Melinda Tanzola

ATLANTA — A blood test can predict nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease, according to results of a study presented at a meeting sponsored by the American Association for the Study of Liver Diseases.

Hepatocyte apoptosis is known to mediate liver injury in nonalcoholic fatty liver disease (NAFLD). The activation of caspases that mediate apoptosis can be measured in the plasma, thus allowing an indirect evaluation of liver damage.

Plasma caspase activation was detected using an enzyme-linked immunosorbent assay for cytokeratin-18 fragments, which are a byproduct of caspase activation. In the study, caspase activation was strongly linked to disease severity; a cutoff value of 395 U/L was 99.9% sensitive and 85.7% specific in predicting nonalcoholic steatohepatitis (NASH).

“A liver biopsy is the only reliable method to differentiate simple steatosis from NASH and stage disease severity,” noted study author Dr. Anna Wieckowska of the Cleveland Clinic. However, biopsy has inherent risks and is not practical to perform multiple times.

Dr. Wieckowska and her associates evaluated a caspase activity blood test in 44 consecutive patients with suspected NAFLD. They measured caspase activity in plasma samples obtained at the time of liver biopsy, and then correlated the blood test results with histopathologic features.

Five patients were excluded because of a hemolyzed blood sample, two were excluded because they had borderline NASH, and two had alternative diagnoses, which left 39 evaluable patients.

Caspase activation was significantly elevated in patients with definitive NASH, with median cytokeratin-18 levels of 767 U/L, compared with 202 U/L in patients with simple steatosis. After adjustment for confounding variables, including aspartate aminotransferase/alanine aminotransferase ratio and body mass index, cytokeratin-18 levels were independently predictive of NASH, with a positive predictive value of 99.9% and a negative predictive value of 85.7%.

“This is potentially a very exciting breakthrough if confirmed in a larger series,” commented Dr. Keith D. Lindor of the Mayo Clinic Foundation in Rochester, Minn. He added that “a noninvasive way to accurately predict mild degrees of fibrosis would allow us to select patients for treatment trials and also perhaps serve as a reliable and clinically relevant end point for these studies.”

ATLANTA — A blood test can predict nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease, according to results of a study presented at a meeting sponsored by the American Association for the Study of Liver Diseases.

Hepatocyte apoptosis is known to mediate liver injury in nonalcoholic fatty liver disease (NAFLD). The activation of caspases that mediate apoptosis can be measured in the plasma, thus allowing an indirect evaluation of liver damage.

Plasma caspase activation was detected using an enzyme-linked immunosorbent assay for cytokeratin-18 fragments, which are a byproduct of caspase activation. In the study, caspase activation was strongly linked to disease severity; a cutoff value of 395 U/L was 99.9% sensitive and 85.7% specific in predicting nonalcoholic steatohepatitis (NASH).

“A liver biopsy is the only reliable method to differentiate simple steatosis from NASH and stage disease severity,” noted study author Dr. Anna Wieckowska of the Cleveland Clinic. However, biopsy has inherent risks and is not practical to perform multiple times.

Dr. Wieckowska and her associates evaluated a caspase activity blood test in 44 consecutive patients with suspected NAFLD. They measured caspase activity in plasma samples obtained at the time of liver biopsy, and then correlated the blood test results with histopathologic features.

Five patients were excluded because of a hemolyzed blood sample, two were excluded because they had borderline NASH, and two had alternative diagnoses, which left 39 evaluable patients.

Caspase activation was significantly elevated in patients with definitive NASH, with median cytokeratin-18 levels of 767 U/L, compared with 202 U/L in patients with simple steatosis. After adjustment for confounding variables, including aspartate aminotransferase/alanine aminotransferase ratio and body mass index, cytokeratin-18 levels were independently predictive of NASH, with a positive predictive value of 99.9% and a negative predictive value of 85.7%.

“This is potentially a very exciting breakthrough if confirmed in a larger series,” commented Dr. Keith D. Lindor of the Mayo Clinic Foundation in Rochester, Minn. He added that “a noninvasive way to accurately predict mild degrees of fibrosis would allow us to select patients for treatment trials and also perhaps serve as a reliable and clinically relevant end point for these studies.”

ATLANTA — A blood test can predict nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease, according to results of a study presented at a meeting sponsored by the American Association for the Study of Liver Diseases.

Hepatocyte apoptosis is known to mediate liver injury in nonalcoholic fatty liver disease (NAFLD). The activation of caspases that mediate apoptosis can be measured in the plasma, thus allowing an indirect evaluation of liver damage.

Plasma caspase activation was detected using an enzyme-linked immunosorbent assay for cytokeratin-18 fragments, which are a byproduct of caspase activation. In the study, caspase activation was strongly linked to disease severity; a cutoff value of 395 U/L was 99.9% sensitive and 85.7% specific in predicting nonalcoholic steatohepatitis (NASH).

“A liver biopsy is the only reliable method to differentiate simple steatosis from NASH and stage disease severity,” noted study author Dr. Anna Wieckowska of the Cleveland Clinic. However, biopsy has inherent risks and is not practical to perform multiple times.

Dr. Wieckowska and her associates evaluated a caspase activity blood test in 44 consecutive patients with suspected NAFLD. They measured caspase activity in plasma samples obtained at the time of liver biopsy, and then correlated the blood test results with histopathologic features.

Five patients were excluded because of a hemolyzed blood sample, two were excluded because they had borderline NASH, and two had alternative diagnoses, which left 39 evaluable patients.

Caspase activation was significantly elevated in patients with definitive NASH, with median cytokeratin-18 levels of 767 U/L, compared with 202 U/L in patients with simple steatosis. After adjustment for confounding variables, including aspartate aminotransferase/alanine aminotransferase ratio and body mass index, cytokeratin-18 levels were independently predictive of NASH, with a positive predictive value of 99.9% and a negative predictive value of 85.7%.

“This is potentially a very exciting breakthrough if confirmed in a larger series,” commented Dr. Keith D. Lindor of the Mayo Clinic Foundation in Rochester, Minn. He added that “a noninvasive way to accurately predict mild degrees of fibrosis would allow us to select patients for treatment trials and also perhaps serve as a reliable and clinically relevant end point for these studies.”

The human monoclonal antibody denosumab has been found to increase bone mineral density in postmenopausal women, results of a recent randomized phase II study suggest.

Evaluation of the primary end point—the percentage change in lumbar spine bone mineral density from baseline to 12 months—indicated that denosumab was active and significantly superior to placebo (N. Engl. J. Med. 2006;354:821–31).

Dr. Michael R. McClung, of the Providence Portland (Ore.) Medical Center, and his fellow researchers evaluated 12 months of denosumab, compared with open-label oral alendronate (70 mg once weekly) or placebo in postmenopausal women with low bone mineral density, as defined by a “T score of −1.8 to −4.0 at the lumbar spine or −1.8 to −3.5 at either the femoral neck or total hip,” the researchers reported.

Subjects randomized to the experimental arm received denosumab every 3 or 6 months.

Of the 412 study participants, 319 women were randomized to the seven denosumab groups, 47 to the alendronate group, and 46 to the placebo group; 369 women completed the 12-month treatment study.

At study end, women receiving denosumab had increases in bone mineral density at the lumbar spine of 3.0%–6.7%, compared with a 0.8% decrease with placebo, or a mean increase of 4.6% with alendronate. Bone mineral density was also found to be superior with denosumab, compared with placebo at the total hip (mean change, 1.9%–3.6% vs. −0.6%, respectively), the distal third of the radius (0.4%–1.3% vs. −2.0%), and the total body (0.6%–2.8% vs. −0.2%), the researchers reported.

They noted that “in exploratory comparisons, the observed mean changes in bone mineral density were at least as great with denosumab as with alendronate.”

Denosumab targets the receptor activator of nuclear factor-β ligand (RANKL). By specifically binding to RANKL with a high affinity, denosumab inhibits RANKL activity.

In an accompanying editorial, Dr. Michael P. Whyte expressed concern that inhibiting RANKL, a member of the “tumor necrosis factor superfamily,” might have unintended effects on the immune system (N. Engl. J. Med. 2006; 354:860–3). “Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications,” Dr. Whyte suggested.

During the study, an investigation into bone turnover indicated a significant decrease in serum C-telopeptide with denosumab that had a dose-dependent duration; a similar pattern was noted for the urinary N-telopeptide to creatinine ratio. These markers of bone turnover were at least equivalent with denosumab, compared with alendronate.

Adverse events were calculated in 406 study participants who received at least one dose of denosumab, alendronate, or placebo. Dyspepsia, however, was found to be greater in the alendronate group.

In the denosumab-treated group, 5.7% of study participants reported a serious adverse event, compared with 4.3% in the placebo group, and 2.2% in the alendronate group. In both the denosumab and placebo arms, 2.2% of the women withdrew from the study due to adverse events, and 3.8% of the denosumab group reported clinical fractures, compared with 2.2% in both the placebo and alendronate groups.

Dr. McClung and his investigators noted that their study was not designed to test equivalency, and denosumab should be further investigated for the treatment and prevention of bone-loss diseases.

The study was developed and supported by Amgen Inc., the manufacturer of denosumab. Dr. McClung disclosed having served as a consultant for, and having received grant support from, Amgen.

The human monoclonal antibody denosumab has been found to increase bone mineral density in postmenopausal women, results of a recent randomized phase II study suggest.

Evaluation of the primary end point—the percentage change in lumbar spine bone mineral density from baseline to 12 months—indicated that denosumab was active and significantly superior to placebo (N. Engl. J. Med. 2006;354:821–31).

Dr. Michael R. McClung, of the Providence Portland (Ore.) Medical Center, and his fellow researchers evaluated 12 months of denosumab, compared with open-label oral alendronate (70 mg once weekly) or placebo in postmenopausal women with low bone mineral density, as defined by a “T score of −1.8 to −4.0 at the lumbar spine or −1.8 to −3.5 at either the femoral neck or total hip,” the researchers reported.

Subjects randomized to the experimental arm received denosumab every 3 or 6 months.

Of the 412 study participants, 319 women were randomized to the seven denosumab groups, 47 to the alendronate group, and 46 to the placebo group; 369 women completed the 12-month treatment study.

At study end, women receiving denosumab had increases in bone mineral density at the lumbar spine of 3.0%–6.7%, compared with a 0.8% decrease with placebo, or a mean increase of 4.6% with alendronate. Bone mineral density was also found to be superior with denosumab, compared with placebo at the total hip (mean change, 1.9%–3.6% vs. −0.6%, respectively), the distal third of the radius (0.4%–1.3% vs. −2.0%), and the total body (0.6%–2.8% vs. −0.2%), the researchers reported.

They noted that “in exploratory comparisons, the observed mean changes in bone mineral density were at least as great with denosumab as with alendronate.”

Denosumab targets the receptor activator of nuclear factor-β ligand (RANKL). By specifically binding to RANKL with a high affinity, denosumab inhibits RANKL activity.

In an accompanying editorial, Dr. Michael P. Whyte expressed concern that inhibiting RANKL, a member of the “tumor necrosis factor superfamily,” might have unintended effects on the immune system (N. Engl. J. Med. 2006; 354:860–3). “Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications,” Dr. Whyte suggested.

During the study, an investigation into bone turnover indicated a significant decrease in serum C-telopeptide with denosumab that had a dose-dependent duration; a similar pattern was noted for the urinary N-telopeptide to creatinine ratio. These markers of bone turnover were at least equivalent with denosumab, compared with alendronate.

Adverse events were calculated in 406 study participants who received at least one dose of denosumab, alendronate, or placebo. Dyspepsia, however, was found to be greater in the alendronate group.

In the denosumab-treated group, 5.7% of study participants reported a serious adverse event, compared with 4.3% in the placebo group, and 2.2% in the alendronate group. In both the denosumab and placebo arms, 2.2% of the women withdrew from the study due to adverse events, and 3.8% of the denosumab group reported clinical fractures, compared with 2.2% in both the placebo and alendronate groups.

Dr. McClung and his investigators noted that their study was not designed to test equivalency, and denosumab should be further investigated for the treatment and prevention of bone-loss diseases.

The study was developed and supported by Amgen Inc., the manufacturer of denosumab. Dr. McClung disclosed having served as a consultant for, and having received grant support from, Amgen.

The human monoclonal antibody denosumab has been found to increase bone mineral density in postmenopausal women, results of a recent randomized phase II study suggest.

Evaluation of the primary end point—the percentage change in lumbar spine bone mineral density from baseline to 12 months—indicated that denosumab was active and significantly superior to placebo (N. Engl. J. Med. 2006;354:821–31).

Dr. Michael R. McClung, of the Providence Portland (Ore.) Medical Center, and his fellow researchers evaluated 12 months of denosumab, compared with open-label oral alendronate (70 mg once weekly) or placebo in postmenopausal women with low bone mineral density, as defined by a “T score of −1.8 to −4.0 at the lumbar spine or −1.8 to −3.5 at either the femoral neck or total hip,” the researchers reported.

Subjects randomized to the experimental arm received denosumab every 3 or 6 months.

Of the 412 study participants, 319 women were randomized to the seven denosumab groups, 47 to the alendronate group, and 46 to the placebo group; 369 women completed the 12-month treatment study.

At study end, women receiving denosumab had increases in bone mineral density at the lumbar spine of 3.0%–6.7%, compared with a 0.8% decrease with placebo, or a mean increase of 4.6% with alendronate. Bone mineral density was also found to be superior with denosumab, compared with placebo at the total hip (mean change, 1.9%–3.6% vs. −0.6%, respectively), the distal third of the radius (0.4%–1.3% vs. −2.0%), and the total body (0.6%–2.8% vs. −0.2%), the researchers reported.

They noted that “in exploratory comparisons, the observed mean changes in bone mineral density were at least as great with denosumab as with alendronate.”

Denosumab targets the receptor activator of nuclear factor-β ligand (RANKL). By specifically binding to RANKL with a high affinity, denosumab inhibits RANKL activity.

In an accompanying editorial, Dr. Michael P. Whyte expressed concern that inhibiting RANKL, a member of the “tumor necrosis factor superfamily,” might have unintended effects on the immune system (N. Engl. J. Med. 2006; 354:860–3). “Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications,” Dr. Whyte suggested.

During the study, an investigation into bone turnover indicated a significant decrease in serum C-telopeptide with denosumab that had a dose-dependent duration; a similar pattern was noted for the urinary N-telopeptide to creatinine ratio. These markers of bone turnover were at least equivalent with denosumab, compared with alendronate.

Adverse events were calculated in 406 study participants who received at least one dose of denosumab, alendronate, or placebo. Dyspepsia, however, was found to be greater in the alendronate group.

In the denosumab-treated group, 5.7% of study participants reported a serious adverse event, compared with 4.3% in the placebo group, and 2.2% in the alendronate group. In both the denosumab and placebo arms, 2.2% of the women withdrew from the study due to adverse events, and 3.8% of the denosumab group reported clinical fractures, compared with 2.2% in both the placebo and alendronate groups.

Dr. McClung and his investigators noted that their study was not designed to test equivalency, and denosumab should be further investigated for the treatment and prevention of bone-loss diseases.

The study was developed and supported by Amgen Inc., the manufacturer of denosumab. Dr. McClung disclosed having served as a consultant for, and having received grant support from, Amgen.

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” he said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the device, developed by NMT Medical Inc. (which also sponsored the study), failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Overall, 42% of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done in 2005 at 13 centers in the United Kingdom. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies showed an association between PFO and these types of migraines, Dr. Dowson said.

Contrast transthoracic echocardiograms showed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, said Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients continued their prophylactic migraine medication, but those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack, and cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches.

Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction. The investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results send “a little bit of a mixed message” Dr. Williams commented. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete,” he said.

The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” Dr. Williams said. “In skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. In the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The researchers plan to evaluate residual shunting in patients who had repairs. Longer follow-up may show greater benefit from implants, Dr. Dowson noted.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

Significantly more patients with the implant had a 50% reduction in headache days, compared with controls. DR. DOWSON

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” he said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the device, developed by NMT Medical Inc. (which also sponsored the study), failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Overall, 42% of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done in 2005 at 13 centers in the United Kingdom. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies showed an association between PFO and these types of migraines, Dr. Dowson said.

Contrast transthoracic echocardiograms showed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, said Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients continued their prophylactic migraine medication, but those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack, and cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches.

Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction. The investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results send “a little bit of a mixed message” Dr. Williams commented. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete,” he said.

The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” Dr. Williams said. “In skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. In the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The researchers plan to evaluate residual shunting in patients who had repairs. Longer follow-up may show greater benefit from implants, Dr. Dowson noted.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

Significantly more patients with the implant had a 50% reduction in headache days, compared with controls. DR. DOWSON

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” he said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the device, developed by NMT Medical Inc. (which also sponsored the study), failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Overall, 42% of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done in 2005 at 13 centers in the United Kingdom. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies showed an association between PFO and these types of migraines, Dr. Dowson said.

Contrast transthoracic echocardiograms showed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, said Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients continued their prophylactic migraine medication, but those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack, and cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches.

Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction. The investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results send “a little bit of a mixed message” Dr. Williams commented. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete,” he said.

The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” Dr. Williams said. “In skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. In the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The researchers plan to evaluate residual shunting in patients who had repairs. Longer follow-up may show greater benefit from implants, Dr. Dowson noted.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

Significantly more patients with the implant had a 50% reduction in headache days, compared with controls. DR. DOWSON

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the sham-controlled study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” Dr. Williams said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the catheter-based device, developed by NMT Medical Inc. (which also sponsored the study) failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Forty-two percent of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a prospective, randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done at 13 centers in the United Kingdom during January-July 2005. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, and frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies have shown an association between PFO and these types of migraines, said Dr. Dowson.

Contrast transthoracic echocardiograms revealed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, reported Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Sham patients underwent general anesthesia and woke up with a groin incision. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients were maintained on their prophylactic migraine medication, although those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack or cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches. Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction.

The MIST investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results sent “a little bit of a mixed message” commented Dr. Williams. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete.” The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” he said. In addition, “in skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

With STARFlex, an umbrellalike Dacron patch is mounted on a pacing lead framework and threaded by catheter through the femoral vein to the right heart. The catheter is then passed into the left atrium through the PFO. After the first umbrella is opened, the catheter is pulled back into the right atrium. Then the second umbrella opened, and the two patches come together, forming a tight seal.

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. For the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The study investigators plan to evaluate residual shunting in the patients who had repairs, Dr. Dawson said. He also proposed that a longer follow-up may show greater benefit from the implants.

Philadelphia Bureau Chief Mitchel L. Zoler contributed to this report.

'Using more conventional migraine trial end points, significant differences were found.' DR. DOWSON

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the sham-controlled study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” Dr. Williams said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the catheter-based device, developed by NMT Medical Inc. (which also sponsored the study) failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Forty-two percent of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a prospective, randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done at 13 centers in the United Kingdom during January-July 2005. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, and frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies have shown an association between PFO and these types of migraines, said Dr. Dowson.

Contrast transthoracic echocardiograms revealed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, reported Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Sham patients underwent general anesthesia and woke up with a groin incision. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients were maintained on their prophylactic migraine medication, although those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack or cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches. Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction.

The MIST investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results sent “a little bit of a mixed message” commented Dr. Williams. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete.” The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” he said. In addition, “in skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

With STARFlex, an umbrellalike Dacron patch is mounted on a pacing lead framework and threaded by catheter through the femoral vein to the right heart. The catheter is then passed into the left atrium through the PFO. After the first umbrella is opened, the catheter is pulled back into the right atrium. Then the second umbrella opened, and the two patches come together, forming a tight seal.

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. For the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The study investigators plan to evaluate residual shunting in the patients who had repairs, Dr. Dawson said. He also proposed that a longer follow-up may show greater benefit from the implants.

Philadelphia Bureau Chief Mitchel L. Zoler contributed to this report.

'Using more conventional migraine trial end points, significant differences were found.' DR. DOWSON

ATLANTA — Patent foramen ovale closure with a septal repair implant gave a modest benefit to patients with migraine and PFO, according to preliminary results of a study with 163 patients.

The enrollment phase of the sham-controlled study also showed that right-to-left cardiac shunts occurred in 60% of the patients with migraine who were screened, Dr. Peter Wilmshurst reported at the annual meeting of the American College of Cardiology.

This prevalence is “very, very high,” commented Dr. David O. Williams, director of interventional cardiology at Rhode Island Hospital in Providence. “The usual prevalence [in the general population] is about 15%–20%,” Dr. Williams said.

Insertion of a STARFlex septal repair implant provided complete migraine relief in 3 of 74 patients (4%) during 6 months of follow-up, the same rate as in the 73 patients who received a sham procedure. Thus the catheter-based device, developed by NMT Medical Inc. (which also sponsored the study) failed to achieve the primary end point of complete headache relief.

“However, using more conventional migraine trial end points, significant differences were found,” noted study investigator Dr. Andrew Dowson, a headache specialist at King's College Hospital in London. Forty-two percent of patients receiving the implant had a 50% reduction in headache days, compared with 23% of sham-treated patients, a statistically significant difference.

The Migraine Intervention with STARFlex Technology (MIST) trial was a prospective, randomized, placebo-controlled, double-blind study that initially screened 432 individuals with migraine. The study was done at 13 centers in the United Kingdom during January-July 2005. Patients were aged 18–60 years, with a minimum 1-year history of migraine with an age at onset no later than 50 years, and frequent migraines (at least 5 days per month but at least 7 headache-free days per month). The study was restricted to those with migraine with aura, because previous studies have shown an association between PFO and these types of migraines, said Dr. Dowson.

Contrast transthoracic echocardiograms revealed that 72 patients had small shunts (atrial and pulmonary), 22 had large pulmonary shunts, 3 had atrial septal defects, and 163 had large patent foramen ovales (PFOs), for a total of 260 shunts, reported Dr. Wilmshurst, a coinvestigator and cardiologist at Royal Shrewsbury (U.K.) Hospital.

The 163 patients with large PFOs were targeted for the study, and after 16 were excluded 147 patients were randomized to receive either PFO closure or a sham operation. Sham patients underwent general anesthesia and woke up with a groin incision. Patients underwent a 3-month healing phase after surgery, followed by a 3-month analysis phase in which migraine occurrences were continually monitored.

Patients were maintained on their prophylactic migraine medication, although those who overused migraine medication were excluded from the study. Other exclusion criteria included prior stroke or transient ischemic attack or cardiac contraindications.

In addition to the significant reduction in headache days, the implant also provided a significantly greater reduction than did sham in headache burden, a measure that incorporates both the frequency and duration of headaches. Patients receiving the implant achieved a 37% reduction in headache burden, from 136 at baseline to 86 at last follow-up, whereas those receiving the sham operation improved from 117 at baseline to 96 at the last 6-month follow-up, a 17% reduction.

The MIST investigators noted that the difference in the magnitude of the reduction between the implant and sham groups was statistically significant.

The results sent “a little bit of a mixed message” commented Dr. Williams. The low rate of complete headache resolution suggests that PFOs may not have an etiologic role in migraine. “On the other hand, there was some improvement, and we wonder whether the closure process may not have been complete.” The high prevalence of cardiac shunts in patients with migraine suggests that screening selected patients with transthoracic echocardiography and then performing repairs when indicated may be a good idea. “It's something to consider for disabled patients,” he said. In addition, “in skilled hands, the risks of PFO closure are very low. The procedural risk is like that for cardiac catheterization.”

With STARFlex, an umbrellalike Dacron patch is mounted on a pacing lead framework and threaded by catheter through the femoral vein to the right heart. The catheter is then passed into the left atrium through the PFO. After the first umbrella is opened, the catheter is pulled back into the right atrium. Then the second umbrella opened, and the two patches come together, forming a tight seal.

In the implant group, five serious adverse events occurred in one patient each: cardiac tamponade, pericardial effusion, retroperitoneal bleeding, atrial fibrillation, and chest pain. For the sham group, one patient had incision site bleeding, two patients had effects of antiplatelet therapy (anemia, nosebleed), and one patient had a brainstem ischemic stroke 4 months into the follow-up.

The study investigators plan to evaluate residual shunting in the patients who had repairs, Dr. Dawson said. He also proposed that a longer follow-up may show greater benefit from the implants.

Philadelphia Bureau Chief Mitchel L. Zoler contributed to this report.

'Using more conventional migraine trial end points, significant differences were found.' DR. DOWSON

Use of selective serotonin reuptake inhibitors during pregnancy is associated with neonatal abstinence syndrome and a slightly increased risk of persistent pulmonary hypertension of the newborn, according to results of two recently published studies.

In a case-control study, infants of women who took SSRIs in the second half of pregnancy were five to six times more likely to develop persistent pulmonary hypertension of the newborn (PPHN), with an overall incidence of 1 case for every 100 exposed infants (N. Engl. J. Med. 2006;354:579–87).

In an accompanying editorial, Dr. James L. Mills wrote that “the association is very unlikely to be due to chance … the current study was well designed and carefully executed.” (N. Engl. J. Med. 2006;354:636–8).

In an interview, however, Dr. Gideon Koren of the Motherisk Program in Toronto, who was not involved in either study, cautioned against placing too much significance on the finding. “If you look more carefully at the numbers, it all hinges on two to three cases. These are very small numbers and although this is a large study, [PPHN] is a very rare condition,” he said.

PPHN, which affects 1–2 infants per 1,000 live births, causes significant morbidity and mortality. In the case-control study, Dr. Christina D. Chambers of the University of California, San Diego, and her associates investigated the association between SSRI use and PPHN in 377 women whose infants had PPHN and 836 matched controls.

Within 6 months after delivery, participants were interviewed by nurses unaware of the study hypothesis. Interviewers collected detailed information on demo-graphics, medications taken during pregnancy, and other risk factors.

Fourteen cases of PPHN were noted among women taking SSRIs after the 20th week of gestation, compared with six cases in control infants (adjusted odds ratio 6.1). PPHN was three times more likely with antidepressant use after the 20th week of pregnancy, five times more likely if the antidepressant was an SSRI, and six times more likely after adjustment for confounding variables. No elevation in risk was observed with SSRI use earlier in pregnancy or when non-SSRI antidepressants were used.

The investigators noted that 3% of infants with PPHN died. Dr. Koren said that he spoke with the study investigators, who told him that none of the infants who died were exposed to SSRIs in utero, a fact that is not noted in the published study.

Dr. Koren cautioned that “it would be sad if because of this study, women discontinue SSRIs in late pregnancy, as [depression] can be life threatening for some and a cause of high rates of morbidity. The best predictor of postpartum depression is depression in late pregnancy.”

An unrelated cohort study found that 30% of 60 infants exposed to SSRIs in utero experienced some degree of neonatal abstinence syndrome; none of 60 control infants showed any symptoms of the syndrome. Among the exposed infants, 10 exhibited mild symptoms and 8 had severe symptoms of neonatal abstinence, according to Dr. Rachel Levinson-Castiel of the Schneider Children's Medical Center of Israel in Petah Tiqwa, and her associates (Arch. Pediatr. Adolesc. Med. 2006;160:173–6).

The most common symptoms, measured using the Finnegan score, included tremors (in 37 SSRI-exposed infants vs. 11 control infants), gastrointestinal disturbances (34 vs. 2), sleep disturbance (21 vs. 2), high-pitched cry (18 vs. 0), and hypertonicity or myoclonus (14 vs. 1). Most symptoms peaked within the first 48 hours after delivery, although maximal scores were observed through day 4.

Although the small study size precluded an evaluation of dose effects for most SSRIs, the investigators found a significant association between paroxetine dose and the degree of neonatal abstinence syndrome symptoms. Infants exposed to doses less than 20 mg showed no signs of the syndrome.

While neonatal abstinence syndrome is indeed a result of withdrawal in most infants, Dr. Koren added that in some cases, the symptoms are instead due to a high level of drug in the neonate.

“This is important because if it is a lack of drug [causing the symptoms], you may want to give the baby an SSRI, whereas if it is poisoning you cannot give the drug,” he said.

The study investigators suggested that infants exposed to SSRIs in utero be followed carefully after delivery. “After birth, close monitoring is mandatory. Early discharge of SSRI-exposed infants should be avoided and observation continued until symptoms subside.”

Use of selective serotonin reuptake inhibitors during pregnancy is associated with neonatal abstinence syndrome and a slightly increased risk of persistent pulmonary hypertension of the newborn, according to results of two recently published studies.

In a case-control study, infants of women who took SSRIs in the second half of pregnancy were five to six times more likely to develop persistent pulmonary hypertension of the newborn (PPHN), with an overall incidence of 1 case for every 100 exposed infants (N. Engl. J. Med. 2006;354:579–87).

In an accompanying editorial, Dr. James L. Mills wrote that “the association is very unlikely to be due to chance … the current study was well designed and carefully executed.” (N. Engl. J. Med. 2006;354:636–8).

In an interview, however, Dr. Gideon Koren of the Motherisk Program in Toronto, who was not involved in either study, cautioned against placing too much significance on the finding. “If you look more carefully at the numbers, it all hinges on two to three cases. These are very small numbers and although this is a large study, [PPHN] is a very rare condition,” he said.

PPHN, which affects 1–2 infants per 1,000 live births, causes significant morbidity and mortality. In the case-control study, Dr. Christina D. Chambers of the University of California, San Diego, and her associates investigated the association between SSRI use and PPHN in 377 women whose infants had PPHN and 836 matched controls.

Within 6 months after delivery, participants were interviewed by nurses unaware of the study hypothesis. Interviewers collected detailed information on demo-graphics, medications taken during pregnancy, and other risk factors.

Fourteen cases of PPHN were noted among women taking SSRIs after the 20th week of gestation, compared with six cases in control infants (adjusted odds ratio 6.1). PPHN was three times more likely with antidepressant use after the 20th week of pregnancy, five times more likely if the antidepressant was an SSRI, and six times more likely after adjustment for confounding variables. No elevation in risk was observed with SSRI use earlier in pregnancy or when non-SSRI antidepressants were used.

The investigators noted that 3% of infants with PPHN died. Dr. Koren said that he spoke with the study investigators, who told him that none of the infants who died were exposed to SSRIs in utero, a fact that is not noted in the published study.

Dr. Koren cautioned that “it would be sad if because of this study, women discontinue SSRIs in late pregnancy, as [depression] can be life threatening for some and a cause of high rates of morbidity. The best predictor of postpartum depression is depression in late pregnancy.”

An unrelated cohort study found that 30% of 60 infants exposed to SSRIs in utero experienced some degree of neonatal abstinence syndrome; none of 60 control infants showed any symptoms of the syndrome. Among the exposed infants, 10 exhibited mild symptoms and 8 had severe symptoms of neonatal abstinence, according to Dr. Rachel Levinson-Castiel of the Schneider Children's Medical Center of Israel in Petah Tiqwa, and her associates (Arch. Pediatr. Adolesc. Med. 2006;160:173–6).

The most common symptoms, measured using the Finnegan score, included tremors (in 37 SSRI-exposed infants vs. 11 control infants), gastrointestinal disturbances (34 vs. 2), sleep disturbance (21 vs. 2), high-pitched cry (18 vs. 0), and hypertonicity or myoclonus (14 vs. 1). Most symptoms peaked within the first 48 hours after delivery, although maximal scores were observed through day 4.

Although the small study size precluded an evaluation of dose effects for most SSRIs, the investigators found a significant association between paroxetine dose and the degree of neonatal abstinence syndrome symptoms. Infants exposed to doses less than 20 mg showed no signs of the syndrome.

While neonatal abstinence syndrome is indeed a result of withdrawal in most infants, Dr. Koren added that in some cases, the symptoms are instead due to a high level of drug in the neonate.

“This is important because if it is a lack of drug [causing the symptoms], you may want to give the baby an SSRI, whereas if it is poisoning you cannot give the drug,” he said.

The study investigators suggested that infants exposed to SSRIs in utero be followed carefully after delivery. “After birth, close monitoring is mandatory. Early discharge of SSRI-exposed infants should be avoided and observation continued until symptoms subside.”

Use of selective serotonin reuptake inhibitors during pregnancy is associated with neonatal abstinence syndrome and a slightly increased risk of persistent pulmonary hypertension of the newborn, according to results of two recently published studies.

In a case-control study, infants of women who took SSRIs in the second half of pregnancy were five to six times more likely to develop persistent pulmonary hypertension of the newborn (PPHN), with an overall incidence of 1 case for every 100 exposed infants (N. Engl. J. Med. 2006;354:579–87).

In an accompanying editorial, Dr. James L. Mills wrote that “the association is very unlikely to be due to chance … the current study was well designed and carefully executed.” (N. Engl. J. Med. 2006;354:636–8).

In an interview, however, Dr. Gideon Koren of the Motherisk Program in Toronto, who was not involved in either study, cautioned against placing too much significance on the finding. “If you look more carefully at the numbers, it all hinges on two to three cases. These are very small numbers and although this is a large study, [PPHN] is a very rare condition,” he said.

PPHN, which affects 1–2 infants per 1,000 live births, causes significant morbidity and mortality. In the case-control study, Dr. Christina D. Chambers of the University of California, San Diego, and her associates investigated the association between SSRI use and PPHN in 377 women whose infants had PPHN and 836 matched controls.

Within 6 months after delivery, participants were interviewed by nurses unaware of the study hypothesis. Interviewers collected detailed information on demo-graphics, medications taken during pregnancy, and other risk factors.

Fourteen cases of PPHN were noted among women taking SSRIs after the 20th week of gestation, compared with six cases in control infants (adjusted odds ratio 6.1). PPHN was three times more likely with antidepressant use after the 20th week of pregnancy, five times more likely if the antidepressant was an SSRI, and six times more likely after adjustment for confounding variables. No elevation in risk was observed with SSRI use earlier in pregnancy or when non-SSRI antidepressants were used.

The investigators noted that 3% of infants with PPHN died. Dr. Koren said that he spoke with the study investigators, who told him that none of the infants who died were exposed to SSRIs in utero, a fact that is not noted in the published study.

Dr. Koren cautioned that “it would be sad if because of this study, women discontinue SSRIs in late pregnancy, as [depression] can be life threatening for some and a cause of high rates of morbidity. The best predictor of postpartum depression is depression in late pregnancy.”

An unrelated cohort study found that 30% of 60 infants exposed to SSRIs in utero experienced some degree of neonatal abstinence syndrome; none of 60 control infants showed any symptoms of the syndrome. Among the exposed infants, 10 exhibited mild symptoms and 8 had severe symptoms of neonatal abstinence, according to Dr. Rachel Levinson-Castiel of the Schneider Children's Medical Center of Israel in Petah Tiqwa, and her associates (Arch. Pediatr. Adolesc. Med. 2006;160:173–6).

The most common symptoms, measured using the Finnegan score, included tremors (in 37 SSRI-exposed infants vs. 11 control infants), gastrointestinal disturbances (34 vs. 2), sleep disturbance (21 vs. 2), high-pitched cry (18 vs. 0), and hypertonicity or myoclonus (14 vs. 1). Most symptoms peaked within the first 48 hours after delivery, although maximal scores were observed through day 4.

Although the small study size precluded an evaluation of dose effects for most SSRIs, the investigators found a significant association between paroxetine dose and the degree of neonatal abstinence syndrome symptoms. Infants exposed to doses less than 20 mg showed no signs of the syndrome.

While neonatal abstinence syndrome is indeed a result of withdrawal in most infants, Dr. Koren added that in some cases, the symptoms are instead due to a high level of drug in the neonate.

“This is important because if it is a lack of drug [causing the symptoms], you may want to give the baby an SSRI, whereas if it is poisoning you cannot give the drug,” he said.

The study investigators suggested that infants exposed to SSRIs in utero be followed carefully after delivery. “After birth, close monitoring is mandatory. Early discharge of SSRI-exposed infants should be avoided and observation continued until symptoms subside.”

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. Established palliative care services might help hospitals better provide for these patients and their families. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing such programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee. “The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” noted the investigators.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. Established palliative care services might help hospitals better provide for these patients and their families. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing such programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee. “The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” noted the investigators.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. Established palliative care services might help hospitals better provide for these patients and their families. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing such programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee. “The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” noted the investigators.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing palliative care programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee.

“The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” the investigators noted.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

The investigators commented that “it takes time to implement a palliative care consultation service,” suggesting that ongoing mentoring and assistance could be beneficial. In fact, 60% of the hospitals participating in the program helped other hospitals develop palliative care services.

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing palliative care programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee.

“The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” the investigators noted.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

The investigators commented that “it takes time to implement a palliative care consultation service,” suggesting that ongoing mentoring and assistance could be beneficial. In fact, 60% of the hospitals participating in the program helped other hospitals develop palliative care services.

A California program has helped hospitals establish palliative care services, according to a recent study evaluating the program 1 year after its completion.

Given that more than half of people in the United States die in a hospital, end-of-life care is an important part of hospital services. The California Hospital Initiative in Palliative Services (CHIPS) program was designed to assist hospitals in organizing palliative care programs (Arch. Intern. Med. 2006;166:227–30).

Dr. Steven Z. Pantilat of the University of California at San Francisco and associates recruited all types of hospitals across California for the program. Interested hospitals had to demonstrate their readiness, obtain administration approval, and pay a $2,500 fee.

“The typical hospital participating in CHIPS was a large, not-for-profit, private hospital in an urban setting that had a hospitalist program,” the investigators noted.

The 38 participating hospitals sent three-person multidisciplinary teams to a skills conference where they were paired with a CHIPS mentor. For 10 months, mentors consulted regularly with the teams. Between 8 and 11 months after the first conference, a reunion conference was held focusing on participants' needs, challenges, and successes. Two cohorts of hospital teams have completed the program.

A follow-up cross-sectional telephone survey was conducted 29 months after the initial conference for cohort 1 (18 months for cohort 2). By the time of the survey, of the 32 hospitals without a palliative care program, 19 had established new palliative care consultation services, a success rate of 60%. The six hospitals with existing services continued to offer them, giving an overall success rate of 66%. Urban hospitals and those with a hospitalist program were significantly more likely to establish new programs.

The investigators commented that “it takes time to implement a palliative care consultation service,” suggesting that ongoing mentoring and assistance could be beneficial. In fact, 60% of the hospitals participating in the program helped other hospitals develop palliative care services.