconomic levels, and 55% had mothers aged 20-29 years at the time of their birth. Only 10.7% of cases lived at the highest socioeconomic level (defined by a combination of seven census indicators, including education and median household income).

The study was supported by grants from the National Institute of Environmental Health Sciences. Ms. Shrestha did not provide conflict of interest information.

MINNEAPOLIS – Prenatal exposure to traffic-related toxins may increase the risk for Wilms tumor, the most common form of childhood kidney cancer, the results of a study suggest.

Furthermore, findings suggest that different toxins may be potent at different pregnancy periods, Anshu Shrestha reported in a poster presentation at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The main culprits – formaldehyde, lead, and chromium VI – all have been shown to increase the risk of kidney cancer in adults, but little is known about their relationship to childhood renal cancers.

Wilms tumor occurs in 1 in 200,000-250,000 children, typically striking at about 3 years and rarely developing after age 8 years. The cure rate is about 90%, if the tumor has not metastasized.

The population-based, case-control study included 84 children in the California Cancer Registry who were aged 5 years and younger at the time of diagnosis with Wilms tumor, and 25,222 controls who were randomly selected from a birth registry and matched by birth year. Cases and controls lived within a 5-mile radius of a California Air Resources Board monitoring site, which measures 24-hour averages of air toxic concentrations every 12 days. Trimester-specific averages were calculated for 20 air toxins that were selected for carcinogenic property and sufficient sample size. Logistic regression analysis was adjusted for birth year, maternal age, maternal race/ethnicity and census-based socioeconomic status.

Third-trimester exposure to formaldehyde increased the risk of Wilms tumor by nearly 1.5-fold (odds ratio, 1.43), said Ms. Shrestha, an epidemiology doctoral student at the school of public health, University of California, Los Angeles.

Exposure to chromium VI in the first trimester and to lead in the second trimester also increased the odds of Wilms tumor, although to a lesser degree (OR, 1.10 and 1.27).

Positive associations were suggested for first-trimester exposure to lead, selenium, and benzene, but not for 1,3-butadiene, styrene, and ortho-dichlorobenzene.

Ms. Shrestha said that the data are preliminary and require more work to confirm that they are not due to chance alone.

Nearly half (47.6%) of the cases were Hispanic, 52.4% lived at the two lowest socioeconomic levels, and 55% had mothers aged 20-29 years at the time of their birth. Only 10.7% of cases lived at the highest socioeconomic level (defined by a combination of seven census indicators, including education and median household income).

The study was supported by grants from the National Institute of Environmental Health Sciences. Ms. Shrestha did not provide conflict of interest information.

The current pertussis epidemic in Washington state and increased rates nationwide underline the critical importance of vaccinating pregnant women and other adults who are in contact with babies against pertussis, Dr. Anne Schuchat said during a Centers for Disease Control and Prevention telebriefing.

Reports of pertussis have been increasing in infants, as well as among children aged 10, 13, and 14 years in Washington and nationwide, making the recommended booster for children with the Tdap vaccine essential, said Dr. Schuchat, director of the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta.

Pertussis vaccination "remains the single most effective approach to preventing infection," she said, noting that unvaccinated children are at an eightfold greater risk of getting pertussis than those who have been fully vaccinated with DTaP. And vaccinated children who do contract pertussis typically have milder cases.

©CDC

In 2010, only 8% of adults had any history of having received a Tdap booster, she said.

In addition to encouraging patients to get the vaccine, clinicians also are being urged to consider pertussis as a possible diagnosis in their patients who have a persistent cough, she said.

Since the middle of 2011, cases of pertussis have been increasing in Washington state, and in April 2012, a pertussis epidemic was declared when 640 cases had been reported. As of June 16, 2,520 cases had been reported in 2012, a 1,300% increase from the same time period the year before, and the highest number of cases reported since the early 1940s (MMWR 2012;61:517-22).

To date, nine babies in the United States have died of whooping cough (one more than reported in the MMWR), Dr. Schuchat reported.

A higher-than-expected number of cases also have been reported in other states, with similar trends in the age groups affected, "and there may be many more coming," Dr. Schuchat said. In 2010, more than 27,000 cases were reported nationally, with 27 deaths (25 in infants).

Pertussis outbreaks occur in waves, with peaks every 3-5 years. During this current wave, the highest rates have been in infants under 1 year of age, with over half in babies under 3 months. These children are too young to be protected with the vaccine that is first administered at age 2 months, so they are dependent on the immunity of people around them, which is why pregnant women and adults who are around babies are being urged to get vaccinated, she said.

The rates of pertussis have started to increase after late childhood, with a higher rate in 10-year-olds, but then the rate decreases in 11- to 12-year-olds, and then increases among 13-year-olds, Dr. Schuchat said. These trends also point to the importance of the recommended Tdap vaccine in those aged 11 and 12 years .

The increase in pertussis cases reported in adolescents aged 13-14 in Washington state and nationally is a concern, and possible causes are being studied further. A contributing factor could be the switch from the whole cell to the acellular vaccine, which may have an effect on how long immunity persists. "Waning of protection over time may be part of the story," she said, pointing out that unvaccinated people are not thought to be driving this current wave of infection.

Dr. Schuchat said that the increase in pertussis cases goes beyond Washington State. "We really think the disease is spreading around the country. ...We’re in for a tough year and a tough couple of years."

The current pertussis epidemic in Washington state and increased rates nationwide underline the critical importance of vaccinating pregnant women and other adults who are in contact with babies against pertussis, Dr. Anne Schuchat said during a Centers for Disease Control and Prevention telebriefing.

Reports of pertussis have been increasing in infants, as well as among children aged 10, 13, and 14 years in Washington and nationwide, making the recommended booster for children with the Tdap vaccine essential, said Dr. Schuchat, director of the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta.

Pertussis vaccination "remains the single most effective approach to preventing infection," she said, noting that unvaccinated children are at an eightfold greater risk of getting pertussis than those who have been fully vaccinated with DTaP. And vaccinated children who do contract pertussis typically have milder cases.

©CDC

In 2010, only 8% of adults had any history of having received a Tdap booster, she said.

In addition to encouraging patients to get the vaccine, clinicians also are being urged to consider pertussis as a possible diagnosis in their patients who have a persistent cough, she said.

Since the middle of 2011, cases of pertussis have been increasing in Washington state, and in April 2012, a pertussis epidemic was declared when 640 cases had been reported. As of June 16, 2,520 cases had been reported in 2012, a 1,300% increase from the same time period the year before, and the highest number of cases reported since the early 1940s (MMWR 2012;61:517-22).

To date, nine babies in the United States have died of whooping cough (one more than reported in the MMWR), Dr. Schuchat reported.

A higher-than-expected number of cases also have been reported in other states, with similar trends in the age groups affected, "and there may be many more coming," Dr. Schuchat said. In 2010, more than 27,000 cases were reported nationally, with 27 deaths (25 in infants).

Pertussis outbreaks occur in waves, with peaks every 3-5 years. During this current wave, the highest rates have been in infants under 1 year of age, with over half in babies under 3 months. These children are too young to be protected with the vaccine that is first administered at age 2 months, so they are dependent on the immunity of people around them, which is why pregnant women and adults who are around babies are being urged to get vaccinated, she said.

The rates of pertussis have started to increase after late childhood, with a higher rate in 10-year-olds, but then the rate decreases in 11- to 12-year-olds, and then increases among 13-year-olds, Dr. Schuchat said. These trends also point to the importance of the recommended Tdap vaccine in those aged 11 and 12 years .

The increase in pertussis cases reported in adolescents aged 13-14 in Washington state and nationally is a concern, and possible causes are being studied further. A contributing factor could be the switch from the whole cell to the acellular vaccine, which may have an effect on how long immunity persists. "Waning of protection over time may be part of the story," she said, pointing out that unvaccinated people are not thought to be driving this current wave of infection.

Dr. Schuchat said that the increase in pertussis cases goes beyond Washington State. "We really think the disease is spreading around the country. ...We’re in for a tough year and a tough couple of years."

The current pertussis epidemic in Washington state and increased rates nationwide underline the critical importance of vaccinating pregnant women and other adults who are in contact with babies against pertussis, Dr. Anne Schuchat said during a Centers for Disease Control and Prevention telebriefing.

Reports of pertussis have been increasing in infants, as well as among children aged 10, 13, and 14 years in Washington and nationwide, making the recommended booster for children with the Tdap vaccine essential, said Dr. Schuchat, director of the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta.

Pertussis vaccination "remains the single most effective approach to preventing infection," she said, noting that unvaccinated children are at an eightfold greater risk of getting pertussis than those who have been fully vaccinated with DTaP. And vaccinated children who do contract pertussis typically have milder cases.

©CDC

In 2010, only 8% of adults had any history of having received a Tdap booster, she said.

In addition to encouraging patients to get the vaccine, clinicians also are being urged to consider pertussis as a possible diagnosis in their patients who have a persistent cough, she said.

Since the middle of 2011, cases of pertussis have been increasing in Washington state, and in April 2012, a pertussis epidemic was declared when 640 cases had been reported. As of June 16, 2,520 cases had been reported in 2012, a 1,300% increase from the same time period the year before, and the highest number of cases reported since the early 1940s (MMWR 2012;61:517-22).

To date, nine babies in the United States have died of whooping cough (one more than reported in the MMWR), Dr. Schuchat reported.

A higher-than-expected number of cases also have been reported in other states, with similar trends in the age groups affected, "and there may be many more coming," Dr. Schuchat said. In 2010, more than 27,000 cases were reported nationally, with 27 deaths (25 in infants).

Pertussis outbreaks occur in waves, with peaks every 3-5 years. During this current wave, the highest rates have been in infants under 1 year of age, with over half in babies under 3 months. These children are too young to be protected with the vaccine that is first administered at age 2 months, so they are dependent on the immunity of people around them, which is why pregnant women and adults who are around babies are being urged to get vaccinated, she said.

The rates of pertussis have started to increase after late childhood, with a higher rate in 10-year-olds, but then the rate decreases in 11- to 12-year-olds, and then increases among 13-year-olds, Dr. Schuchat said. These trends also point to the importance of the recommended Tdap vaccine in those aged 11 and 12 years .

The increase in pertussis cases reported in adolescents aged 13-14 in Washington state and nationally is a concern, and possible causes are being studied further. A contributing factor could be the switch from the whole cell to the acellular vaccine, which may have an effect on how long immunity persists. "Waning of protection over time may be part of the story," she said, pointing out that unvaccinated people are not thought to be driving this current wave of infection.

Dr. Schuchat said that the increase in pertussis cases goes beyond Washington State. "We really think the disease is spreading around the country. ...We’re in for a tough year and a tough couple of years."

HOUSTON – The U.S. Environmental Protection Agency and other groups that evaluate chemicals need to assess endocrine-disrupting chemicals during critical life periods and strengthen screening programs to identify such chemicals, according to recommendations from the Endocrine Society.

"We believe now that the science behind endocrine-disrupting chemicals [EDCs] is incredibly strong," said Andrea C. Gore, Ph.D., professor of pharmacology and toxicology at the University of Texas, Austin. "The current regulatory process is not up to the standards that endocrinologists would use in their own labs," added Dr. Gore, one of the authors of a statement from the society.

For those reasons, the society released a set of principles calling for acknowledgement that changes in hormone action from EDC exposure during development are not correctable, and that they permanently and adversely affect cognitive function and other aspects of health. In addition, the newly released principles call for an acknowledgement that people are exposed to multiple EDCs in daily life, and that these exposures can have a cumulative effect.

Sherry Boschert/IMNG Medical Media

The Endocrine Society also recommended a simplified definition of endocrine-disrupting chemicals in light of mounting evidence of potential harm from exposure to them. By that definition, an EDC would be defined as an exogenous chemical (or mixture of chemicals) that interferes with any aspect of hormone action, Dr. Gore said at the annual meeting of the Endocrine Society.

The ability of a chemical to interfere with any aspect of hormone action is a clear predictor of adverse outcomes if a person is exposed during critical periods or developmental processes, said Dr. Gore.

Furthermore, "low-dose testing is absolutely critical," she said. "There is no safe dose, studies suggest."

The society released the statement of principles online in advance of publication in the journal Endocrinology (2012 June 25 [doi:10.1210/en.2012-1422]). The document updates the society’s first scientific statement about EDCs in 2009 (Endocrine Reviews 30:293-342).

A Look at the Data

Studies presented at the society’s annual meeting – along with hundreds of others in the last few years – prompted the new definition and principles.

In the first study presented at the meeting, children with higher levels of the EDC di(2-ethylhexyl) phthalate (DEHP) were more likely to be obese. In addition, serum levels of DEHP were associated with weight in a dose-dependent fashion, according to findings from the prospective study of 204 Korean schoolchildren, aged 6-13 years, including 105 obese children and 99 nonobese controls, Dr. Mi Jung Park reported at a press briefing.

Compared with the lowest quartile of serum DEHP, the risk of obesity increased by 25% in the second quartile, nearly quadrupled in the third quartile, and increased fivefold in the highest quartile after adjustment for the effects of age, sex, physical activity, household income, and daily caloric intake.

Mean serum DEHP levels were 107 ng/mL, significantly higher than the mean of 54 ng/mL in control children, said Dr. Park, a pediatric endocrinologist at Sanggye Paik Hospital in Seoul, Korea.

Serum DEHP levels showed significant positive correlations with body mass index, serum ALT, body fat mass, and uric acid levels, but did not correlate significantly with HDL cholesterol level, triglycerides, fasting blood sugar level, or fasting insulin level.

The worldwide epidemic in obesity over the past 40 years cannot be fully explained by overeating and inactivity and parallels increased use of chemicals in our societies, Dr. Park said. She called for prospective studies to determine whether DEHP exposure is a cause of childhood obesity.

Animal In Utero Studies

In the second study, eight pregnant mice exposed to the ubiquitous EDC bisphenol A (BPA) demonstrated "major and permanent changes in gene expression" in female offspring that became apparent only when they were exposed to estrogen through puberty or estrogen treatment, Dr. Hugh S. Taylor reported at the briefing.

"It seems the BPA exposure in utero was programming their response to estrogen later in life" by permanently altering the expression of more than 400 genes, said Dr. Taylor, professor of ob.gyn. and reproductive sciences and chief of reproductive endocrinology and infertility at Yale University, New Haven, Conn.

The changes may help explain the increased incidence of estrogen-related disorders seen after exposure to EDCs, he said.

Pregnant women should minimize their exposure to BPA, and their physicians should advise them on this, he added. "I think it’s something that we don’t do enough of right now as obstetricians or pediatricians. ... It’s important that all obstetricians be educated in endocrine disruptors. It’s not part of any formal medical school curriculum or obstetrics and gynecology training program," but should be, he said.

A third study randomized 23 pregnant rats to low levels of a mix of polychlorinated biphenyls (PCBs) and 22 to an inactive substance. Researchers found that these EDCs disrupted five genes that are critical to the normal hypothalamic control of reproduction. Compared with the control group, the EDC group showed delayed puberty in male offspring and disrupted reproductive cycles in adult female offspring.

The data collectively suggest that determinations of the potential risks or safety of any EDCs should be particular to specific age groups, Dr. Park said.

The EDCs identified so far are just the tip of the iceberg, she added. "Many more chemicals will be found" to be EDCs, she predicted.

Many products contain EDCs. Phthalates are part of some vinyl floor tiles, toys, blood transfusion bags, medical tubing, perfumes, lotions, cosmetics, air fresheners, laundry products, and more. BPA is found in many hard plastic bottles, cash register receipts, and the epoxy resin that lines canned goods. PCBs had been used in plastics, floor finishes, and electrical equipment before being banned in 1979 but are still present in air, water, and soil.

Tools for Clinicians

Dr. Gore and Dr. Taylor recommended these resources for clinicians who are wondering what and how to advise patients about EDCs in their environment:

• The Collaborative on Health and the Environment.

• Environment and Human Health.

Some other resources are available from the University of California's program on reproductive health and the environment.

The speakers reported having no relevant financial disclosures.

HOUSTON – The U.S. Environmental Protection Agency and other groups that evaluate chemicals need to assess endocrine-disrupting chemicals during critical life periods and strengthen screening programs to identify such chemicals, according to recommendations from the Endocrine Society.

"We believe now that the science behind endocrine-disrupting chemicals [EDCs] is incredibly strong," said Andrea C. Gore, Ph.D., professor of pharmacology and toxicology at the University of Texas, Austin. "The current regulatory process is not up to the standards that endocrinologists would use in their own labs," added Dr. Gore, one of the authors of a statement from the society.

For those reasons, the society released a set of principles calling for acknowledgement that changes in hormone action from EDC exposure during development are not correctable, and that they permanently and adversely affect cognitive function and other aspects of health. In addition, the newly released principles call for an acknowledgement that people are exposed to multiple EDCs in daily life, and that these exposures can have a cumulative effect.

Sherry Boschert/IMNG Medical Media

The Endocrine Society also recommended a simplified definition of endocrine-disrupting chemicals in light of mounting evidence of potential harm from exposure to them. By that definition, an EDC would be defined as an exogenous chemical (or mixture of chemicals) that interferes with any aspect of hormone action, Dr. Gore said at the annual meeting of the Endocrine Society.

The ability of a chemical to interfere with any aspect of hormone action is a clear predictor of adverse outcomes if a person is exposed during critical periods or developmental processes, said Dr. Gore.

Furthermore, "low-dose testing is absolutely critical," she said. "There is no safe dose, studies suggest."

The society released the statement of principles online in advance of publication in the journal Endocrinology (2012 June 25 [doi:10.1210/en.2012-1422]). The document updates the society’s first scientific statement about EDCs in 2009 (Endocrine Reviews 30:293-342).

A Look at the Data

Studies presented at the society’s annual meeting – along with hundreds of others in the last few years – prompted the new definition and principles.

In the first study presented at the meeting, children with higher levels of the EDC di(2-ethylhexyl) phthalate (DEHP) were more likely to be obese. In addition, serum levels of DEHP were associated with weight in a dose-dependent fashion, according to findings from the prospective study of 204 Korean schoolchildren, aged 6-13 years, including 105 obese children and 99 nonobese controls, Dr. Mi Jung Park reported at a press briefing.

Compared with the lowest quartile of serum DEHP, the risk of obesity increased by 25% in the second quartile, nearly quadrupled in the third quartile, and increased fivefold in the highest quartile after adjustment for the effects of age, sex, physical activity, household income, and daily caloric intake.

Mean serum DEHP levels were 107 ng/mL, significantly higher than the mean of 54 ng/mL in control children, said Dr. Park, a pediatric endocrinologist at Sanggye Paik Hospital in Seoul, Korea.

Serum DEHP levels showed significant positive correlations with body mass index, serum ALT, body fat mass, and uric acid levels, but did not correlate significantly with HDL cholesterol level, triglycerides, fasting blood sugar level, or fasting insulin level.

The worldwide epidemic in obesity over the past 40 years cannot be fully explained by overeating and inactivity and parallels increased use of chemicals in our societies, Dr. Park said. She called for prospective studies to determine whether DEHP exposure is a cause of childhood obesity.

Animal In Utero Studies

In the second study, eight pregnant mice exposed to the ubiquitous EDC bisphenol A (BPA) demonstrated "major and permanent changes in gene expression" in female offspring that became apparent only when they were exposed to estrogen through puberty or estrogen treatment, Dr. Hugh S. Taylor reported at the briefing.

"It seems the BPA exposure in utero was programming their response to estrogen later in life" by permanently altering the expression of more than 400 genes, said Dr. Taylor, professor of ob.gyn. and reproductive sciences and chief of reproductive endocrinology and infertility at Yale University, New Haven, Conn.

The changes may help explain the increased incidence of estrogen-related disorders seen after exposure to EDCs, he said.

Pregnant women should minimize their exposure to BPA, and their physicians should advise them on this, he added. "I think it’s something that we don’t do enough of right now as obstetricians or pediatricians. ... It’s important that all obstetricians be educated in endocrine disruptors. It’s not part of any formal medical school curriculum or obstetrics and gynecology training program," but should be, he said.

A third study randomized 23 pregnant rats to low levels of a mix of polychlorinated biphenyls (PCBs) and 22 to an inactive substance. Researchers found that these EDCs disrupted five genes that are critical to the normal hypothalamic control of reproduction. Compared with the control group, the EDC group showed delayed puberty in male offspring and disrupted reproductive cycles in adult female offspring.

The data collectively suggest that determinations of the potential risks or safety of any EDCs should be particular to specific age groups, Dr. Park said.

The EDCs identified so far are just the tip of the iceberg, she added. "Many more chemicals will be found" to be EDCs, she predicted.

Many products contain EDCs. Phthalates are part of some vinyl floor tiles, toys, blood transfusion bags, medical tubing, perfumes, lotions, cosmetics, air fresheners, laundry products, and more. BPA is found in many hard plastic bottles, cash register receipts, and the epoxy resin that lines canned goods. PCBs had been used in plastics, floor finishes, and electrical equipment before being banned in 1979 but are still present in air, water, and soil.

Tools for Clinicians

Dr. Gore and Dr. Taylor recommended these resources for clinicians who are wondering what and how to advise patients about EDCs in their environment:

• The Collaborative on Health and the Environment.

• Environment and Human Health.

Some other resources are available from the University of California's program on reproductive health and the environment.

The speakers reported having no relevant financial disclosures.

HOUSTON – The U.S. Environmental Protection Agency and other groups that evaluate chemicals need to assess endocrine-disrupting chemicals during critical life periods and strengthen screening programs to identify such chemicals, according to recommendations from the Endocrine Society.

"We believe now that the science behind endocrine-disrupting chemicals [EDCs] is incredibly strong," said Andrea C. Gore, Ph.D., professor of pharmacology and toxicology at the University of Texas, Austin. "The current regulatory process is not up to the standards that endocrinologists would use in their own labs," added Dr. Gore, one of the authors of a statement from the society.

For those reasons, the society released a set of principles calling for acknowledgement that changes in hormone action from EDC exposure during development are not correctable, and that they permanently and adversely affect cognitive function and other aspects of health. In addition, the newly released principles call for an acknowledgement that people are exposed to multiple EDCs in daily life, and that these exposures can have a cumulative effect.

Sherry Boschert/IMNG Medical Media

The Endocrine Society also recommended a simplified definition of endocrine-disrupting chemicals in light of mounting evidence of potential harm from exposure to them. By that definition, an EDC would be defined as an exogenous chemical (or mixture of chemicals) that interferes with any aspect of hormone action, Dr. Gore said at the annual meeting of the Endocrine Society.

The ability of a chemical to interfere with any aspect of hormone action is a clear predictor of adverse outcomes if a person is exposed during critical periods or developmental processes, said Dr. Gore.

Furthermore, "low-dose testing is absolutely critical," she said. "There is no safe dose, studies suggest."

The society released the statement of principles online in advance of publication in the journal Endocrinology (2012 June 25 [doi:10.1210/en.2012-1422]). The document updates the society’s first scientific statement about EDCs in 2009 (Endocrine Reviews 30:293-342).

A Look at the Data

Studies presented at the society’s annual meeting – along with hundreds of others in the last few years – prompted the new definition and principles.

In the first study presented at the meeting, children with higher levels of the EDC di(2-ethylhexyl) phthalate (DEHP) were more likely to be obese. In addition, serum levels of DEHP were associated with weight in a dose-dependent fashion, according to findings from the prospective study of 204 Korean schoolchildren, aged 6-13 years, including 105 obese children and 99 nonobese controls, Dr. Mi Jung Park reported at a press briefing.

Compared with the lowest quartile of serum DEHP, the risk of obesity increased by 25% in the second quartile, nearly quadrupled in the third quartile, and increased fivefold in the highest quartile after adjustment for the effects of age, sex, physical activity, household income, and daily caloric intake.

Mean serum DEHP levels were 107 ng/mL, significantly higher than the mean of 54 ng/mL in control children, said Dr. Park, a pediatric endocrinologist at Sanggye Paik Hospital in Seoul, Korea.

Serum DEHP levels showed significant positive correlations with body mass index, serum ALT, body fat mass, and uric acid levels, but did not correlate significantly with HDL cholesterol level, triglycerides, fasting blood sugar level, or fasting insulin level.

The worldwide epidemic in obesity over the past 40 years cannot be fully explained by overeating and inactivity and parallels increased use of chemicals in our societies, Dr. Park said. She called for prospective studies to determine whether DEHP exposure is a cause of childhood obesity.

Animal In Utero Studies

In the second study, eight pregnant mice exposed to the ubiquitous EDC bisphenol A (BPA) demonstrated "major and permanent changes in gene expression" in female offspring that became apparent only when they were exposed to estrogen through puberty or estrogen treatment, Dr. Hugh S. Taylor reported at the briefing.

"It seems the BPA exposure in utero was programming their response to estrogen later in life" by permanently altering the expression of more than 400 genes, said Dr. Taylor, professor of ob.gyn. and reproductive sciences and chief of reproductive endocrinology and infertility at Yale University, New Haven, Conn.

The changes may help explain the increased incidence of estrogen-related disorders seen after exposure to EDCs, he said.

Pregnant women should minimize their exposure to BPA, and their physicians should advise them on this, he added. "I think it’s something that we don’t do enough of right now as obstetricians or pediatricians. ... It’s important that all obstetricians be educated in endocrine disruptors. It’s not part of any formal medical school curriculum or obstetrics and gynecology training program," but should be, he said.

A third study randomized 23 pregnant rats to low levels of a mix of polychlorinated biphenyls (PCBs) and 22 to an inactive substance. Researchers found that these EDCs disrupted five genes that are critical to the normal hypothalamic control of reproduction. Compared with the control group, the EDC group showed delayed puberty in male offspring and disrupted reproductive cycles in adult female offspring.

The data collectively suggest that determinations of the potential risks or safety of any EDCs should be particular to specific age groups, Dr. Park said.

The EDCs identified so far are just the tip of the iceberg, she added. "Many more chemicals will be found" to be EDCs, she predicted.

Many products contain EDCs. Phthalates are part of some vinyl floor tiles, toys, blood transfusion bags, medical tubing, perfumes, lotions, cosmetics, air fresheners, laundry products, and more. BPA is found in many hard plastic bottles, cash register receipts, and the epoxy resin that lines canned goods. PCBs had been used in plastics, floor finishes, and electrical equipment before being banned in 1979 but are still present in air, water, and soil.

Tools for Clinicians

Dr. Gore and Dr. Taylor recommended these resources for clinicians who are wondering what and how to advise patients about EDCs in their environment:

• The Collaborative on Health and the Environment.

• Environment and Human Health.

Some other resources are available from the University of California's program on reproductive health and the environment.

The speakers reported having no relevant financial disclosures.

BALTIMORE – Starting treatment with a combination of doxylamine and pyridoxine before the onset of nausea and vomiting significantly reduced the incidence of severe nausea and vomiting of pregnancy, compared with starting treatment at the first sign of symptoms, in a study of 59 women with a history of severe nausea and vomiting of pregnancy, Caroline Maltepe reported.

In the prospective, randomized, open-label study of women with a history of nausea and vomiting of pregnancy (NVP), 30 women began taking the delayed-release combination of 10 mg of doxylamine and 10 mg of pyridoxine (vitamin B₆) as soon as they learned they were pregnant, before they started to experience nausea and vomiting (at a mean of 4 weeks’ gestation). Another 29 pregnant women started taking the combination when they started to experience symptoms, Ms. Maltepe said at the annual meeting of the Teratology Society.

Women in both groups started to experience NVP symptoms at a mean of about 5 to almost 6 weeks, said Ms. Maltepe, the lead author of the study, who is with the Motherisk Program at the Hospital for Sick Children in Toronto. The program conducts research and provides information about the safety of maternal exposure to drugs, chemicals, diseases, radiation, and environmental agents to the developing fetus or infant.

The women (mean age, 31-32 years) had experienced severe NVP or hyperemesis gravidarum (HG) in their previous pregnancy, and enrolled when they were planning a pregnancy or in early pregnancy at a point when they had not yet experienced any symptoms. Women in both groups took 2-9 tablets of the doxylamine-pyridoxine combination a day, and received counseling and follow-up calls.

In Canada, the combination is approved and marketed as Diclectin, by Duchesnay, and is the only drug labeled for treating NVP in Canada. There it is considered a first-line treatment and is taken at a standard dose of four tablets a day, said Ms. Maltepe, the coordinator of the NVP helpline at Motherisk.

Diclectin is a generic form of the drug Bendectin, which was marketed in the United States until 1983, when it was voluntarily withdrawn by its manufacturer, Merrell Dow Pharmaceuticals, after a series of lawsuits claiming it caused birth defects. For several years, Duchesnay has been working toward Food and Drug Administration clearance to market Diclectin in the United States, but it would be premature to predict when it would become available in the United States, a spokesman for the company said.

In the study, symptoms were evaluated using the PUQE (Pregnancy–Unique Quantification of Emesis and Nausea) score, a validated scoring system that takes into account the frequency of vomiting; the frequency of retching, gagging, or dry heaves; and the number of hours spent feeling nauseous over a 24-hour period. The score was developed by Dr. Gideon Koren, director of Motherisk and coauthor of this study, and his associates. A score of 7-12 is considered moderate; a score of 13 or higher is considered severe.

In the study, preemptive treatment was associated with 70% fewer cases of moderate to severe NVP during the first 3 weeks women experienced symptoms: 4 of the 26 (15%) evaluable women had a PUQE score of 11 or more during the first 3 weeks of NVP symptoms, compared with 9 of the 23 (39%) evaluable women in the control group, a significant difference. Of the 19 women in the preemptively treated group who had HG during the previous pregnancy, 6 (32%) experienced HG, compared with 6 of the 11 (55%) in the control group, also a significant difference. Some women who enrolled were not evaluable for reasons that included having a miscarriage.

NVP resolved before labor in significantly more of the women in the preemptively treated group than in the control group (almost 80% vs. about 50%), and there was a negative correlation between PUQE scores and a well-being score, indicating that treatment is associated with improved quality of life for these patients, Ms. Maltepe said.

In women who have experienced severe NVP or HG in a previous pregnancy, preemptive treatment with doxylamine-pyridoxine events can reduce the recurrence of NVP in subsequent pregnancies, and improve their quality of life during pregnancy, as well as reduce time off from work and the need for enteral and parenteral therapy, hospitalization, and other costs associated with severe NVP, she concluded.

The NVP helpline at Motherisk is the only dedicated NVP helpline in the world, according to Ms. Maltepe, who provides evidence-based recommendations on pharmaceutical and nonpharmaceutical approaches to treating NVP for pregnant women, their family members, and clinicians via the helpline (800-436-8477 in North America).

The study was funded by Duchesnay. Ms. Maltepe and her coauthors said they had no relevant conflict of interest to disclose.

The Motherisk site is available at www.motherisk.org/women/index.jsp.

BALTIMORE – Starting treatment with a combination of doxylamine and pyridoxine before the onset of nausea and vomiting significantly reduced the incidence of severe nausea and vomiting of pregnancy, compared with starting treatment at the first sign of symptoms, in a study of 59 women with a history of severe nausea and vomiting of pregnancy, Caroline Maltepe reported.

In the prospective, randomized, open-label study of women with a history of nausea and vomiting of pregnancy (NVP), 30 women began taking the delayed-release combination of 10 mg of doxylamine and 10 mg of pyridoxine (vitamin B₆) as soon as they learned they were pregnant, before they started to experience nausea and vomiting (at a mean of 4 weeks’ gestation). Another 29 pregnant women started taking the combination when they started to experience symptoms, Ms. Maltepe said at the annual meeting of the Teratology Society.

Women in both groups started to experience NVP symptoms at a mean of about 5 to almost 6 weeks, said Ms. Maltepe, the lead author of the study, who is with the Motherisk Program at the Hospital for Sick Children in Toronto. The program conducts research and provides information about the safety of maternal exposure to drugs, chemicals, diseases, radiation, and environmental agents to the developing fetus or infant.

The women (mean age, 31-32 years) had experienced severe NVP or hyperemesis gravidarum (HG) in their previous pregnancy, and enrolled when they were planning a pregnancy or in early pregnancy at a point when they had not yet experienced any symptoms. Women in both groups took 2-9 tablets of the doxylamine-pyridoxine combination a day, and received counseling and follow-up calls.

In Canada, the combination is approved and marketed as Diclectin, by Duchesnay, and is the only drug labeled for treating NVP in Canada. There it is considered a first-line treatment and is taken at a standard dose of four tablets a day, said Ms. Maltepe, the coordinator of the NVP helpline at Motherisk.

Diclectin is a generic form of the drug Bendectin, which was marketed in the United States until 1983, when it was voluntarily withdrawn by its manufacturer, Merrell Dow Pharmaceuticals, after a series of lawsuits claiming it caused birth defects. For several years, Duchesnay has been working toward Food and Drug Administration clearance to market Diclectin in the United States, but it would be premature to predict when it would become available in the United States, a spokesman for the company said.

In the study, symptoms were evaluated using the PUQE (Pregnancy–Unique Quantification of Emesis and Nausea) score, a validated scoring system that takes into account the frequency of vomiting; the frequency of retching, gagging, or dry heaves; and the number of hours spent feeling nauseous over a 24-hour period. The score was developed by Dr. Gideon Koren, director of Motherisk and coauthor of this study, and his associates. A score of 7-12 is considered moderate; a score of 13 or higher is considered severe.

In the study, preemptive treatment was associated with 70% fewer cases of moderate to severe NVP during the first 3 weeks women experienced symptoms: 4 of the 26 (15%) evaluable women had a PUQE score of 11 or more during the first 3 weeks of NVP symptoms, compared with 9 of the 23 (39%) evaluable women in the control group, a significant difference. Of the 19 women in the preemptively treated group who had HG during the previous pregnancy, 6 (32%) experienced HG, compared with 6 of the 11 (55%) in the control group, also a significant difference. Some women who enrolled were not evaluable for reasons that included having a miscarriage.

NVP resolved before labor in significantly more of the women in the preemptively treated group than in the control group (almost 80% vs. about 50%), and there was a negative correlation between PUQE scores and a well-being score, indicating that treatment is associated with improved quality of life for these patients, Ms. Maltepe said.

In women who have experienced severe NVP or HG in a previous pregnancy, preemptive treatment with doxylamine-pyridoxine events can reduce the recurrence of NVP in subsequent pregnancies, and improve their quality of life during pregnancy, as well as reduce time off from work and the need for enteral and parenteral therapy, hospitalization, and other costs associated with severe NVP, she concluded.

The NVP helpline at Motherisk is the only dedicated NVP helpline in the world, according to Ms. Maltepe, who provides evidence-based recommendations on pharmaceutical and nonpharmaceutical approaches to treating NVP for pregnant women, their family members, and clinicians via the helpline (800-436-8477 in North America).

The study was funded by Duchesnay. Ms. Maltepe and her coauthors said they had no relevant conflict of interest to disclose.

The Motherisk site is available at www.motherisk.org/women/index.jsp.

BALTIMORE – Starting treatment with a combination of doxylamine and pyridoxine before the onset of nausea and vomiting significantly reduced the incidence of severe nausea and vomiting of pregnancy, compared with starting treatment at the first sign of symptoms, in a study of 59 women with a history of severe nausea and vomiting of pregnancy, Caroline Maltepe reported.

In the prospective, randomized, open-label study of women with a history of nausea and vomiting of pregnancy (NVP), 30 women began taking the delayed-release combination of 10 mg of doxylamine and 10 mg of pyridoxine (vitamin B₆) as soon as they learned they were pregnant, before they started to experience nausea and vomiting (at a mean of 4 weeks’ gestation). Another 29 pregnant women started taking the combination when they started to experience symptoms, Ms. Maltepe said at the annual meeting of the Teratology Society.

Women in both groups started to experience NVP symptoms at a mean of about 5 to almost 6 weeks, said Ms. Maltepe, the lead author of the study, who is with the Motherisk Program at the Hospital for Sick Children in Toronto. The program conducts research and provides information about the safety of maternal exposure to drugs, chemicals, diseases, radiation, and environmental agents to the developing fetus or infant.

The women (mean age, 31-32 years) had experienced severe NVP or hyperemesis gravidarum (HG) in their previous pregnancy, and enrolled when they were planning a pregnancy or in early pregnancy at a point when they had not yet experienced any symptoms. Women in both groups took 2-9 tablets of the doxylamine-pyridoxine combination a day, and received counseling and follow-up calls.

In Canada, the combination is approved and marketed as Diclectin, by Duchesnay, and is the only drug labeled for treating NVP in Canada. There it is considered a first-line treatment and is taken at a standard dose of four tablets a day, said Ms. Maltepe, the coordinator of the NVP helpline at Motherisk.

Diclectin is a generic form of the drug Bendectin, which was marketed in the United States until 1983, when it was voluntarily withdrawn by its manufacturer, Merrell Dow Pharmaceuticals, after a series of lawsuits claiming it caused birth defects. For several years, Duchesnay has been working toward Food and Drug Administration clearance to market Diclectin in the United States, but it would be premature to predict when it would become available in the United States, a spokesman for the company said.

In the study, symptoms were evaluated using the PUQE (Pregnancy–Unique Quantification of Emesis and Nausea) score, a validated scoring system that takes into account the frequency of vomiting; the frequency of retching, gagging, or dry heaves; and the number of hours spent feeling nauseous over a 24-hour period. The score was developed by Dr. Gideon Koren, director of Motherisk and coauthor of this study, and his associates. A score of 7-12 is considered moderate; a score of 13 or higher is considered severe.

In the study, preemptive treatment was associated with 70% fewer cases of moderate to severe NVP during the first 3 weeks women experienced symptoms: 4 of the 26 (15%) evaluable women had a PUQE score of 11 or more during the first 3 weeks of NVP symptoms, compared with 9 of the 23 (39%) evaluable women in the control group, a significant difference. Of the 19 women in the preemptively treated group who had HG during the previous pregnancy, 6 (32%) experienced HG, compared with 6 of the 11 (55%) in the control group, also a significant difference. Some women who enrolled were not evaluable for reasons that included having a miscarriage.

NVP resolved before labor in significantly more of the women in the preemptively treated group than in the control group (almost 80% vs. about 50%), and there was a negative correlation between PUQE scores and a well-being score, indicating that treatment is associated with improved quality of life for these patients, Ms. Maltepe said.

In women who have experienced severe NVP or HG in a previous pregnancy, preemptive treatment with doxylamine-pyridoxine events can reduce the recurrence of NVP in subsequent pregnancies, and improve their quality of life during pregnancy, as well as reduce time off from work and the need for enteral and parenteral therapy, hospitalization, and other costs associated with severe NVP, she concluded.

The NVP helpline at Motherisk is the only dedicated NVP helpline in the world, according to Ms. Maltepe, who provides evidence-based recommendations on pharmaceutical and nonpharmaceutical approaches to treating NVP for pregnant women, their family members, and clinicians via the helpline (800-436-8477 in North America).

The study was funded by Duchesnay. Ms. Maltepe and her coauthors said they had no relevant conflict of interest to disclose.

The Motherisk site is available at www.motherisk.org/women/index.jsp.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

The combination of phentermine and topiramate has been approved for the treatment of weight loss with stipulations: a risk evaluation and mitigation strategy that addresses the potential teratogenic and adverse cardiac effects of the product, according to the Food and Drug Administration.

In the widely anticipated FDA announcement on July 17, Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said in a statement that the phentermine-topiramate combination "used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition."

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities.

The product contains an immediate-release formulation of phentermine, a sympathomimetic amine approved for short-term weight loss that has been marketed in the United States since 1959; and a controlled-release formulation of topiramate, approved for treating adult epilepsy in 1996, migraine prophylaxis in 2004, and pediatric epilepsy in 2011.

The combination has been approved for treatment of adults with a body mass index of at least 30 kg/m², or those with a BMI of at least 27 who also have weight-related comorbidities, in combination with diet and exercise.

The risk evaluation and mitigation strategy (REMS) addresses the teratogenicity of topiramate, which is known to increase the risk of oral clefts at the higher doses used for treating epilepsy, and the possible adverse cardiac effects of phentermine, which increases the pulse rate. The REMS includes a patient medication guide that is provided with each filled prescription, health care provider training, and distribution of the product through certified pharmacies.

It will be marketed as Qsymia by Vivus, not Qnexa, the original proposed trade name. After a starting dose of 3.75 mg/23 mg of phentermine/topiramate daily for 2 weeks, the recommended dose is 7.5 mg of phentermine with 46 mg of extended-release topiramate. A higher dose (15 mg/92 mg) is available for select patients who do not reach their weight-loss goal. These phentermine and topiramate doses are lower than the doses available for the two products available separately.

"Females of reproductive potential must not be pregnant when starting Qsymia therapy or become pregnant while taking Qsymia," should have a negative pregnancy test before starting treatment and monthly during treatment, and should consistently use effective contraception while on the weight-loss drug, according to the FDA statement. If a patient on treatment does not lose at least 5% of body weight after 12 weeks on the higher dose, treatment should be stopped, "as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment," the statement added.

Approval was based on the results of two, 1-year studies involving nearly 4,000 obese and overweight people, mostly white females, with and without significant comorbidities, comparing phentermine-topiramate to placebo. Patients on the recommended and the higher doses of phentermine-topiramate lost an average of 6.7% and 8.9% of their weight, respectively, over those on placebo. About 62% of those on the recommended dose and 69% of those on the highest dose lost at least 5% of their baseline body weight, compared with about 20% of those on placebo. The most common side effects associated with treatment are paresthesias, dizziness, altered taste sensation, insomnia, constipation, and dry mouth.

In the studies, those who had not lost at least 3% of their body weight by week 12 of treatment were unlikely to achieve and sustain weight loss with continued treatment. As a result, it’s recommended that patients be evaluated by 12 weeks to determine whether they should stop treatment or start the higher dose, according to the FDA.

At a meeting in February, the majority of an FDA advisory panel voted that the benefit-risk profile of the medication supported its approval, with panelists in favor of approval citing evidence in clinical trials that treatment was associated with substantial weight loss and a favorable impact on obesity-related comorbidities in some patients, and the small number of effective nonsurgical weight loss treatments currently available. However, they stressed that the drug should be used only in appropriate patients, and they remained concerned about increases in pulse rate associated with treatment; the potential for cardiac adverse events; and the potential for an increased risk of oral clefts, although that risk may be lower than with the higher doses used for epilepsy and migraine prophylaxis, they said.

When the advisory panel first reviewed the phentermine-topiramate combination in July 2010, the majority voted against approval because of concerns about associated teratogenicity and increases in heart rate (by a mean of 1.6 beats/min at the highest dose). At the FDA’s request, the company studied the cardiovascular risks and teratogenic potential further and developed the REMS.

Vivus is required to conduct 10 postmarketing studies, including long-term cardiovascular outcomes studies in overweight and obese people with cardiovascular disease, studies in obese children and adolescents, and studies to evaluate drug utilization and pregnancy exposures. The company expects to make the drug available in the fourth quarter of 2012.

This is the second drug product approved for weight loss in 13 years. In June, the FDA approved lorcaserin hydrochloride (Belviq), a selective serotonin 2C receptor agonist at a dosage of 10 mg twice a day for the same indication.

Click here for prescribing information.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Extremes in prepregnancy body mass index are linked with slower mental development, an analysis of a large, nationally representative cohort suggests.

 After researchers adjusted for sociodemographics, children whose mothers were obese or underweight were 1.5-times more likely than were children of normal-weight mothers to have delayed mental development at 2 years.

No such association with body mass index (BMI) was observed for motor skills.

Given the obesity epidemic, the findings have implications for pre- and inter-conception care, early intervention programs, and obesity prevention and policy, Stefanie Hinkle, Ph.D., said at the meeting.

"Focusing on obesity in children is a particular concern given they our next generation of mothers," she said at the annual meeting of the Society for Pediatric and Perinatal Epidemiologic Research.

The analysis included 6,850 children from the Early Childhood Longitudinal Study–Birth Cohort, a nationally representative sample of 3.6 million children born in 2001. At about two years of age, certified interviewers used a validated shortened version of the Bayley Scales of Infant Development II to assess mental and psychomotor development.

At 9 months postpartum, 5% of mothers reported a prepregnancy BMI categorized as underweight (less than 18.5 kg/m²); 56% normal weight (18.5-24.9 kg/m²); 25% overweight (25-29.9 kg/m²); 8% class I obese (30-34.9 kg/m²); and 6% class II & III obese (at least 35 kg/m²).

Compared with children of normal-weight mothers, mental development T scores were significantly lower for children of underweight or class II-III obese mothers. The greatest difference, a gap of 2.13 points, was observed among children of mothers with severe obesity or a BMI of 35 kg/m² or more, said Dr. Hinkle, a postdoctoral fellow with the division of reproductive health, Centers for Disease Control and Prevention in Atlanta.

The adjusted odds for the more clinically relevant endpoint of delayed mental development, defined as at least one standard deviation below reference, were 1.48 for children of underweight moms and 1.50 for those of severely obese moms.

T scores for motor development and delayed motor development were not significantly different based on prepregnancy BMI, Dr. Hinkle said.

During a discussion at the meeting, one attendee asked whether the analysis included low birth-weight infants or took into consideration such factors as parenting styles, home environment or neighborhood environment.

"I’m just a little skeptical that obesity, all by itself, has this direct effect because there are a lot of other things that happen during child development in the first few years," said Russell Kirby, Ph.D., professor of community and family health, University of South Florida, Tampa.

Dr. Hinkle said they adjusted the models for maternal age, race/ethnicity, marital status, parity, years of schooling, smoking during pregnancy, and household poverty at the time of the assessment and for the child’s gender. Additional data were collected on factors relating to the home and will be used in a future analysis of the children at 5 years. The investigators also performed an analysis among low birth-weight infants and the findings were similar.

Session moderator Dr. Fiona Stanley, professor of pediatrics at University of Western Australia in Perth, said single-factor analyses are frustrating given that the pathways into obesity are known to be complex and involve several factors that can influence child outcomes such as maternal mental health, self-esteem and poverty.

"There are many pathways into children not doing well on Bayley scores at age 2, and maternal obesity is a marker for a pathway or set of pathways," she said in an interview. "To target just obesity is not the way forward."

Finally, an attendee pointed out that the effect of factors influencing perinatal IQ often disappears as time goes on.

The Oak Ridge (Tenn.) Institute for Science and Education sponsored the analysis. The Department of Education sponsored the Early Childhood Longitudinal Study–Birth Cohort study. Dr. Hinkle and her coauthors report no relevant conflicts of interest.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

MINNEAPOLIS – Maternal hypertension and intrapartum fever increase the risk for ischemic stroke in infants, a large retrospective analysis suggests.

Gestational diabetes, a known risk factor for maternal hypertension and neonatal hypoglycemia, does not increase stroke risk.

"Additional research is needed to determine the mechanism underlying these associations and to develop effective preventive methods for high-risk infants," Dr. Joshua R. Mann reported at the meeting.

Approximately 2-4 children per 10,000 births experience ischemic stroke in the first 28 days of life. Roughly 60% of infants present immediately, typically with neonatal seizures. In the remaining 40%, stroke is recognized later in childhood during evaluation for abnormal neurologic or cognitive development.

There were 43 cases of ischemic stroke before 30 days of life and 118 additional cases diagnosed from day 30 through 364 days in the retrospective analysis of 226,117 children (199,934 full-term births) born from 2000 through 2007 and enrolled in the South Carolina Medicaid program.

Of these, 37 cases and 96 cases, respectively, had confirmed ischemic strokes, defined as more than one ICD-9 code for ischemic stroke or a single diagnosis of ischemic stroke plus a neurocognitive condition that could be indicative of stroke.

Compared with infants without stroke, maternal hypertension was significantly more common for infants with ischemic stroke before 30 days (32.5% vs. 14%; P value = .0004) and before 365 days (28% vs. 14%; P less than .0001), reported Dr. Mann of family and preventive medicine at the University of South Carolina, Columbia.

Fever at delivery was significantly more common in mothers of infants with stroke prior to 365 days (4.9% vs. 1.2%; P less than .0001), but not in those with stroke before 30 days (4.6% vs. 1.2%; P = .09).

Maternal diabetes was not significant at either time point.

In a logistic regression analysis that adjusted for a broad range of demographic and other confounding risk factors, infants born to mothers with hypertension had more than twice the risk of any stroke, defined as one or more diagnoses indicating ischemic stroke, before 30 days (odds ratio 2.31; P = .0071), or a confirmed ischemic stroke (OR 2.75; P = .0021), he said.

Maternal fever at delivery more than tripled the risk of any ischemic stroke (OR 3.36; P = .048) and quadrupled the risk of confirmed ischemic stroke (OR 4.02; P = .025), he reported in a poster presentation.

Maternal diabetes did not significantly increase the odds of any stroke (OR 0.35; P = .08) or confirmed stroke (OR 0.40; P = .13).

Although it was not the primary goal of the study, the investigators also found multiple child characteristics to be associated with increased odds of any stroke prior to 365 days. The significant covariates were birth trauma (OR 5.99), birth asphyxia (OR 11.42), sickle cell disease (OR 3.58), sickle cell trait (OR 2.45), congenital infection (OR 5.39), neonatal infection (OR 6.06), meningitis (OR 6.05), encephalitis (OR 3.99) and child thrombophilia, which had a staggering odds ratio of 157.99.

There was also evidence of synergy between maternal hypertension and the presence of at least one other risk factor for stroke diagnosed before 365 days.

A recent study among 44 children indicated that the timing of the stroke has a bearing on outcomes. Children who had a stroke between 1 and 6 years had better neuropsychological outcomes than did children who had a stroke before age 1 or after age 6 (Child Neuropsychol. 2011 Dec. 6 [doi:10.1080/09297049.2011.639756]).

The full paper is in press with the journal Developmental Medicine and Child Neurology, Dr. Mann noted.

Funding for the study was provided by a Health Resources Services Administration Maternal Child Health grant. Dr. Mann and his coauthors reported having no disclosures.

The monovalent inactivated ASO3-adjuvanted influenza A(H1N1)pdm09 vaccine used in Denmark during the 2009 flu pandemic showed no association with adverse fetal outcomes, according to a report in the July 11 issue of JAMA.

This vaccine, which contained the same H1N1 viral antigens to those in the nonadjuvanted vaccine used in the United States, was not related to major birth defects, preterm birth, or fetal growth restriction in a nationwide cohort study of 53,432 live-born singleton infants delivered in Denmark during the 2009-2010 influenza A(H1N1) pandemic, said Dr. Björn Pasternak of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.

©AvailableLight/istockphoto.com

"Together with our [previous] findings of no significantly increased risk of spontaneous abortion and stillbirth associated with vaccination, these data provide reassurance of the safety of the ASO3-adjuvanted A(H1N1)pdm09 vaccine in pregnancy.

"Our data might be generalizable to nonadjuvanted A(H1N1)pdm09 vaccines because they contain identical viral antigens, although the antigen doses and manufacturing processes may differ. However, results from this study do not provide evidence of safety for vaccines with other adjuvants," the researchers noted.

They added that "apart from providing information on influenza A(H1N1)pdm09 vaccine safety in pregnancy in retrospect, studies such as ours may have implications for future influenza seasons and pandemics; in some circumstances, the use of adjuvanted vaccines will likely be critical to achieve sufficient host immune response."

Dr. Pasternak and his colleagues identified 6,989 infants (13% of the total born that year) who had been exposed to the vaccine during pregnancy. This included 345 infants who had been exposed during the first trimester and 6,644 who had been exposed in the second or third trimesters.

They adjusted the data to account for numerous potential confounders of an association between exposure and fetal outcome, such as maternal age, parity, smoking status, body mass index, comorbidities, drug use, and reproductive history.

In an unmatched analysis, infants exposed to the vaccine during the second or third trimesters did not have an increased prevalence of any adverse outcome, compared with unexposed infants. Rates of preterm birth were 4.6% with second- or third-trimester exposure and 4.6% with no exposure, and rates of small size for gestational age were 9.7% and 9.9%, respectively.

Because this analysis was based on data from well over 6,000 exposed infants, it provides "robust evidence of [vaccine] safety with high precision," the investigators said (JAMA 2012;308:165-74).

However, the number of infants exposed during the first trimester was much smaller, and because first-trimester vaccination was largely restricted to high-risk pregnancies, these infants were already at elevated risk for adverse outcomes. So a different method of analysis was needed to accurately compare this group with unexposed infants.

Therefore, 330 of the infants exposed during the first trimester were propensity-matched with 330 unexposed infants. No unexpected cluster of birth defects occurred, nor was there any significant difference in rates of low birth weight (4.5% and 5.5%, respectively) or preterm birth (9.4% vs. 7.3%). But given the small numbers, these results "should be viewed as preliminary and in need of confirmation," Dr. Pasternak and his associates said.

This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported among the study authors.

The monovalent inactivated ASO3-adjuvanted influenza A(H1N1)pdm09 vaccine used in Denmark during the 2009 flu pandemic showed no association with adverse fetal outcomes, according to a report in the July 11 issue of JAMA.

This vaccine, which contained the same H1N1 viral antigens to those in the nonadjuvanted vaccine used in the United States, was not related to major birth defects, preterm birth, or fetal growth restriction in a nationwide cohort study of 53,432 live-born singleton infants delivered in Denmark during the 2009-2010 influenza A(H1N1) pandemic, said Dr. Björn Pasternak of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.

©AvailableLight/istockphoto.com

"Together with our [previous] findings of no significantly increased risk of spontaneous abortion and stillbirth associated with vaccination, these data provide reassurance of the safety of the ASO3-adjuvanted A(H1N1)pdm09 vaccine in pregnancy.

"Our data might be generalizable to nonadjuvanted A(H1N1)pdm09 vaccines because they contain identical viral antigens, although the antigen doses and manufacturing processes may differ. However, results from this study do not provide evidence of safety for vaccines with other adjuvants," the researchers noted.

They added that "apart from providing information on influenza A(H1N1)pdm09 vaccine safety in pregnancy in retrospect, studies such as ours may have implications for future influenza seasons and pandemics; in some circumstances, the use of adjuvanted vaccines will likely be critical to achieve sufficient host immune response."

Dr. Pasternak and his colleagues identified 6,989 infants (13% of the total born that year) who had been exposed to the vaccine during pregnancy. This included 345 infants who had been exposed during the first trimester and 6,644 who had been exposed in the second or third trimesters.

They adjusted the data to account for numerous potential confounders of an association between exposure and fetal outcome, such as maternal age, parity, smoking status, body mass index, comorbidities, drug use, and reproductive history.

In an unmatched analysis, infants exposed to the vaccine during the second or third trimesters did not have an increased prevalence of any adverse outcome, compared with unexposed infants. Rates of preterm birth were 4.6% with second- or third-trimester exposure and 4.6% with no exposure, and rates of small size for gestational age were 9.7% and 9.9%, respectively.

Because this analysis was based on data from well over 6,000 exposed infants, it provides "robust evidence of [vaccine] safety with high precision," the investigators said (JAMA 2012;308:165-74).

However, the number of infants exposed during the first trimester was much smaller, and because first-trimester vaccination was largely restricted to high-risk pregnancies, these infants were already at elevated risk for adverse outcomes. So a different method of analysis was needed to accurately compare this group with unexposed infants.

Therefore, 330 of the infants exposed during the first trimester were propensity-matched with 330 unexposed infants. No unexpected cluster of birth defects occurred, nor was there any significant difference in rates of low birth weight (4.5% and 5.5%, respectively) or preterm birth (9.4% vs. 7.3%). But given the small numbers, these results "should be viewed as preliminary and in need of confirmation," Dr. Pasternak and his associates said.

This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported among the study authors.

The monovalent inactivated ASO3-adjuvanted influenza A(H1N1)pdm09 vaccine used in Denmark during the 2009 flu pandemic showed no association with adverse fetal outcomes, according to a report in the July 11 issue of JAMA.

This vaccine, which contained the same H1N1 viral antigens to those in the nonadjuvanted vaccine used in the United States, was not related to major birth defects, preterm birth, or fetal growth restriction in a nationwide cohort study of 53,432 live-born singleton infants delivered in Denmark during the 2009-2010 influenza A(H1N1) pandemic, said Dr. Björn Pasternak of the department of epidemiology research at Statens Serum Institut, Copenhagen, and his associates.

©AvailableLight/istockphoto.com

"Together with our [previous] findings of no significantly increased risk of spontaneous abortion and stillbirth associated with vaccination, these data provide reassurance of the safety of the ASO3-adjuvanted A(H1N1)pdm09 vaccine in pregnancy.

"Our data might be generalizable to nonadjuvanted A(H1N1)pdm09 vaccines because they contain identical viral antigens, although the antigen doses and manufacturing processes may differ. However, results from this study do not provide evidence of safety for vaccines with other adjuvants," the researchers noted.

They added that "apart from providing information on influenza A(H1N1)pdm09 vaccine safety in pregnancy in retrospect, studies such as ours may have implications for future influenza seasons and pandemics; in some circumstances, the use of adjuvanted vaccines will likely be critical to achieve sufficient host immune response."

Dr. Pasternak and his colleagues identified 6,989 infants (13% of the total born that year) who had been exposed to the vaccine during pregnancy. This included 345 infants who had been exposed during the first trimester and 6,644 who had been exposed in the second or third trimesters.

They adjusted the data to account for numerous potential confounders of an association between exposure and fetal outcome, such as maternal age, parity, smoking status, body mass index, comorbidities, drug use, and reproductive history.

In an unmatched analysis, infants exposed to the vaccine during the second or third trimesters did not have an increased prevalence of any adverse outcome, compared with unexposed infants. Rates of preterm birth were 4.6% with second- or third-trimester exposure and 4.6% with no exposure, and rates of small size for gestational age were 9.7% and 9.9%, respectively.

Because this analysis was based on data from well over 6,000 exposed infants, it provides "robust evidence of [vaccine] safety with high precision," the investigators said (JAMA 2012;308:165-74).

However, the number of infants exposed during the first trimester was much smaller, and because first-trimester vaccination was largely restricted to high-risk pregnancies, these infants were already at elevated risk for adverse outcomes. So a different method of analysis was needed to accurately compare this group with unexposed infants.

Therefore, 330 of the infants exposed during the first trimester were propensity-matched with 330 unexposed infants. No unexpected cluster of birth defects occurred, nor was there any significant difference in rates of low birth weight (4.5% and 5.5%, respectively) or preterm birth (9.4% vs. 7.3%). But given the small numbers, these results "should be viewed as preliminary and in need of confirmation," Dr. Pasternak and his associates said.

This study was funded by the Danish Medical Research Council. No financial conflicts of interest were reported among the study authors.

CHICAGO – Women with mechanical heart valves who unintentionally become pregnant while on warfarin often expect their obstetricians to recommend pregnancy termination, but that’s not what contemporary practice guidelines advocate.

Neither the latest American College of Chest Physicians guidelines (CHEST 2012;141[2 suppl]: e691S-e736S doi 10.1378/chest.11-2300) nor the European Society of Cardiology guidelines (Eur. Heart J. 2011;32:3147-97) recommend pregnancy termination under those circumstances, Dr. Anthony R. Gregg noted at the annual meeting of the American College of Cardiology.

"Studies show the risk to the fetus is fairly low overall, so there’s no recommendation for pregnancy termination," said Dr. Gregg, professor of obstetrics and gynecology, chief of maternal-fetal medicine, and director of obstetrics at the University of Florida Shands Hospital, Gainesville.

This assertion may come as a surprise to many cardiologists and primary care physicians. After all, every medical student has heard of the fetal warfarin syndrome. But while it affects about 30% of pregnancies with first-trimester warfarin exposure, the degree of severity is highly variable, he explained.

Often a woman doesn’t realize she is pregnant until weeks 6-8 of gestation or even later. The fetus has already been exposed to warfarin. Under those circumstances, the guidelines uniformly recommend that the patient with a mechanical heart valve be switched to low-molecular-weight heparin or unfractionated heparin, then returned to warfarin after 13 weeks’ gestation. She is then maintained on that well-studied oral anticoagulant until week 34, when she should once again be switched to low-molecular-weight heparin or unfractionated heparin as the time of delivery draws closer.

In the case of a planned pregnancy, the recommendation is for a patient with a mechanical valve to be on low-molecular-weight heparin or unfractionated heparin from the time of conception through 13 weeks’ gestation before switching back to warfarin. But that guidance doesn’t apply to women with the older mechanical heart valves posing maximum thromboembolic risk; those patients are best managed on warfarin continuously throughout pregnancy until the week-34 switch to low-molecular-weight heparin or unfractionated heparin.

"We try to point out to patients that they’re not out of the woods despite the fact that we’re following professional organizations’ guidelines. Sometimes they assume that since we’re following guidelines there’s no risk at all. The bottom line is warfarin can cross the placenta in pregnancy. There are lots of documented cases of fetal intracranial bleeding. We follow our patients across pregnancy looking for any evidence of warfarin-induced fetal intracranial hemorrhage," he said.

Dr. Gregg reported having no financial conflicts.

CHICAGO – Women with mechanical heart valves who unintentionally become pregnant while on warfarin often expect their obstetricians to recommend pregnancy termination, but that’s not what contemporary practice guidelines advocate.

Neither the latest American College of Chest Physicians guidelines (CHEST 2012;141[2 suppl]: e691S-e736S doi 10.1378/chest.11-2300) nor the European Society of Cardiology guidelines (Eur. Heart J. 2011;32:3147-97) recommend pregnancy termination under those circumstances, Dr. Anthony R. Gregg noted at the annual meeting of the American College of Cardiology.

"Studies show the risk to the fetus is fairly low overall, so there’s no recommendation for pregnancy termination," said Dr. Gregg, professor of obstetrics and gynecology, chief of maternal-fetal medicine, and director of obstetrics at the University of Florida Shands Hospital, Gainesville.

This assertion may come as a surprise to many cardiologists and primary care physicians. After all, every medical student has heard of the fetal warfarin syndrome. But while it affects about 30% of pregnancies with first-trimester warfarin exposure, the degree of severity is highly variable, he explained.

Often a woman doesn’t realize she is pregnant until weeks 6-8 of gestation or even later. The fetus has already been exposed to warfarin. Under those circumstances, the guidelines uniformly recommend that the patient with a mechanical heart valve be switched to low-molecular-weight heparin or unfractionated heparin, then returned to warfarin after 13 weeks’ gestation. She is then maintained on that well-studied oral anticoagulant until week 34, when she should once again be switched to low-molecular-weight heparin or unfractionated heparin as the time of delivery draws closer.

In the case of a planned pregnancy, the recommendation is for a patient with a mechanical valve to be on low-molecular-weight heparin or unfractionated heparin from the time of conception through 13 weeks’ gestation before switching back to warfarin. But that guidance doesn’t apply to women with the older mechanical heart valves posing maximum thromboembolic risk; those patients are best managed on warfarin continuously throughout pregnancy until the week-34 switch to low-molecular-weight heparin or unfractionated heparin.

"We try to point out to patients that they’re not out of the woods despite the fact that we’re following professional organizations’ guidelines. Sometimes they assume that since we’re following guidelines there’s no risk at all. The bottom line is warfarin can cross the placenta in pregnancy. There are lots of documented cases of fetal intracranial bleeding. We follow our patients across pregnancy looking for any evidence of warfarin-induced fetal intracranial hemorrhage," he said.

Dr. Gregg reported having no financial conflicts.

CHICAGO – Women with mechanical heart valves who unintentionally become pregnant while on warfarin often expect their obstetricians to recommend pregnancy termination, but that’s not what contemporary practice guidelines advocate.

Neither the latest American College of Chest Physicians guidelines (CHEST 2012;141[2 suppl]: e691S-e736S doi 10.1378/chest.11-2300) nor the European Society of Cardiology guidelines (Eur. Heart J. 2011;32:3147-97) recommend pregnancy termination under those circumstances, Dr. Anthony R. Gregg noted at the annual meeting of the American College of Cardiology.

"Studies show the risk to the fetus is fairly low overall, so there’s no recommendation for pregnancy termination," said Dr. Gregg, professor of obstetrics and gynecology, chief of maternal-fetal medicine, and director of obstetrics at the University of Florida Shands Hospital, Gainesville.

This assertion may come as a surprise to many cardiologists and primary care physicians. After all, every medical student has heard of the fetal warfarin syndrome. But while it affects about 30% of pregnancies with first-trimester warfarin exposure, the degree of severity is highly variable, he explained.

Often a woman doesn’t realize she is pregnant until weeks 6-8 of gestation or even later. The fetus has already been exposed to warfarin. Under those circumstances, the guidelines uniformly recommend that the patient with a mechanical heart valve be switched to low-molecular-weight heparin or unfractionated heparin, then returned to warfarin after 13 weeks’ gestation. She is then maintained on that well-studied oral anticoagulant until week 34, when she should once again be switched to low-molecular-weight heparin or unfractionated heparin as the time of delivery draws closer.

In the case of a planned pregnancy, the recommendation is for a patient with a mechanical valve to be on low-molecular-weight heparin or unfractionated heparin from the time of conception through 13 weeks’ gestation before switching back to warfarin. But that guidance doesn’t apply to women with the older mechanical heart valves posing maximum thromboembolic risk; those patients are best managed on warfarin continuously throughout pregnancy until the week-34 switch to low-molecular-weight heparin or unfractionated heparin.

"We try to point out to patients that they’re not out of the woods despite the fact that we’re following professional organizations’ guidelines. Sometimes they assume that since we’re following guidelines there’s no risk at all. The bottom line is warfarin can cross the placenta in pregnancy. There are lots of documented cases of fetal intracranial bleeding. We follow our patients across pregnancy looking for any evidence of warfarin-induced fetal intracranial hemorrhage," he said.

Dr. Gregg reported having no financial conflicts.