Obstetrics

ASHEVILLE, N.C. — Small changes in technique can make a big difference in cesarean section outcomes, which is why it's important to keep up to date with the evidence concerning this procedure, Thomas Ivester, M.D., said at the Southern Obstetric and Gynecologic Seminar.

With an estimated 800,000–1,000,000 C-sections performed in the United States each year, “small improvements in our technique and reductions in morbidity and mortality have a profound effect on the public's health and confer substantial benefits with regard to maternal health,” said Dr. Ivester, of the University of North Carolina at Chapel Hill.

Still, “for a lot of things that we do, we don't really know why we do it. I think that a lot of our specialty is governed by tradition and convention that's just been handed down over the years,” said Dr. Ivester. He offered his thoughts on the existing data for a number of aspects of C-section.

Incision Type

Low transverse incisions (Pfannenstiel, Maylard, Cherney) have a far lower rate of dehiscence than do midline incisions. Good exposure is possible, especially with extension techniques. These incisions are less painful for patients. Low transverse abdominal incisions are appropriate for obese patients, who have complication rates similar to or better than those of patients receiving vertical incisions.

Cautery Use

Minimal cautery use is generally recommended; the assumption is that cauterization devitalizes tissue, hindering the angiogenesis needed for wound repair.

Bladder Flaps

Forming a bladder flap is very commonly done, but there's actually not much data to support it or refute this practice, said Dr. Ivester. In one small study, forming a bladder flap increased operative time by as much as 5 minutes and resulted in a small increase in the amount of blood lost, compared with no bladder flap (Obstet. Gynecol. 2001;98:1089–92).

Blunt vs. Sharp Extension

Data suggest that extension 3 cm beyond the proposed incision occurs less frequently with blunt dissection than with dissection using banded scissors. In addition, sharp dissection appears to lead to slightly greater blood loss and a higher transfusion rate than does blunt dissection.

Placental Delivery

There does not appear to be a difference in the amount of blood loss or in transfusion rates between women who undergo manual extraction versus spontaneous delivery of the placenta. A significant reduction in the rate of endometriosis for women who had spontaneous placental delivery compared with manual extraction has been noted in the literature. Postpartum hemorrhage may occur less frequently with spontaneous delivery, and wound infection rates appear to be lower, too.

Additional Deliveries

Less than 18 months between deliveries increases the risk of uterine rupture by 3–4 times compared with intervals of 18 months or greater, said Dr. Ivester. Ensure that your patients are on appropriate birth control to avoid deliveries less than 18 months apart.

Avoid using a T-incision in cases when an extension is needed to deliver a baby. “You've now interrupted blood flow in two different directions, and you've actually increased the risk of rupture [during subsequent deliveries] to the same degree as with the classic incision,” if not more, he said.

Uterine Repair

The question remains whether to take the uterus out or leave it in. The potential advantages of exteriorization of the uterus include better exposure, decreased blood loss, easier access for uterine massage and inspection of the pelvic nexa, but maternal postoperative and intrapartum discomfort is greater, said Dr. Ivester.

Peritoneal Closure

Peritoneal closure is another hotly debated topic. “There's probably 15%–20% of obstetricians who close the peritoneum, because in their own series, they had a significantly lower risk of adhesion formation,” said Dr. Ivester.

Most of the limited data come from retrospective series, in which it was often hard to tease out who had peritoneal closure. In these small prospective series, patients who did not have peritoneal closure had lower rates of narcotic use, improved bowel function at 24 hours, decreased operative time, and decreased rates of cystitis. There are a number of studies in progress that might shed some light on whether to close the peritoneum.

There is also a question about the choice of suture material. “If you're closing this peritoneum with some highly inflammatory type suture material like chromic, certainly some inflammatory changes or responses may be elicited,” said Dr. Ivester. Switching to something less reactive, such as Vicryl or Monocryl, might be a better choice. Recent evidence from Stanford University demonstrates that closure of the parietal peritoneum resulted in substantially improved rates of adhesion formation for women undergoing cesarean delivery (Obstet. Gynecol. 2005;106:275–80).

Fascia Closure

A number of studies have shown that a continuous running suture works well for fascia closure. Vicryl is an appropriate choice of suture material for a first delivery. Polydioxanone suture is a good choice for obese or diabetic patients. A loop is preferable, because it tends to reduce the number of knots.

The zone of optimal healing is 0.75 mm back from the incision edge. Dr. Ivester recommends working 1 cm back and 1 cm apart with sutures. This provides a balance between optimizing the strength of the repair and allowing space to promote angiogenesis and healing of the incision.

Avoid “postage-stamping” the incision. “You don't necessarily want to be neat. Frequently you'll see—especially in obese patients—it's not the sutures themselves that break. It's this line that's created from this perfectly approximated fascia that looks really beautiful and is really neat. You've basically just created a perforation line like a postage stamp that they rip open the first time they cough or have a good chuckle,” said Dr. Ivester.

The data are mixed on whether to use drains or subcutaneous closure. Some studies have shown significant reductions in wound complications by using drains or subcutaneous closure compared with patients who received neither. Other studies have shown no differences.

“In patients with low platelets or bleeding disorders, drains may be useful, while we tend toward subcutaneous closure in obese women,” Dr. Ivester said.

Antibiotic Use

The debate continues over when to give antibiotics. At Dr. Ivester's hospital antibiotics were previously given on the way to the operating room. Now they are given at cord clamping. The gynecology literature suggests that the best results are obtained when antibiotics are given 30–60 minutes preoperatively. Prophylactic antibiotics (first-generation cephalosporins) have reduced endometritis rates at his hospital.

Wound complications also appear to be lower in the literature for prophylactic antibiotics.

ASHEVILLE, N.C. — Small changes in technique can make a big difference in cesarean section outcomes, which is why it's important to keep up to date with the evidence concerning this procedure, Thomas Ivester, M.D., said at the Southern Obstetric and Gynecologic Seminar.

With an estimated 800,000–1,000,000 C-sections performed in the United States each year, “small improvements in our technique and reductions in morbidity and mortality have a profound effect on the public's health and confer substantial benefits with regard to maternal health,” said Dr. Ivester, of the University of North Carolina at Chapel Hill.

Still, “for a lot of things that we do, we don't really know why we do it. I think that a lot of our specialty is governed by tradition and convention that's just been handed down over the years,” said Dr. Ivester. He offered his thoughts on the existing data for a number of aspects of C-section.

Incision Type

Low transverse incisions (Pfannenstiel, Maylard, Cherney) have a far lower rate of dehiscence than do midline incisions. Good exposure is possible, especially with extension techniques. These incisions are less painful for patients. Low transverse abdominal incisions are appropriate for obese patients, who have complication rates similar to or better than those of patients receiving vertical incisions.

Cautery Use

Minimal cautery use is generally recommended; the assumption is that cauterization devitalizes tissue, hindering the angiogenesis needed for wound repair.

Bladder Flaps

Forming a bladder flap is very commonly done, but there's actually not much data to support it or refute this practice, said Dr. Ivester. In one small study, forming a bladder flap increased operative time by as much as 5 minutes and resulted in a small increase in the amount of blood lost, compared with no bladder flap (Obstet. Gynecol. 2001;98:1089–92).

Blunt vs. Sharp Extension

Data suggest that extension 3 cm beyond the proposed incision occurs less frequently with blunt dissection than with dissection using banded scissors. In addition, sharp dissection appears to lead to slightly greater blood loss and a higher transfusion rate than does blunt dissection.

Placental Delivery

There does not appear to be a difference in the amount of blood loss or in transfusion rates between women who undergo manual extraction versus spontaneous delivery of the placenta. A significant reduction in the rate of endometriosis for women who had spontaneous placental delivery compared with manual extraction has been noted in the literature. Postpartum hemorrhage may occur less frequently with spontaneous delivery, and wound infection rates appear to be lower, too.

Additional Deliveries

Less than 18 months between deliveries increases the risk of uterine rupture by 3–4 times compared with intervals of 18 months or greater, said Dr. Ivester. Ensure that your patients are on appropriate birth control to avoid deliveries less than 18 months apart.

Avoid using a T-incision in cases when an extension is needed to deliver a baby. “You've now interrupted blood flow in two different directions, and you've actually increased the risk of rupture [during subsequent deliveries] to the same degree as with the classic incision,” if not more, he said.

Uterine Repair

The question remains whether to take the uterus out or leave it in. The potential advantages of exteriorization of the uterus include better exposure, decreased blood loss, easier access for uterine massage and inspection of the pelvic nexa, but maternal postoperative and intrapartum discomfort is greater, said Dr. Ivester.

Peritoneal Closure

Peritoneal closure is another hotly debated topic. “There's probably 15%–20% of obstetricians who close the peritoneum, because in their own series, they had a significantly lower risk of adhesion formation,” said Dr. Ivester.

Most of the limited data come from retrospective series, in which it was often hard to tease out who had peritoneal closure. In these small prospective series, patients who did not have peritoneal closure had lower rates of narcotic use, improved bowel function at 24 hours, decreased operative time, and decreased rates of cystitis. There are a number of studies in progress that might shed some light on whether to close the peritoneum.

There is also a question about the choice of suture material. “If you're closing this peritoneum with some highly inflammatory type suture material like chromic, certainly some inflammatory changes or responses may be elicited,” said Dr. Ivester. Switching to something less reactive, such as Vicryl or Monocryl, might be a better choice. Recent evidence from Stanford University demonstrates that closure of the parietal peritoneum resulted in substantially improved rates of adhesion formation for women undergoing cesarean delivery (Obstet. Gynecol. 2005;106:275–80).

Fascia Closure

A number of studies have shown that a continuous running suture works well for fascia closure. Vicryl is an appropriate choice of suture material for a first delivery. Polydioxanone suture is a good choice for obese or diabetic patients. A loop is preferable, because it tends to reduce the number of knots.

The zone of optimal healing is 0.75 mm back from the incision edge. Dr. Ivester recommends working 1 cm back and 1 cm apart with sutures. This provides a balance between optimizing the strength of the repair and allowing space to promote angiogenesis and healing of the incision.

Avoid “postage-stamping” the incision. “You don't necessarily want to be neat. Frequently you'll see—especially in obese patients—it's not the sutures themselves that break. It's this line that's created from this perfectly approximated fascia that looks really beautiful and is really neat. You've basically just created a perforation line like a postage stamp that they rip open the first time they cough or have a good chuckle,” said Dr. Ivester.

The data are mixed on whether to use drains or subcutaneous closure. Some studies have shown significant reductions in wound complications by using drains or subcutaneous closure compared with patients who received neither. Other studies have shown no differences.

“In patients with low platelets or bleeding disorders, drains may be useful, while we tend toward subcutaneous closure in obese women,” Dr. Ivester said.

Antibiotic Use

The debate continues over when to give antibiotics. At Dr. Ivester's hospital antibiotics were previously given on the way to the operating room. Now they are given at cord clamping. The gynecology literature suggests that the best results are obtained when antibiotics are given 30–60 minutes preoperatively. Prophylactic antibiotics (first-generation cephalosporins) have reduced endometritis rates at his hospital.

Wound complications also appear to be lower in the literature for prophylactic antibiotics.

ASHEVILLE, N.C. — Small changes in technique can make a big difference in cesarean section outcomes, which is why it's important to keep up to date with the evidence concerning this procedure, Thomas Ivester, M.D., said at the Southern Obstetric and Gynecologic Seminar.

With an estimated 800,000–1,000,000 C-sections performed in the United States each year, “small improvements in our technique and reductions in morbidity and mortality have a profound effect on the public's health and confer substantial benefits with regard to maternal health,” said Dr. Ivester, of the University of North Carolina at Chapel Hill.

Still, “for a lot of things that we do, we don't really know why we do it. I think that a lot of our specialty is governed by tradition and convention that's just been handed down over the years,” said Dr. Ivester. He offered his thoughts on the existing data for a number of aspects of C-section.

Incision Type

Low transverse incisions (Pfannenstiel, Maylard, Cherney) have a far lower rate of dehiscence than do midline incisions. Good exposure is possible, especially with extension techniques. These incisions are less painful for patients. Low transverse abdominal incisions are appropriate for obese patients, who have complication rates similar to or better than those of patients receiving vertical incisions.

Cautery Use

Minimal cautery use is generally recommended; the assumption is that cauterization devitalizes tissue, hindering the angiogenesis needed for wound repair.

Bladder Flaps

Forming a bladder flap is very commonly done, but there's actually not much data to support it or refute this practice, said Dr. Ivester. In one small study, forming a bladder flap increased operative time by as much as 5 minutes and resulted in a small increase in the amount of blood lost, compared with no bladder flap (Obstet. Gynecol. 2001;98:1089–92).

Blunt vs. Sharp Extension

Data suggest that extension 3 cm beyond the proposed incision occurs less frequently with blunt dissection than with dissection using banded scissors. In addition, sharp dissection appears to lead to slightly greater blood loss and a higher transfusion rate than does blunt dissection.

Placental Delivery

There does not appear to be a difference in the amount of blood loss or in transfusion rates between women who undergo manual extraction versus spontaneous delivery of the placenta. A significant reduction in the rate of endometriosis for women who had spontaneous placental delivery compared with manual extraction has been noted in the literature. Postpartum hemorrhage may occur less frequently with spontaneous delivery, and wound infection rates appear to be lower, too.

Additional Deliveries

Less than 18 months between deliveries increases the risk of uterine rupture by 3–4 times compared with intervals of 18 months or greater, said Dr. Ivester. Ensure that your patients are on appropriate birth control to avoid deliveries less than 18 months apart.

Avoid using a T-incision in cases when an extension is needed to deliver a baby. “You've now interrupted blood flow in two different directions, and you've actually increased the risk of rupture [during subsequent deliveries] to the same degree as with the classic incision,” if not more, he said.

Uterine Repair

The question remains whether to take the uterus out or leave it in. The potential advantages of exteriorization of the uterus include better exposure, decreased blood loss, easier access for uterine massage and inspection of the pelvic nexa, but maternal postoperative and intrapartum discomfort is greater, said Dr. Ivester.

Peritoneal Closure

Peritoneal closure is another hotly debated topic. “There's probably 15%–20% of obstetricians who close the peritoneum, because in their own series, they had a significantly lower risk of adhesion formation,” said Dr. Ivester.

Most of the limited data come from retrospective series, in which it was often hard to tease out who had peritoneal closure. In these small prospective series, patients who did not have peritoneal closure had lower rates of narcotic use, improved bowel function at 24 hours, decreased operative time, and decreased rates of cystitis. There are a number of studies in progress that might shed some light on whether to close the peritoneum.

There is also a question about the choice of suture material. “If you're closing this peritoneum with some highly inflammatory type suture material like chromic, certainly some inflammatory changes or responses may be elicited,” said Dr. Ivester. Switching to something less reactive, such as Vicryl or Monocryl, might be a better choice. Recent evidence from Stanford University demonstrates that closure of the parietal peritoneum resulted in substantially improved rates of adhesion formation for women undergoing cesarean delivery (Obstet. Gynecol. 2005;106:275–80).

Fascia Closure

A number of studies have shown that a continuous running suture works well for fascia closure. Vicryl is an appropriate choice of suture material for a first delivery. Polydioxanone suture is a good choice for obese or diabetic patients. A loop is preferable, because it tends to reduce the number of knots.

The zone of optimal healing is 0.75 mm back from the incision edge. Dr. Ivester recommends working 1 cm back and 1 cm apart with sutures. This provides a balance between optimizing the strength of the repair and allowing space to promote angiogenesis and healing of the incision.

Avoid “postage-stamping” the incision. “You don't necessarily want to be neat. Frequently you'll see—especially in obese patients—it's not the sutures themselves that break. It's this line that's created from this perfectly approximated fascia that looks really beautiful and is really neat. You've basically just created a perforation line like a postage stamp that they rip open the first time they cough or have a good chuckle,” said Dr. Ivester.

The data are mixed on whether to use drains or subcutaneous closure. Some studies have shown significant reductions in wound complications by using drains or subcutaneous closure compared with patients who received neither. Other studies have shown no differences.

“In patients with low platelets or bleeding disorders, drains may be useful, while we tend toward subcutaneous closure in obese women,” Dr. Ivester said.

Antibiotic Use

The debate continues over when to give antibiotics. At Dr. Ivester's hospital antibiotics were previously given on the way to the operating room. Now they are given at cord clamping. The gynecology literature suggests that the best results are obtained when antibiotics are given 30–60 minutes preoperatively. Prophylactic antibiotics (first-generation cephalosporins) have reduced endometritis rates at his hospital.

Wound complications also appear to be lower in the literature for prophylactic antibiotics.

CHARLESTON, S.C. — Oral valacyclovir was the most economically favorable treatment choice for the prevention of intrapartum herpes transmission in a recent analysis.

The clinical outcomes and costs of the three strategies, including oral valacyclovir, oral acyclovir, and no prophylaxis, were compared using a decision analysis model in a hypothetical cohort of 1 million women with recurrent herpes infection. All strategies included cesarean section for patients with active lesions during labor, Monique G. Lin, M.D., of the University of Alabama, Birmingham, and her colleagues reported in a poster at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The valacyclovir model included 500 mg given twice daily beginning at 36 weeks' gestation; the oral acyclovir model included 200 mg given four times daily beginning at 36 weeks' gestation.

The investigators used the literature and “local sources” to determine baseline costs, and based their analysis on current treatment strategies that employ polymerase chain reaction, viral culture, and high-dose intravenous acyclovir for treatment of affected neonates. Using this model, the researchers showed that the total costs in the hypothetical cohort were $9.94 billion for valacyclovir, $9.93 billion for acyclovir, and $13.7 billion for no prophylaxis.

The number of cases of neonatal death or moderate-to-severe neonatal morbidity associated with each treatment in this model was 1,911 with valacyclovir, 2,111 with acyclovir, and 8,240 with no prophylaxis.

The number of cases prevented by using valacyclovir prophylaxis was 6,239, and the number prevented by using acyclovir prophylaxis was 6,129.

The cost per case prevented was $1.57 million for valacyclovir and $1.62 million for acyclovir, the investigators reported at the meeting.

CHARLESTON, S.C. — Oral valacyclovir was the most economically favorable treatment choice for the prevention of intrapartum herpes transmission in a recent analysis.

The clinical outcomes and costs of the three strategies, including oral valacyclovir, oral acyclovir, and no prophylaxis, were compared using a decision analysis model in a hypothetical cohort of 1 million women with recurrent herpes infection. All strategies included cesarean section for patients with active lesions during labor, Monique G. Lin, M.D., of the University of Alabama, Birmingham, and her colleagues reported in a poster at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The valacyclovir model included 500 mg given twice daily beginning at 36 weeks' gestation; the oral acyclovir model included 200 mg given four times daily beginning at 36 weeks' gestation.

The investigators used the literature and “local sources” to determine baseline costs, and based their analysis on current treatment strategies that employ polymerase chain reaction, viral culture, and high-dose intravenous acyclovir for treatment of affected neonates. Using this model, the researchers showed that the total costs in the hypothetical cohort were $9.94 billion for valacyclovir, $9.93 billion for acyclovir, and $13.7 billion for no prophylaxis.

The number of cases of neonatal death or moderate-to-severe neonatal morbidity associated with each treatment in this model was 1,911 with valacyclovir, 2,111 with acyclovir, and 8,240 with no prophylaxis.

The number of cases prevented by using valacyclovir prophylaxis was 6,239, and the number prevented by using acyclovir prophylaxis was 6,129.

The cost per case prevented was $1.57 million for valacyclovir and $1.62 million for acyclovir, the investigators reported at the meeting.

CHARLESTON, S.C. — Oral valacyclovir was the most economically favorable treatment choice for the prevention of intrapartum herpes transmission in a recent analysis.

The clinical outcomes and costs of the three strategies, including oral valacyclovir, oral acyclovir, and no prophylaxis, were compared using a decision analysis model in a hypothetical cohort of 1 million women with recurrent herpes infection. All strategies included cesarean section for patients with active lesions during labor, Monique G. Lin, M.D., of the University of Alabama, Birmingham, and her colleagues reported in a poster at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

The valacyclovir model included 500 mg given twice daily beginning at 36 weeks' gestation; the oral acyclovir model included 200 mg given four times daily beginning at 36 weeks' gestation.

The investigators used the literature and “local sources” to determine baseline costs, and based their analysis on current treatment strategies that employ polymerase chain reaction, viral culture, and high-dose intravenous acyclovir for treatment of affected neonates. Using this model, the researchers showed that the total costs in the hypothetical cohort were $9.94 billion for valacyclovir, $9.93 billion for acyclovir, and $13.7 billion for no prophylaxis.

The number of cases of neonatal death or moderate-to-severe neonatal morbidity associated with each treatment in this model was 1,911 with valacyclovir, 2,111 with acyclovir, and 8,240 with no prophylaxis.

The number of cases prevented by using valacyclovir prophylaxis was 6,239, and the number prevented by using acyclovir prophylaxis was 6,129.

The cost per case prevented was $1.57 million for valacyclovir and $1.62 million for acyclovir, the investigators reported at the meeting.

ASHEVILLE, N.C. — Peripartum hemorrhage is one of the leading causes of maternal mortality, making it important to understand the myriad options for controlling bleeding, David C. Mayer, M.D., said at the Southern Obstetric and Gynecologic Seminar.

“Unfortunately, over the decades, hemorrhage has never been moved out of the top three causes of maternal mortality,” said Dr. Mayer of the department of anesthesiology at the University of North Carolina at Chapel Hill.

Peripartum hemorrhage accounts for as much as 18% of pregnancy-related deaths in the United States, according to one estimate.

Resuscitation is the first goal in the management of peripartum hemorrhage (PPH). Make sure there is an adequate number of intravenous lines and maintain adequate volume by using crystalloids, colloids, packed red blood cells, fresh frozen plasma, or platelets, as necessary. Get baseline blood laboratory tests, including a coagulation profile, and monitor arterial blood gas levels and urinary output. Invasive monitoring with arterial or central venous lines may be necessary, as may consultation with specialists, cautioned Dr. Mayer.

There are a number of options to control bleeding: pharmacologic (such as prostaglandins), autologous blood transfusion, and selective arterial embolization. Pharmacologic therapy includes oxytocics, ergot alkaloids, prostaglandins, and recombinant activated factor VII (rFVIIa). Keep in mind almost all studies of pharmacologic therapies are based on routine elective cesarean sections.

“It may have very little applicability to a patient with an atonic uterus,” Dr. Mayer said.

Oxytocin (Pitocin) is the pharmacologic therapy that most obstetricians go to first to control bleeding. The drug can be used as prophylaxis in women who are at high risk for PPH, with doses of 10–40 U/L administered intravenously. “For uterine atony, I'm very aggressive with oxytocin, except for giving a large bolus,” Dr. Mayer said during the meeting.

He recommends using up to 40–60 U/L given intravenously. Avoid using an intravenous bolus greater than 2 IU. A bolus less than 2 IU can be effective and is unlikely to be problematic, especially if blood pressure is supported. “Just remember that if your patient is already hypotensive, it's probably not the thing to do—increasing the rate of oxytocin,” said Dr. Mayer, also of the department of obstetrics and gynecology at the university.

Ergot alkaloids—ergonovine and methylergonovine—are very effective at inducing contractions. While the exact mechanism of action is unclear, ergot alkaloids are believed to have adrenergic, dopaminergic, and tryptaminergic effects. “Most people now think that it's the adrenergic effect that causes the increased uterine contractility,” Dr. Mayer said.

However, it's also thought that the adrenergic effect is responsible for some of the concerning side effects. Ergot alkaloids produce vasoconstriction that can last for 1–4 hours. These drugs are associated with hypertension, increased central blood volume, coronary vasospasm, pulmonary edema, and cerebrovascular accidents. The dopaminergic stimulation produces nausea and vomiting that can be severe in about 20% of patients. Ergot alkaloids should be given in a very controlled manner to avoid complications such as vasospasm and decreased ejection fractions.

The range of options in the prostaglandin family could grow in the future. “We don't have the whole armamentarium that they do in Europe and I think that someday we may,” Dr. Mayer said. Prostaglandins available in the United States include carboprost (15-methyl prostaglandin F_2α), misoprostol (prostaglandin E₁), dinoprost (prostaglandin F_2α), and dinoprostone (prostaglandin E₂).

The side effect profile for these drugs is different from that of the oxytocics or ergot alkaloids. Prostaglandins do not contribute to significant vasoconstriction. One big drawback for these drugs is that they cannot be administered intravenously. Instead, prostaglandins can be administered intramuscularly and intramyometrially. Prostaglandins E₁ and E₂ also can be administered orally, vaginally, or rectally.

“There's nothing to suggest that there's a better drug than carboprost,” Dr. Mayer said. Carboprost (Hemabate) is 10 times more potent than the parent compound (prostaglandin F_2α). It has minimal effect on the cardiovascular system. Severe bronchial constriction is the one real problem associated with carboprost, even in patients without asthma. This can result in bronchospasm, regional ventilation perfusion mismatch, and arterial desaturation. Patients receiving carboprost should be monitored with a pulse oximeter until at least an hour after the last dose. Dosing is 250 mcg given every 15 to 45 minutes, up to a maximum of 8 doses.

Both carboprost and methylergonovine are contraindicated in patients with cardiovascular and respiratory problems. Misoprostol—a synthetic oral prostaglandin E₁ analog—may be one option for these patients. “Misoprostol plays a major role in [the management of] peripartum hemorrhage,” Dr. Mayer said. It is not associated with bronchospasm, has no major cardiovascular effects, and can be stored for a long time without refrigeration.

Based on the literature, the evidence is not sufficient at this time to support routine use of misoprostol for the prevention of PPH. “The drug has such a high safety profile that it may be more useful in a treatment role” said Dr. Mayer. He recommends using 800–1,000 mcg administered rectally.

Many PPH cases have a major component of acquired coagulopathy, making rFVIIa (Novoseven) a treatment option, indicated for hemophilia A or B, with inhibitors of factor VII or factor IX. The drug induces hemostasis independent of factor VII or IX. It complexes with tissue factor to promote the conversion of factor IX to factor IXa, factor X to factor Xa, and prothrombin to thrombin—the key parts of the coagulation cascade. The drug produces clots, making it theoretically contraindicated in patients with disseminated intravascular coagulopathy.

The literature on the use of rFVIIa for PPH has been encouraging so far. In a recent study, 12 patients with severe PPH (estimated blood loss of 5–25 L) were treated with the drug (Br. J. Anaesth. 2005;94:592–5). All had previously undergone surgery, and one-third had arterial ligation. Eleven patients had a positive response.

“They're feeling was to give the drug at 1.5 L blood volume loss—it buys time,” said Dr. Mayer.

However, the drug is very expensive. The cost equivalent of a single 90-mcg/kg dose is 50 units of packed red blood cells, 2 days in the ICU, or an embolization procedure. In patients for whom surgical options have been explored, for whom there are no vascular interventional radiology options, for whom significant blood products are required, and for whom results of the coagulation studies are elevated, “this is a very reasonable drug to give,” Dr. Mayer said.

Intraoperative autologous transfusion should be considered when there is major blood loss and an inadequate amount of packed red blood cells is available. Potential risks associated with obstetric use include amniotic fluid embolism and maternal exposure to fetal red cells. However, in 400 exposures to intraoperative autologous transfusion, there has been only one case of amniotic fluid embolism that was not confirmed pathologically. Heparin toxicity also has been associated with the technique.

At the University of North Carolina at Chapel Hill, the cell saver has been used for 12 obstetric patients. “It's a perfect solution for Jehovah's Witnesses with risk factors, such as a known placenta percreta,” said Dr. Mayer. Blood was autotransfused in only one case though. This patient received 1,200 mL of salvaged blood with no problems.

Selective arterial embolization is highly successful when it can be performed. There are very few complications—fever is the most common. The technique also can be used prophylactically using a balloon. Coagulopathy is not a contraindication, so it's a good option for these patients.

ASHEVILLE, N.C. — Peripartum hemorrhage is one of the leading causes of maternal mortality, making it important to understand the myriad options for controlling bleeding, David C. Mayer, M.D., said at the Southern Obstetric and Gynecologic Seminar.

“Unfortunately, over the decades, hemorrhage has never been moved out of the top three causes of maternal mortality,” said Dr. Mayer of the department of anesthesiology at the University of North Carolina at Chapel Hill.

Peripartum hemorrhage accounts for as much as 18% of pregnancy-related deaths in the United States, according to one estimate.

Resuscitation is the first goal in the management of peripartum hemorrhage (PPH). Make sure there is an adequate number of intravenous lines and maintain adequate volume by using crystalloids, colloids, packed red blood cells, fresh frozen plasma, or platelets, as necessary. Get baseline blood laboratory tests, including a coagulation profile, and monitor arterial blood gas levels and urinary output. Invasive monitoring with arterial or central venous lines may be necessary, as may consultation with specialists, cautioned Dr. Mayer.

There are a number of options to control bleeding: pharmacologic (such as prostaglandins), autologous blood transfusion, and selective arterial embolization. Pharmacologic therapy includes oxytocics, ergot alkaloids, prostaglandins, and recombinant activated factor VII (rFVIIa). Keep in mind almost all studies of pharmacologic therapies are based on routine elective cesarean sections.

“It may have very little applicability to a patient with an atonic uterus,” Dr. Mayer said.

Oxytocin (Pitocin) is the pharmacologic therapy that most obstetricians go to first to control bleeding. The drug can be used as prophylaxis in women who are at high risk for PPH, with doses of 10–40 U/L administered intravenously. “For uterine atony, I'm very aggressive with oxytocin, except for giving a large bolus,” Dr. Mayer said during the meeting.

He recommends using up to 40–60 U/L given intravenously. Avoid using an intravenous bolus greater than 2 IU. A bolus less than 2 IU can be effective and is unlikely to be problematic, especially if blood pressure is supported. “Just remember that if your patient is already hypotensive, it's probably not the thing to do—increasing the rate of oxytocin,” said Dr. Mayer, also of the department of obstetrics and gynecology at the university.

Ergot alkaloids—ergonovine and methylergonovine—are very effective at inducing contractions. While the exact mechanism of action is unclear, ergot alkaloids are believed to have adrenergic, dopaminergic, and tryptaminergic effects. “Most people now think that it's the adrenergic effect that causes the increased uterine contractility,” Dr. Mayer said.

However, it's also thought that the adrenergic effect is responsible for some of the concerning side effects. Ergot alkaloids produce vasoconstriction that can last for 1–4 hours. These drugs are associated with hypertension, increased central blood volume, coronary vasospasm, pulmonary edema, and cerebrovascular accidents. The dopaminergic stimulation produces nausea and vomiting that can be severe in about 20% of patients. Ergot alkaloids should be given in a very controlled manner to avoid complications such as vasospasm and decreased ejection fractions.

The range of options in the prostaglandin family could grow in the future. “We don't have the whole armamentarium that they do in Europe and I think that someday we may,” Dr. Mayer said. Prostaglandins available in the United States include carboprost (15-methyl prostaglandin F_2α), misoprostol (prostaglandin E₁), dinoprost (prostaglandin F_2α), and dinoprostone (prostaglandin E₂).

The side effect profile for these drugs is different from that of the oxytocics or ergot alkaloids. Prostaglandins do not contribute to significant vasoconstriction. One big drawback for these drugs is that they cannot be administered intravenously. Instead, prostaglandins can be administered intramuscularly and intramyometrially. Prostaglandins E₁ and E₂ also can be administered orally, vaginally, or rectally.

“There's nothing to suggest that there's a better drug than carboprost,” Dr. Mayer said. Carboprost (Hemabate) is 10 times more potent than the parent compound (prostaglandin F_2α). It has minimal effect on the cardiovascular system. Severe bronchial constriction is the one real problem associated with carboprost, even in patients without asthma. This can result in bronchospasm, regional ventilation perfusion mismatch, and arterial desaturation. Patients receiving carboprost should be monitored with a pulse oximeter until at least an hour after the last dose. Dosing is 250 mcg given every 15 to 45 minutes, up to a maximum of 8 doses.

Both carboprost and methylergonovine are contraindicated in patients with cardiovascular and respiratory problems. Misoprostol—a synthetic oral prostaglandin E₁ analog—may be one option for these patients. “Misoprostol plays a major role in [the management of] peripartum hemorrhage,” Dr. Mayer said. It is not associated with bronchospasm, has no major cardiovascular effects, and can be stored for a long time without refrigeration.

Based on the literature, the evidence is not sufficient at this time to support routine use of misoprostol for the prevention of PPH. “The drug has such a high safety profile that it may be more useful in a treatment role” said Dr. Mayer. He recommends using 800–1,000 mcg administered rectally.

Many PPH cases have a major component of acquired coagulopathy, making rFVIIa (Novoseven) a treatment option, indicated for hemophilia A or B, with inhibitors of factor VII or factor IX. The drug induces hemostasis independent of factor VII or IX. It complexes with tissue factor to promote the conversion of factor IX to factor IXa, factor X to factor Xa, and prothrombin to thrombin—the key parts of the coagulation cascade. The drug produces clots, making it theoretically contraindicated in patients with disseminated intravascular coagulopathy.

The literature on the use of rFVIIa for PPH has been encouraging so far. In a recent study, 12 patients with severe PPH (estimated blood loss of 5–25 L) were treated with the drug (Br. J. Anaesth. 2005;94:592–5). All had previously undergone surgery, and one-third had arterial ligation. Eleven patients had a positive response.

“They're feeling was to give the drug at 1.5 L blood volume loss—it buys time,” said Dr. Mayer.

However, the drug is very expensive. The cost equivalent of a single 90-mcg/kg dose is 50 units of packed red blood cells, 2 days in the ICU, or an embolization procedure. In patients for whom surgical options have been explored, for whom there are no vascular interventional radiology options, for whom significant blood products are required, and for whom results of the coagulation studies are elevated, “this is a very reasonable drug to give,” Dr. Mayer said.

Intraoperative autologous transfusion should be considered when there is major blood loss and an inadequate amount of packed red blood cells is available. Potential risks associated with obstetric use include amniotic fluid embolism and maternal exposure to fetal red cells. However, in 400 exposures to intraoperative autologous transfusion, there has been only one case of amniotic fluid embolism that was not confirmed pathologically. Heparin toxicity also has been associated with the technique.

At the University of North Carolina at Chapel Hill, the cell saver has been used for 12 obstetric patients. “It's a perfect solution for Jehovah's Witnesses with risk factors, such as a known placenta percreta,” said Dr. Mayer. Blood was autotransfused in only one case though. This patient received 1,200 mL of salvaged blood with no problems.

Selective arterial embolization is highly successful when it can be performed. There are very few complications—fever is the most common. The technique also can be used prophylactically using a balloon. Coagulopathy is not a contraindication, so it's a good option for these patients.

ASHEVILLE, N.C. — Peripartum hemorrhage is one of the leading causes of maternal mortality, making it important to understand the myriad options for controlling bleeding, David C. Mayer, M.D., said at the Southern Obstetric and Gynecologic Seminar.

“Unfortunately, over the decades, hemorrhage has never been moved out of the top three causes of maternal mortality,” said Dr. Mayer of the department of anesthesiology at the University of North Carolina at Chapel Hill.

Peripartum hemorrhage accounts for as much as 18% of pregnancy-related deaths in the United States, according to one estimate.

Resuscitation is the first goal in the management of peripartum hemorrhage (PPH). Make sure there is an adequate number of intravenous lines and maintain adequate volume by using crystalloids, colloids, packed red blood cells, fresh frozen plasma, or platelets, as necessary. Get baseline blood laboratory tests, including a coagulation profile, and monitor arterial blood gas levels and urinary output. Invasive monitoring with arterial or central venous lines may be necessary, as may consultation with specialists, cautioned Dr. Mayer.

There are a number of options to control bleeding: pharmacologic (such as prostaglandins), autologous blood transfusion, and selective arterial embolization. Pharmacologic therapy includes oxytocics, ergot alkaloids, prostaglandins, and recombinant activated factor VII (rFVIIa). Keep in mind almost all studies of pharmacologic therapies are based on routine elective cesarean sections.

“It may have very little applicability to a patient with an atonic uterus,” Dr. Mayer said.

Oxytocin (Pitocin) is the pharmacologic therapy that most obstetricians go to first to control bleeding. The drug can be used as prophylaxis in women who are at high risk for PPH, with doses of 10–40 U/L administered intravenously. “For uterine atony, I'm very aggressive with oxytocin, except for giving a large bolus,” Dr. Mayer said during the meeting.

He recommends using up to 40–60 U/L given intravenously. Avoid using an intravenous bolus greater than 2 IU. A bolus less than 2 IU can be effective and is unlikely to be problematic, especially if blood pressure is supported. “Just remember that if your patient is already hypotensive, it's probably not the thing to do—increasing the rate of oxytocin,” said Dr. Mayer, also of the department of obstetrics and gynecology at the university.

Ergot alkaloids—ergonovine and methylergonovine—are very effective at inducing contractions. While the exact mechanism of action is unclear, ergot alkaloids are believed to have adrenergic, dopaminergic, and tryptaminergic effects. “Most people now think that it's the adrenergic effect that causes the increased uterine contractility,” Dr. Mayer said.

However, it's also thought that the adrenergic effect is responsible for some of the concerning side effects. Ergot alkaloids produce vasoconstriction that can last for 1–4 hours. These drugs are associated with hypertension, increased central blood volume, coronary vasospasm, pulmonary edema, and cerebrovascular accidents. The dopaminergic stimulation produces nausea and vomiting that can be severe in about 20% of patients. Ergot alkaloids should be given in a very controlled manner to avoid complications such as vasospasm and decreased ejection fractions.

The range of options in the prostaglandin family could grow in the future. “We don't have the whole armamentarium that they do in Europe and I think that someday we may,” Dr. Mayer said. Prostaglandins available in the United States include carboprost (15-methyl prostaglandin F_2α), misoprostol (prostaglandin E₁), dinoprost (prostaglandin F_2α), and dinoprostone (prostaglandin E₂).

The side effect profile for these drugs is different from that of the oxytocics or ergot alkaloids. Prostaglandins do not contribute to significant vasoconstriction. One big drawback for these drugs is that they cannot be administered intravenously. Instead, prostaglandins can be administered intramuscularly and intramyometrially. Prostaglandins E₁ and E₂ also can be administered orally, vaginally, or rectally.

“There's nothing to suggest that there's a better drug than carboprost,” Dr. Mayer said. Carboprost (Hemabate) is 10 times more potent than the parent compound (prostaglandin F_2α). It has minimal effect on the cardiovascular system. Severe bronchial constriction is the one real problem associated with carboprost, even in patients without asthma. This can result in bronchospasm, regional ventilation perfusion mismatch, and arterial desaturation. Patients receiving carboprost should be monitored with a pulse oximeter until at least an hour after the last dose. Dosing is 250 mcg given every 15 to 45 minutes, up to a maximum of 8 doses.

Both carboprost and methylergonovine are contraindicated in patients with cardiovascular and respiratory problems. Misoprostol—a synthetic oral prostaglandin E₁ analog—may be one option for these patients. “Misoprostol plays a major role in [the management of] peripartum hemorrhage,” Dr. Mayer said. It is not associated with bronchospasm, has no major cardiovascular effects, and can be stored for a long time without refrigeration.

Based on the literature, the evidence is not sufficient at this time to support routine use of misoprostol for the prevention of PPH. “The drug has such a high safety profile that it may be more useful in a treatment role” said Dr. Mayer. He recommends using 800–1,000 mcg administered rectally.

Many PPH cases have a major component of acquired coagulopathy, making rFVIIa (Novoseven) a treatment option, indicated for hemophilia A or B, with inhibitors of factor VII or factor IX. The drug induces hemostasis independent of factor VII or IX. It complexes with tissue factor to promote the conversion of factor IX to factor IXa, factor X to factor Xa, and prothrombin to thrombin—the key parts of the coagulation cascade. The drug produces clots, making it theoretically contraindicated in patients with disseminated intravascular coagulopathy.

The literature on the use of rFVIIa for PPH has been encouraging so far. In a recent study, 12 patients with severe PPH (estimated blood loss of 5–25 L) were treated with the drug (Br. J. Anaesth. 2005;94:592–5). All had previously undergone surgery, and one-third had arterial ligation. Eleven patients had a positive response.

“They're feeling was to give the drug at 1.5 L blood volume loss—it buys time,” said Dr. Mayer.

However, the drug is very expensive. The cost equivalent of a single 90-mcg/kg dose is 50 units of packed red blood cells, 2 days in the ICU, or an embolization procedure. In patients for whom surgical options have been explored, for whom there are no vascular interventional radiology options, for whom significant blood products are required, and for whom results of the coagulation studies are elevated, “this is a very reasonable drug to give,” Dr. Mayer said.

Intraoperative autologous transfusion should be considered when there is major blood loss and an inadequate amount of packed red blood cells is available. Potential risks associated with obstetric use include amniotic fluid embolism and maternal exposure to fetal red cells. However, in 400 exposures to intraoperative autologous transfusion, there has been only one case of amniotic fluid embolism that was not confirmed pathologically. Heparin toxicity also has been associated with the technique.

At the University of North Carolina at Chapel Hill, the cell saver has been used for 12 obstetric patients. “It's a perfect solution for Jehovah's Witnesses with risk factors, such as a known placenta percreta,” said Dr. Mayer. Blood was autotransfused in only one case though. This patient received 1,200 mL of salvaged blood with no problems.

Selective arterial embolization is highly successful when it can be performed. There are very few complications—fever is the most common. The technique also can be used prophylactically using a balloon. Coagulopathy is not a contraindication, so it's a good option for these patients.

CHARLESTON, S.C. — Recent deaths due to sepsis following medical abortion may be the result of an interaction between factors specific to mifepristone—one of the drugs used in the abortions—and Clostridium sordellii, the cause of infection in at least three of the five patients who died, James A. McGregor, M.D., said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Five deaths linked with the use of mifepristone (Mifeprex) for medical abortion have been reported and have prompted revisions to the product's package insert. The Food and Drug Administration and the drug's maker, Danco Laboratories LLC, announced the most recent change in July. The insert will now advise physicians to tell patients to seek care if they develop diarrhea, nausea, or vomiting with or without abdominal pain in the days after using the drug.

The first of the five deaths that prompted the warnings occurred in Canada in 2001 during a clinical trial of mifepristone. That case and two others that occurred in California since 2003 were associated with C. sordellii infection. The cause of infection in the two other deaths, which also occurred in California, has not been identified, but all five patients died after using oral mifepristone followed by vaginal misoprostol, rather than the FDA-approved regimen, which consists of oral mifepristone followed by oral misoprostol.

In a poster presented at the meeting, Dr. McGregor of the University of Southern California, Los Angeles, described case findings in the two California patients with confirmed C. sordellii infection and associated toxic shock-like syndrome.

Both were previously healthy, young (aged 18 and 22), primiparous women treated with the modified mifepristone/misoprostol medical abortion protocol, including 200-mg mifepristone orally followed by 800-mcg misoprostol inserted vaginally by the patient the next day. The patients reported to local emergency departments within 6 days complaining of abdominal pain, nausea, and light-headedness or faintness. Both were afebrile, tachycardic, tachypneic, and hypotensive.

Laboratory findings demonstrated hemoconcentration and dramatic leukocytosis, and both patients suffered refractory shock and cardiopulmonary arrest, Dr. McGregor noted.

“Mifepristone has multiple pharmacologic properties that may interfere with innate immune responses to infection, toxin exposures, and inflammatory stimuli,” he explained in an interview.

The drug is long-lasting, and it blocks steroid stress responses and the inflammation-dampening effects of cortisol, he explained.

And C. sordellii, which is present in the vagina in approximately 5% of all women and in up to 29% of women after pregnancy loss, can be toxigenic, he added.

Based on the findings from the two cases he presented, Dr. McGregor proposes that the following five factors comprise a case definition of C. sordellii-associated toxic shock-like syndrome after pregnancy termination:

▸ Previously well woman with early pregnancy.

▸ Onset of nonspecific complaints of flulike illness, such as abdominal/pelvic pain, faintness, and/or light-headedness, within 2 weeks of pregnancy termination.

▸ Physical findings of hypotension, tachycardia, tachypnea, and fever or hypothermia.

▸ Laboratory findings of elevated hematocrit and hemoglobin levels, dramatic leukocytosis left shift with increased band forms greater than 10%, and positive culture or nucleic acid-based microbial testing for C. sordellii.

▸ Exclusion of other toxic shock syndrome or other toxic shock-like syndrome, including sepsis syndrome caused by other bacteria, viruses, fungi, or parasites.

Research on host-environment susceptibility factors might further elucidate the mechanisms of this syndrome and contribute to primary prevention, he added.

Dr. McGregor speculated that infection recognized early could possibly be treated successfully with combined approaches including appropriate antibiotics, a protein C inhibitor (a new treatment for shock), high-dose steroids, and surgical removal of infected tissues.

However, factors associated with these deaths raise unanswered questions about the clustering of cases in California, the role of mifepristone in removing cortisol's suppression of inflammation, and the importance of vaginal self-administration of the drug on vaginal microflora.

Danco Laboratories has noted that more than 460,000 prescriptions for mifepristone have been written since it was approved in 2000, making the fatal sepsis rate about 1 in 100,000.

CHARLESTON, S.C. — Recent deaths due to sepsis following medical abortion may be the result of an interaction between factors specific to mifepristone—one of the drugs used in the abortions—and Clostridium sordellii, the cause of infection in at least three of the five patients who died, James A. McGregor, M.D., said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Five deaths linked with the use of mifepristone (Mifeprex) for medical abortion have been reported and have prompted revisions to the product's package insert. The Food and Drug Administration and the drug's maker, Danco Laboratories LLC, announced the most recent change in July. The insert will now advise physicians to tell patients to seek care if they develop diarrhea, nausea, or vomiting with or without abdominal pain in the days after using the drug.

The first of the five deaths that prompted the warnings occurred in Canada in 2001 during a clinical trial of mifepristone. That case and two others that occurred in California since 2003 were associated with C. sordellii infection. The cause of infection in the two other deaths, which also occurred in California, has not been identified, but all five patients died after using oral mifepristone followed by vaginal misoprostol, rather than the FDA-approved regimen, which consists of oral mifepristone followed by oral misoprostol.

In a poster presented at the meeting, Dr. McGregor of the University of Southern California, Los Angeles, described case findings in the two California patients with confirmed C. sordellii infection and associated toxic shock-like syndrome.

Both were previously healthy, young (aged 18 and 22), primiparous women treated with the modified mifepristone/misoprostol medical abortion protocol, including 200-mg mifepristone orally followed by 800-mcg misoprostol inserted vaginally by the patient the next day. The patients reported to local emergency departments within 6 days complaining of abdominal pain, nausea, and light-headedness or faintness. Both were afebrile, tachycardic, tachypneic, and hypotensive.

Laboratory findings demonstrated hemoconcentration and dramatic leukocytosis, and both patients suffered refractory shock and cardiopulmonary arrest, Dr. McGregor noted.

“Mifepristone has multiple pharmacologic properties that may interfere with innate immune responses to infection, toxin exposures, and inflammatory stimuli,” he explained in an interview.

The drug is long-lasting, and it blocks steroid stress responses and the inflammation-dampening effects of cortisol, he explained.

And C. sordellii, which is present in the vagina in approximately 5% of all women and in up to 29% of women after pregnancy loss, can be toxigenic, he added.

Based on the findings from the two cases he presented, Dr. McGregor proposes that the following five factors comprise a case definition of C. sordellii-associated toxic shock-like syndrome after pregnancy termination:

▸ Previously well woman with early pregnancy.

▸ Onset of nonspecific complaints of flulike illness, such as abdominal/pelvic pain, faintness, and/or light-headedness, within 2 weeks of pregnancy termination.

▸ Physical findings of hypotension, tachycardia, tachypnea, and fever or hypothermia.

▸ Laboratory findings of elevated hematocrit and hemoglobin levels, dramatic leukocytosis left shift with increased band forms greater than 10%, and positive culture or nucleic acid-based microbial testing for C. sordellii.

▸ Exclusion of other toxic shock syndrome or other toxic shock-like syndrome, including sepsis syndrome caused by other bacteria, viruses, fungi, or parasites.

Research on host-environment susceptibility factors might further elucidate the mechanisms of this syndrome and contribute to primary prevention, he added.

Dr. McGregor speculated that infection recognized early could possibly be treated successfully with combined approaches including appropriate antibiotics, a protein C inhibitor (a new treatment for shock), high-dose steroids, and surgical removal of infected tissues.

However, factors associated with these deaths raise unanswered questions about the clustering of cases in California, the role of mifepristone in removing cortisol's suppression of inflammation, and the importance of vaginal self-administration of the drug on vaginal microflora.

Danco Laboratories has noted that more than 460,000 prescriptions for mifepristone have been written since it was approved in 2000, making the fatal sepsis rate about 1 in 100,000.

CHARLESTON, S.C. — Recent deaths due to sepsis following medical abortion may be the result of an interaction between factors specific to mifepristone—one of the drugs used in the abortions—and Clostridium sordellii, the cause of infection in at least three of the five patients who died, James A. McGregor, M.D., said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Five deaths linked with the use of mifepristone (Mifeprex) for medical abortion have been reported and have prompted revisions to the product's package insert. The Food and Drug Administration and the drug's maker, Danco Laboratories LLC, announced the most recent change in July. The insert will now advise physicians to tell patients to seek care if they develop diarrhea, nausea, or vomiting with or without abdominal pain in the days after using the drug.

The first of the five deaths that prompted the warnings occurred in Canada in 2001 during a clinical trial of mifepristone. That case and two others that occurred in California since 2003 were associated with C. sordellii infection. The cause of infection in the two other deaths, which also occurred in California, has not been identified, but all five patients died after using oral mifepristone followed by vaginal misoprostol, rather than the FDA-approved regimen, which consists of oral mifepristone followed by oral misoprostol.

In a poster presented at the meeting, Dr. McGregor of the University of Southern California, Los Angeles, described case findings in the two California patients with confirmed C. sordellii infection and associated toxic shock-like syndrome.

Both were previously healthy, young (aged 18 and 22), primiparous women treated with the modified mifepristone/misoprostol medical abortion protocol, including 200-mg mifepristone orally followed by 800-mcg misoprostol inserted vaginally by the patient the next day. The patients reported to local emergency departments within 6 days complaining of abdominal pain, nausea, and light-headedness or faintness. Both were afebrile, tachycardic, tachypneic, and hypotensive.

Laboratory findings demonstrated hemoconcentration and dramatic leukocytosis, and both patients suffered refractory shock and cardiopulmonary arrest, Dr. McGregor noted.

“Mifepristone has multiple pharmacologic properties that may interfere with innate immune responses to infection, toxin exposures, and inflammatory stimuli,” he explained in an interview.

The drug is long-lasting, and it blocks steroid stress responses and the inflammation-dampening effects of cortisol, he explained.

And C. sordellii, which is present in the vagina in approximately 5% of all women and in up to 29% of women after pregnancy loss, can be toxigenic, he added.

Based on the findings from the two cases he presented, Dr. McGregor proposes that the following five factors comprise a case definition of C. sordellii-associated toxic shock-like syndrome after pregnancy termination:

▸ Previously well woman with early pregnancy.

▸ Onset of nonspecific complaints of flulike illness, such as abdominal/pelvic pain, faintness, and/or light-headedness, within 2 weeks of pregnancy termination.

▸ Physical findings of hypotension, tachycardia, tachypnea, and fever or hypothermia.

▸ Laboratory findings of elevated hematocrit and hemoglobin levels, dramatic leukocytosis left shift with increased band forms greater than 10%, and positive culture or nucleic acid-based microbial testing for C. sordellii.

▸ Exclusion of other toxic shock syndrome or other toxic shock-like syndrome, including sepsis syndrome caused by other bacteria, viruses, fungi, or parasites.

Research on host-environment susceptibility factors might further elucidate the mechanisms of this syndrome and contribute to primary prevention, he added.

Dr. McGregor speculated that infection recognized early could possibly be treated successfully with combined approaches including appropriate antibiotics, a protein C inhibitor (a new treatment for shock), high-dose steroids, and surgical removal of infected tissues.

However, factors associated with these deaths raise unanswered questions about the clustering of cases in California, the role of mifepristone in removing cortisol's suppression of inflammation, and the importance of vaginal self-administration of the drug on vaginal microflora.

Danco Laboratories has noted that more than 460,000 prescriptions for mifepristone have been written since it was approved in 2000, making the fatal sepsis rate about 1 in 100,000.

A single course of betamethasone before an elective cesarean section at term may decrease the risk of developing neonatal respiratory distress or transient tachypnea, according to the results of a randomized, controlled trial.

The 10-center trial is the first of its kind to test the use of prenatal corticosteroids in women who were delivered by elective cesarean section at term (BMJ, doi:10.1136/bmj.38547.416493.06 [2005]).

Infants whose mothers received betamethasone had a significantly lower rate of admission to the special care baby unit (11 of 467) than control infants (24 of 475). Betamethasone treatment reduced the incidence of admission to a special care baby unit by 54%, reported Peter Stutchfield, M.D., of Glan Clwyd Hospital (Wales) and his colleagues.

Still, Alex Vidaeff, M.D., of the University of Texas, Houston, questioned the significance of the study. “I don't see any clinical utility for U.S. practitioners because of a lack of external validity,” he said in an interview.

Dr. Vidaeff, who has particular interest in research on corticosteroids and fetal maturation, as well as expertise working with H-441 adenocarcinoma lung cells, said interpretation of the study results is difficult without more information on the selection of patients for the study. He also noted that the risk-benefit ratio at more than 34 weeks' gestation is not favorable because the risk level already is low in this group.

In the study, during the 48 hours before elective cesarean section, the women received either two intramuscular doses of 12 mg of betamethasone separated by 24 hours or treatment as usual without corticosteroids.

The severity and type of respiratory distress (transient tachypnea in 10 treated and 19 control babies or respiratory distress syndrome in 1 treated and 5 control babies) were similar among all babies who were admitted to a special care baby unit.

Among mothers who had a baby admitted to a special care baby unit, significantly more mothers of infants exposed to betamethasone received general anesthesia than did mothers of control infants (45% vs. 0%). Admitted babies exposed to betamethasone needed neonatal resuscitation (73% vs. 12%) or ventilation through a mask (36% vs. 0%) significantly more often than control babies.

But 2.9% of control babies received intensive care, compared with only 0.4% of babies treated with betamethasone.

The probability of admission to the special care baby unit with respiratory distress declined as the gestational age of the baby increased in the betamethasone and control groups from 37 weeks (5% vs. 11%, respectively) to 38 weeks (3% vs. 6%) to 39 weeks (0.6% vs. 1.5%), according to a logistic regression model.

There were no reports of wound infection or neonatal sepsis. Among seven women who received betamethasone, five reported generalized flushing, one had nausea, one had tenderness at the injection site, and one noted increased energy with difficulty sleeping.

“The reduced incidence of transient tachypnea in the steroid group is consistent with the hypothesis that corticosteroids, increased in mother and fetus through the stress of labor, encourage the expression of the epithelial channel gene and allow the lung to switch from fluid secretion to fluid absorption,” Dr. Stutchfield and his colleagues wrote. “Without another source of corticosteroid, elective cesarean section will disrupt this process.”

A single course of betamethasone before an elective cesarean section at term may decrease the risk of developing neonatal respiratory distress or transient tachypnea, according to the results of a randomized, controlled trial.

The 10-center trial is the first of its kind to test the use of prenatal corticosteroids in women who were delivered by elective cesarean section at term (BMJ, doi:10.1136/bmj.38547.416493.06 [2005]).

Infants whose mothers received betamethasone had a significantly lower rate of admission to the special care baby unit (11 of 467) than control infants (24 of 475). Betamethasone treatment reduced the incidence of admission to a special care baby unit by 54%, reported Peter Stutchfield, M.D., of Glan Clwyd Hospital (Wales) and his colleagues.

Still, Alex Vidaeff, M.D., of the University of Texas, Houston, questioned the significance of the study. “I don't see any clinical utility for U.S. practitioners because of a lack of external validity,” he said in an interview.

Dr. Vidaeff, who has particular interest in research on corticosteroids and fetal maturation, as well as expertise working with H-441 adenocarcinoma lung cells, said interpretation of the study results is difficult without more information on the selection of patients for the study. He also noted that the risk-benefit ratio at more than 34 weeks' gestation is not favorable because the risk level already is low in this group.

In the study, during the 48 hours before elective cesarean section, the women received either two intramuscular doses of 12 mg of betamethasone separated by 24 hours or treatment as usual without corticosteroids.

The severity and type of respiratory distress (transient tachypnea in 10 treated and 19 control babies or respiratory distress syndrome in 1 treated and 5 control babies) were similar among all babies who were admitted to a special care baby unit.

Among mothers who had a baby admitted to a special care baby unit, significantly more mothers of infants exposed to betamethasone received general anesthesia than did mothers of control infants (45% vs. 0%). Admitted babies exposed to betamethasone needed neonatal resuscitation (73% vs. 12%) or ventilation through a mask (36% vs. 0%) significantly more often than control babies.

But 2.9% of control babies received intensive care, compared with only 0.4% of babies treated with betamethasone.

The probability of admission to the special care baby unit with respiratory distress declined as the gestational age of the baby increased in the betamethasone and control groups from 37 weeks (5% vs. 11%, respectively) to 38 weeks (3% vs. 6%) to 39 weeks (0.6% vs. 1.5%), according to a logistic regression model.

There were no reports of wound infection or neonatal sepsis. Among seven women who received betamethasone, five reported generalized flushing, one had nausea, one had tenderness at the injection site, and one noted increased energy with difficulty sleeping.

“The reduced incidence of transient tachypnea in the steroid group is consistent with the hypothesis that corticosteroids, increased in mother and fetus through the stress of labor, encourage the expression of the epithelial channel gene and allow the lung to switch from fluid secretion to fluid absorption,” Dr. Stutchfield and his colleagues wrote. “Without another source of corticosteroid, elective cesarean section will disrupt this process.”

A single course of betamethasone before an elective cesarean section at term may decrease the risk of developing neonatal respiratory distress or transient tachypnea, according to the results of a randomized, controlled trial.

The 10-center trial is the first of its kind to test the use of prenatal corticosteroids in women who were delivered by elective cesarean section at term (BMJ, doi:10.1136/bmj.38547.416493.06 [2005]).

Infants whose mothers received betamethasone had a significantly lower rate of admission to the special care baby unit (11 of 467) than control infants (24 of 475). Betamethasone treatment reduced the incidence of admission to a special care baby unit by 54%, reported Peter Stutchfield, M.D., of Glan Clwyd Hospital (Wales) and his colleagues.

Still, Alex Vidaeff, M.D., of the University of Texas, Houston, questioned the significance of the study. “I don't see any clinical utility for U.S. practitioners because of a lack of external validity,” he said in an interview.

Dr. Vidaeff, who has particular interest in research on corticosteroids and fetal maturation, as well as expertise working with H-441 adenocarcinoma lung cells, said interpretation of the study results is difficult without more information on the selection of patients for the study. He also noted that the risk-benefit ratio at more than 34 weeks' gestation is not favorable because the risk level already is low in this group.

In the study, during the 48 hours before elective cesarean section, the women received either two intramuscular doses of 12 mg of betamethasone separated by 24 hours or treatment as usual without corticosteroids.

The severity and type of respiratory distress (transient tachypnea in 10 treated and 19 control babies or respiratory distress syndrome in 1 treated and 5 control babies) were similar among all babies who were admitted to a special care baby unit.

Among mothers who had a baby admitted to a special care baby unit, significantly more mothers of infants exposed to betamethasone received general anesthesia than did mothers of control infants (45% vs. 0%). Admitted babies exposed to betamethasone needed neonatal resuscitation (73% vs. 12%) or ventilation through a mask (36% vs. 0%) significantly more often than control babies.

But 2.9% of control babies received intensive care, compared with only 0.4% of babies treated with betamethasone.

The probability of admission to the special care baby unit with respiratory distress declined as the gestational age of the baby increased in the betamethasone and control groups from 37 weeks (5% vs. 11%, respectively) to 38 weeks (3% vs. 6%) to 39 weeks (0.6% vs. 1.5%), according to a logistic regression model.

There were no reports of wound infection or neonatal sepsis. Among seven women who received betamethasone, five reported generalized flushing, one had nausea, one had tenderness at the injection site, and one noted increased energy with difficulty sleeping.

“The reduced incidence of transient tachypnea in the steroid group is consistent with the hypothesis that corticosteroids, increased in mother and fetus through the stress of labor, encourage the expression of the epithelial channel gene and allow the lung to switch from fluid secretion to fluid absorption,” Dr. Stutchfield and his colleagues wrote. “Without another source of corticosteroid, elective cesarean section will disrupt this process.”

The antibiotic ceftriaxone is an effective treatment for early syphilis in pregnancy, a small study has shown.

Researchers studied the efficacy of broad-spectrum cephalosporin in 11 HIV-negative pregnant women with early syphilis and histories of penicillin allergy or skin test reactions to penicillin antigen. Gestation at the initiation of treatment was 4 to 18 weeks (Sex. Transm. Dis. 2005;32:495–8).

Three women were diagnosed with primary syphilis and eight with secondary syphilis. Those with primary syphilis received intramuscular injections of 250 mg ceftriaxone (Rocephin) once daily for 7 days. Those with secondary syphilis got once-daily injections for 10 days. The same course was repeated for both groups at 28 weeks' gestation, said Dr. Pingyu Zhou, M.D., Ph.D., and colleagues at Shanghai (China) Skin and STD Hospital.

The patients were reexamined eight times over 24 months. All completed the first course of treatment, and 8 of the 11 completed the second course.

Within 1 month of the first course of treatment, syphilitic skin lesions disappeared in all patients and did not recur in the follow-up period. Within 3 months, there was a fourfold reduction in serum rapid plasma reagin (RPR) titers with no increase in the follow-up period. Ten women developed negative RPR measures in the follow-up period.

None of the neonates had clinical or radiographic manifestations of congenital syphilis at birth or in the 2-year follow-up period. At birth, 5 infants had serum RPR measures equal to those of their mothers at delivery, but all were negative within 12 months.

Although the study is limited by its size and the fact that the patients studied were less likely to transmit syphilis to their newborns than other risk groups, the findings suggest ceftriaxone can be considered as a therapeutic alternative for the treatment of early syphilis “in the appropriate clinical setting,” the authors wrote.

There was no evidence of the necessity of the second course of therapy, Dr. Zhou and associates said.

The antibiotic ceftriaxone is an effective treatment for early syphilis in pregnancy, a small study has shown.

Researchers studied the efficacy of broad-spectrum cephalosporin in 11 HIV-negative pregnant women with early syphilis and histories of penicillin allergy or skin test reactions to penicillin antigen. Gestation at the initiation of treatment was 4 to 18 weeks (Sex. Transm. Dis. 2005;32:495–8).

Three women were diagnosed with primary syphilis and eight with secondary syphilis. Those with primary syphilis received intramuscular injections of 250 mg ceftriaxone (Rocephin) once daily for 7 days. Those with secondary syphilis got once-daily injections for 10 days. The same course was repeated for both groups at 28 weeks' gestation, said Dr. Pingyu Zhou, M.D., Ph.D., and colleagues at Shanghai (China) Skin and STD Hospital.

The patients were reexamined eight times over 24 months. All completed the first course of treatment, and 8 of the 11 completed the second course.

Within 1 month of the first course of treatment, syphilitic skin lesions disappeared in all patients and did not recur in the follow-up period. Within 3 months, there was a fourfold reduction in serum rapid plasma reagin (RPR) titers with no increase in the follow-up period. Ten women developed negative RPR measures in the follow-up period.

None of the neonates had clinical or radiographic manifestations of congenital syphilis at birth or in the 2-year follow-up period. At birth, 5 infants had serum RPR measures equal to those of their mothers at delivery, but all were negative within 12 months.

Although the study is limited by its size and the fact that the patients studied were less likely to transmit syphilis to their newborns than other risk groups, the findings suggest ceftriaxone can be considered as a therapeutic alternative for the treatment of early syphilis “in the appropriate clinical setting,” the authors wrote.

There was no evidence of the necessity of the second course of therapy, Dr. Zhou and associates said.

The antibiotic ceftriaxone is an effective treatment for early syphilis in pregnancy, a small study has shown.

Researchers studied the efficacy of broad-spectrum cephalosporin in 11 HIV-negative pregnant women with early syphilis and histories of penicillin allergy or skin test reactions to penicillin antigen. Gestation at the initiation of treatment was 4 to 18 weeks (Sex. Transm. Dis. 2005;32:495–8).

Three women were diagnosed with primary syphilis and eight with secondary syphilis. Those with primary syphilis received intramuscular injections of 250 mg ceftriaxone (Rocephin) once daily for 7 days. Those with secondary syphilis got once-daily injections for 10 days. The same course was repeated for both groups at 28 weeks' gestation, said Dr. Pingyu Zhou, M.D., Ph.D., and colleagues at Shanghai (China) Skin and STD Hospital.

The patients were reexamined eight times over 24 months. All completed the first course of treatment, and 8 of the 11 completed the second course.

Within 1 month of the first course of treatment, syphilitic skin lesions disappeared in all patients and did not recur in the follow-up period. Within 3 months, there was a fourfold reduction in serum rapid plasma reagin (RPR) titers with no increase in the follow-up period. Ten women developed negative RPR measures in the follow-up period.

None of the neonates had clinical or radiographic manifestations of congenital syphilis at birth or in the 2-year follow-up period. At birth, 5 infants had serum RPR measures equal to those of their mothers at delivery, but all were negative within 12 months.

Although the study is limited by its size and the fact that the patients studied were less likely to transmit syphilis to their newborns than other risk groups, the findings suggest ceftriaxone can be considered as a therapeutic alternative for the treatment of early syphilis “in the appropriate clinical setting,” the authors wrote.

There was no evidence of the necessity of the second course of therapy, Dr. Zhou and associates said.

Maternal celiac disease, undiagnosed at the time of delivery, is a risk factor for adverse fetal outcomes, but celiac disease diagnosed before giving birth is not associated with such outcomes, results from a large Swedish population study suggest.

“Our results underline the importance of screening for CD [celiac disease] among women of reproductive age because some 1% of young people may have CD, and treatment seems to reduce dramatically the rate of complications in pregnancy,” reported the investigators, led by Jonas F. Ludvigsson, M.D., of the pediatric department at örebro University Hospital, Sweden.

Celiac disease is a chronic intestinal malabsorption disorder caused by intolerance to gluten. Diagnosis is suspected on the basis of symptoms, enhanced by laboratory and x-ray studies, confirmed by biopsy, and improved by going on a gluten-free diet, which is the only treatment for this disorder.

Using a national medical registry, Ludvigsson and his associates identified 2,078 women aged 15–44 with a diagnosis of CD who delivered singleton live-born infants from 1973 to 2001. A total of 1,149 women were diagnosed with CD before giving birth, and 929 were diagnosed after giving birth (Gastroenterology 2005;129:454–63).

After adjusting for potential confounding factors such as smoking, age, parity, and diabetes mellitus, the subjects diagnosed with CD after the birth of their offspring were associated with an increased risk of intrauterine growth retardation (odds ratio of 1.62), preterm birth (OR 1.71), cesarean section (OR 1.82), low birth weight (OR 2.13), and very low birth weight (OR 2.45). Subjects diagnosed with CD before the birth of their offspring were not significantly associated with an increased risk of these outcomes.

The investigators reported that the risk for nearly all adverse outcomes was highest among women who received a diagnosis of CD during the 5 years after giving birth.

They postulated that insufficient fetal nutrition causes the increased risk of intrauterine growth retardation and low birth weight seen in offspring of women diagnosed after giving birth.

Maternal celiac disease, undiagnosed at the time of delivery, is a risk factor for adverse fetal outcomes, but celiac disease diagnosed before giving birth is not associated with such outcomes, results from a large Swedish population study suggest.

“Our results underline the importance of screening for CD [celiac disease] among women of reproductive age because some 1% of young people may have CD, and treatment seems to reduce dramatically the rate of complications in pregnancy,” reported the investigators, led by Jonas F. Ludvigsson, M.D., of the pediatric department at örebro University Hospital, Sweden.

Celiac disease is a chronic intestinal malabsorption disorder caused by intolerance to gluten. Diagnosis is suspected on the basis of symptoms, enhanced by laboratory and x-ray studies, confirmed by biopsy, and improved by going on a gluten-free diet, which is the only treatment for this disorder.

Using a national medical registry, Ludvigsson and his associates identified 2,078 women aged 15–44 with a diagnosis of CD who delivered singleton live-born infants from 1973 to 2001. A total of 1,149 women were diagnosed with CD before giving birth, and 929 were diagnosed after giving birth (Gastroenterology 2005;129:454–63).

After adjusting for potential confounding factors such as smoking, age, parity, and diabetes mellitus, the subjects diagnosed with CD after the birth of their offspring were associated with an increased risk of intrauterine growth retardation (odds ratio of 1.62), preterm birth (OR 1.71), cesarean section (OR 1.82), low birth weight (OR 2.13), and very low birth weight (OR 2.45). Subjects diagnosed with CD before the birth of their offspring were not significantly associated with an increased risk of these outcomes.

The investigators reported that the risk for nearly all adverse outcomes was highest among women who received a diagnosis of CD during the 5 years after giving birth.

They postulated that insufficient fetal nutrition causes the increased risk of intrauterine growth retardation and low birth weight seen in offspring of women diagnosed after giving birth.

Maternal celiac disease, undiagnosed at the time of delivery, is a risk factor for adverse fetal outcomes, but celiac disease diagnosed before giving birth is not associated with such outcomes, results from a large Swedish population study suggest.

“Our results underline the importance of screening for CD [celiac disease] among women of reproductive age because some 1% of young people may have CD, and treatment seems to reduce dramatically the rate of complications in pregnancy,” reported the investigators, led by Jonas F. Ludvigsson, M.D., of the pediatric department at örebro University Hospital, Sweden.

Celiac disease is a chronic intestinal malabsorption disorder caused by intolerance to gluten. Diagnosis is suspected on the basis of symptoms, enhanced by laboratory and x-ray studies, confirmed by biopsy, and improved by going on a gluten-free diet, which is the only treatment for this disorder.

Using a national medical registry, Ludvigsson and his associates identified 2,078 women aged 15–44 with a diagnosis of CD who delivered singleton live-born infants from 1973 to 2001. A total of 1,149 women were diagnosed with CD before giving birth, and 929 were diagnosed after giving birth (Gastroenterology 2005;129:454–63).

After adjusting for potential confounding factors such as smoking, age, parity, and diabetes mellitus, the subjects diagnosed with CD after the birth of their offspring were associated with an increased risk of intrauterine growth retardation (odds ratio of 1.62), preterm birth (OR 1.71), cesarean section (OR 1.82), low birth weight (OR 2.13), and very low birth weight (OR 2.45). Subjects diagnosed with CD before the birth of their offspring were not significantly associated with an increased risk of these outcomes.

The investigators reported that the risk for nearly all adverse outcomes was highest among women who received a diagnosis of CD during the 5 years after giving birth.

They postulated that insufficient fetal nutrition causes the increased risk of intrauterine growth retardation and low birth weight seen in offspring of women diagnosed after giving birth.

KEVIN FOLEY, RESEARCH

KEVIN FOLEY, RESEARCH

KEVIN FOLEY, RESEARCH

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

ST. PETE BEACH, FLA. — Diclectin used for nausea and vomiting of pregnancy does not appear to affect the later neurocognitive development of children who are exposed to the drug in utero, Irena Nulman, M.D., and her colleagues at the Hospital for Sick Children, Toronto, reported at the annual meeting of the Teratology Society.

The drug, available in Canada but not in the United States at this time, has proved safe in terms of fetal dysmorphology, but its effects on the developing central nervous system have been unclear, the investigators reported in a poster presentation at the meeting.

In a prospective, randomized, double-blind study, they compared the children's neurocognitive development and measures of child behavior and language development. The study included 42 mother-child pairs exposed to nausea and vomiting of pregnancy (NVP) and diclectin, 37 pairs exposed to NVP but not to pharmacotherapy, and 25 pairs not exposed to NVP.

No significant differences were found among groups in any of these measures. Children in all groups had scores in the normal range on total indexes of IQ and on measures of temperament, behavior, and language. For example, performance IQ scores were a mean of 119.76 in the NVP/diclectin-exposed group, 111.75 in the NVP-only group, and 110.08 in the unexposed group.

NVP affects 70%–80% of pregnant women and can lead to hyperemesis gravidarum, the investigators noted.

“Exposure to diclectin does not adversely affect child long-term full-scale IQ. … When indicated, diclectin therapy should be instituted to prevent hyperemesis gravid[ar]um and improve pregnant women's life style,” they concluded.

Diclectin, manufactured by Duchesnay Inc., 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 Inc., following a series of lawsuits claiming the drug caused birth defects. Although the company won every case and numerous studies have confirmed the drug's safety, the drug was never put back on the U.S. market. Duchesnay Inc. is currently attempting to gain Food and Drug Administration clearance to market diclectin in the United States.

ST. PETE BEACH, FLA. — Diclectin used for nausea and vomiting of pregnancy does not appear to affect the later neurocognitive development of children who are exposed to the drug in utero, Irena Nulman, M.D., and her colleagues at the Hospital for Sick Children, Toronto, reported at the annual meeting of the Teratology Society.

The drug, available in Canada but not in the United States at this time, has proved safe in terms of fetal dysmorphology, but its effects on the developing central nervous system have been unclear, the investigators reported in a poster presentation at the meeting.

In a prospective, randomized, double-blind study, they compared the children's neurocognitive development and measures of child behavior and language development. The study included 42 mother-child pairs exposed to nausea and vomiting of pregnancy (NVP) and diclectin, 37 pairs exposed to NVP but not to pharmacotherapy, and 25 pairs not exposed to NVP.

No significant differences were found among groups in any of these measures. Children in all groups had scores in the normal range on total indexes of IQ and on measures of temperament, behavior, and language. For example, performance IQ scores were a mean of 119.76 in the NVP/diclectin-exposed group, 111.75 in the NVP-only group, and 110.08 in the unexposed group.

NVP affects 70%–80% of pregnant women and can lead to hyperemesis gravidarum, the investigators noted.

“Exposure to diclectin does not adversely affect child long-term full-scale IQ. … When indicated, diclectin therapy should be instituted to prevent hyperemesis gravid[ar]um and improve pregnant women's life style,” they concluded.

Diclectin, manufactured by Duchesnay Inc., 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 Inc., following a series of lawsuits claiming the drug caused birth defects. Although the company won every case and numerous studies have confirmed the drug's safety, the drug was never put back on the U.S. market. Duchesnay Inc. is currently attempting to gain Food and Drug Administration clearance to market diclectin in the United States.

ST. PETE BEACH, FLA. — Diclectin used for nausea and vomiting of pregnancy does not appear to affect the later neurocognitive development of children who are exposed to the drug in utero, Irena Nulman, M.D., and her colleagues at the Hospital for Sick Children, Toronto, reported at the annual meeting of the Teratology Society.

The drug, available in Canada but not in the United States at this time, has proved safe in terms of fetal dysmorphology, but its effects on the developing central nervous system have been unclear, the investigators reported in a poster presentation at the meeting.

In a prospective, randomized, double-blind study, they compared the children's neurocognitive development and measures of child behavior and language development. The study included 42 mother-child pairs exposed to nausea and vomiting of pregnancy (NVP) and diclectin, 37 pairs exposed to NVP but not to pharmacotherapy, and 25 pairs not exposed to NVP.

No significant differences were found among groups in any of these measures. Children in all groups had scores in the normal range on total indexes of IQ and on measures of temperament, behavior, and language. For example, performance IQ scores were a mean of 119.76 in the NVP/diclectin-exposed group, 111.75 in the NVP-only group, and 110.08 in the unexposed group.

NVP affects 70%–80% of pregnant women and can lead to hyperemesis gravidarum, the investigators noted.

“Exposure to diclectin does not adversely affect child long-term full-scale IQ. … When indicated, diclectin therapy should be instituted to prevent hyperemesis gravid[ar]um and improve pregnant women's life style,” they concluded.

Diclectin, manufactured by Duchesnay Inc., 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 Inc., following a series of lawsuits claiming the drug caused birth defects. Although the company won every case and numerous studies have confirmed the drug's safety, the drug was never put back on the U.S. market. Duchesnay Inc. is currently attempting to gain Food and Drug Administration clearance to market diclectin in the United States.