Suddenly, indigo carmine is in short supply throughout the United States. One manufacturer has stopped production because of a raw materials shortage; another is experiencing manufacturing delays. Neither company can estimate a resupply or product return date.¹

Indigo carmine is approved by the US Food and Drug Administration (FDA) to localize ureteral orifices during cystoscopy and is commonly used in obstetrics and gynecology as a marker dye in the following additional situations:

• administered in a dilute solution via a catheter to back fill the bladder and test for bladder injury
• administered via a cannula in the uterine cavity to test the patency of the fallopian tubes
• injected into the amniotic fluid compartment to test for premature rupture of the membranes (PROM)
• injected into the amniotic fluid of a twin gestation to mark the amniotic fluid of one twin.

With this agent in short supply, we need to identify alternative marker dyes to use in our clinical practice. In this editorial, I provide a list of possible options to replace indigo carmine. Evidence supporting the use and safety of marker dyes in obstetrics and gynecology is based on small cohorts or case reports. The available evidence is of modest to low quality, and it is especially challenging to identify uncommon adverse effects. Consequently, expert opinion guides most practice recommendations.

Options to test the function of the ureters at cystoscopy
Given the lack of availability of indigo carmine, I recommend one of the following three options to test the function of the ureters at cystoscopy.

Partially fill the bladder with a solution of either sterile water or a 10% dextrose solution. (Experienced surgeons may prefer to use saline.) The turbulence of the interaction between the ureteral urine jet and instilled fluid in the bladder may permit visualization of the urine stream exiting the ureteral orifices as it swirls through the sterile water or dextrose solution. Both sterile water and a 10% dextrose solution offer a contrast in viscosity between the urine and the cystoscopy fluid, which may enhance the ability to detect the urine jet leaving the ureter.²

Administer IV methylene blue. Methylene blue is FDA approved for methemoglobinemia treatment. For this indication, it is administered intravenously at a dose of 1 to 2 mg/kgover 5 to 10 minutes. Paradoxically, when administered at a dose of >7 mg/kg, methylene blue can cause methemoglobinemia.³

Methylene blue often is provided as a 1% solution of 10 mg/mL in 10-mL vials. To use intravenous (IV) methylene blue to test ureteral function at cystoscopy, administer IV methylene blue 50 mg over 5 minutes. Use the cystoscope to view the colored urine exiting the ureteral orifices.^4,5 Administering a small dose of IV furosemide may accelerate the appearance of methylene blue in the urine.

When to use caution. Methylene blue blocks serotonin metabolism by inhibiting monoamine oxidase and may precipitate a serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs).

Common findings in the serotonin syndrome include: temperature above 38° C (100.4° F), anxiety, agitation, delirium, clonus, tremor, and hypertonia.⁶ I recommend that you DO NOT use IV methylene blue in patients taking these medications.^7,8

Great caution should be used before administering IV methylene blue in the presence of the following clinical situations:

• renal impairment  
• G6PD deficiency
• pediatric patients.

Methylene blue never should be given by a subcutaneous or intrathecal route. In pregnant women it should never be injected into the amniotic fluid compartment.

Use preoperative oral phenazo-pyridine. If the preoperative plan includes a cystoscopy procedure to test ureteral function, administering oral phenazopyridine in the preoperative holding area will result in colorization of the urine within 30 minutes, and it will persist for approximately 4 to 5 hours. To use this approach, administer one dose of phenazopyridine (Pyridium, Azo-Gesic), 100 mg or 200 mg orally, 30 minutes to 1 hour before the planned surgical start time, in the preoperative holding area.⁹ During cystoscopy, the urine from the ureteral jet will be colored orange.

When to use caution. Phenazo­pyridine should not be administered to patients with G6PD deficiency.

Option to test for bladder injury
Methylene blue. If methylene blue is used to test the integrity of the bladder, I recommend diluting 10 mg methylene blue in 1 L normal saline and then instilling the dilute solution through a catheter into the bladder.¹⁰

It is unlikely that this technique will be associated with sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs, and MAOIs.

Option to test patency of the fallopian tubes (chromopertubation)
Methylene blue. If methylene blue is used via a cannula in the uterine cavity to test the patency of the fallopian tubes, I recommend diluting 10 mg methylene blue in 150 mL normal saline and using the dilute solution to test tubal patency.

It is unlikely that this process will lead to sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs and MAOIs. However, if intrauterine injection of the dilute dye solution results in extravasation of the dye into the pelvic veins, a significant amount of dye can enter the circulation.¹¹ There are case reports of anaphylaxis following intrauterine injection of methylene blue to test tubal patency.^12,13

Options to diagnose PROM and to use for twin amniocentesis
None. Most experts recommend against the intra-amniotic injection of methylene blue to diagnose PROM or in twin amniocentesis procedures. Methylene blue injected into the intra-amniotic fluid during amniocentesis in multiple gestations has been reported to cause fetal bowel obstruction or atresia.^14,15 Fetal death also has been reported.¹⁶ Decades ago, indocyanine green, which is FDA approved to determine cardiac output, liver blood flow, and hepatic function, was reported to be useful to mark one sac of a twin gestation during amniocentesis.¹⁷ With modern ultrasonography technology, the need to rely on a dye to mark a sac of a twin has decreased significantly.

Our only option is to cope—effectively as possible Over decades, the medical community develops patterns of patient care that are critically dependent on the availability of key pharmaceuticals and devices. When a pharmaceutical or device suddenly becomes unavailable, it can disrupt important patterns of patient care. Imagine the impact on obstetrics practice if oxytocin became unavailable due to manufacturing shortages. Likely, both market forces and government regulation are the root cause of the shortfalls. Preventing the adverse consequences of the sudden loss of key pharmaceuticals and devices is an important priority to ensure optimal care of our patients.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Suddenly, indigo carmine is in short supply throughout the United States. One manufacturer has stopped production because of a raw materials shortage; another is experiencing manufacturing delays. Neither company can estimate a resupply or product return date.¹

Indigo carmine is approved by the US Food and Drug Administration (FDA) to localize ureteral orifices during cystoscopy and is commonly used in obstetrics and gynecology as a marker dye in the following additional situations:

• administered in a dilute solution via a catheter to back fill the bladder and test for bladder injury
• administered via a cannula in the uterine cavity to test the patency of the fallopian tubes
• injected into the amniotic fluid compartment to test for premature rupture of the membranes (PROM)
• injected into the amniotic fluid of a twin gestation to mark the amniotic fluid of one twin.

With this agent in short supply, we need to identify alternative marker dyes to use in our clinical practice. In this editorial, I provide a list of possible options to replace indigo carmine. Evidence supporting the use and safety of marker dyes in obstetrics and gynecology is based on small cohorts or case reports. The available evidence is of modest to low quality, and it is especially challenging to identify uncommon adverse effects. Consequently, expert opinion guides most practice recommendations.

Options to test the function of the ureters at cystoscopy
Given the lack of availability of indigo carmine, I recommend one of the following three options to test the function of the ureters at cystoscopy.

Partially fill the bladder with a solution of either sterile water or a 10% dextrose solution. (Experienced surgeons may prefer to use saline.) The turbulence of the interaction between the ureteral urine jet and instilled fluid in the bladder may permit visualization of the urine stream exiting the ureteral orifices as it swirls through the sterile water or dextrose solution. Both sterile water and a 10% dextrose solution offer a contrast in viscosity between the urine and the cystoscopy fluid, which may enhance the ability to detect the urine jet leaving the ureter.²

Administer IV methylene blue. Methylene blue is FDA approved for methemoglobinemia treatment. For this indication, it is administered intravenously at a dose of 1 to 2 mg/kgover 5 to 10 minutes. Paradoxically, when administered at a dose of >7 mg/kg, methylene blue can cause methemoglobinemia.³

Methylene blue often is provided as a 1% solution of 10 mg/mL in 10-mL vials. To use intravenous (IV) methylene blue to test ureteral function at cystoscopy, administer IV methylene blue 50 mg over 5 minutes. Use the cystoscope to view the colored urine exiting the ureteral orifices.^4,5 Administering a small dose of IV furosemide may accelerate the appearance of methylene blue in the urine.

When to use caution. Methylene blue blocks serotonin metabolism by inhibiting monoamine oxidase and may precipitate a serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs).

Common findings in the serotonin syndrome include: temperature above 38° C (100.4° F), anxiety, agitation, delirium, clonus, tremor, and hypertonia.⁶ I recommend that you DO NOT use IV methylene blue in patients taking these medications.^7,8

Great caution should be used before administering IV methylene blue in the presence of the following clinical situations:

• renal impairment  
• G6PD deficiency
• pediatric patients.

Methylene blue never should be given by a subcutaneous or intrathecal route. In pregnant women it should never be injected into the amniotic fluid compartment.

Use preoperative oral phenazo-pyridine. If the preoperative plan includes a cystoscopy procedure to test ureteral function, administering oral phenazopyridine in the preoperative holding area will result in colorization of the urine within 30 minutes, and it will persist for approximately 4 to 5 hours. To use this approach, administer one dose of phenazopyridine (Pyridium, Azo-Gesic), 100 mg or 200 mg orally, 30 minutes to 1 hour before the planned surgical start time, in the preoperative holding area.⁹ During cystoscopy, the urine from the ureteral jet will be colored orange.

When to use caution. Phenazo­pyridine should not be administered to patients with G6PD deficiency.

Option to test for bladder injury
Methylene blue. If methylene blue is used to test the integrity of the bladder, I recommend diluting 10 mg methylene blue in 1 L normal saline and then instilling the dilute solution through a catheter into the bladder.¹⁰

It is unlikely that this technique will be associated with sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs, and MAOIs.

Option to test patency of the fallopian tubes (chromopertubation)
Methylene blue. If methylene blue is used via a cannula in the uterine cavity to test the patency of the fallopian tubes, I recommend diluting 10 mg methylene blue in 150 mL normal saline and using the dilute solution to test tubal patency.

It is unlikely that this process will lead to sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs and MAOIs. However, if intrauterine injection of the dilute dye solution results in extravasation of the dye into the pelvic veins, a significant amount of dye can enter the circulation.¹¹ There are case reports of anaphylaxis following intrauterine injection of methylene blue to test tubal patency.^12,13

Options to diagnose PROM and to use for twin amniocentesis
None. Most experts recommend against the intra-amniotic injection of methylene blue to diagnose PROM or in twin amniocentesis procedures. Methylene blue injected into the intra-amniotic fluid during amniocentesis in multiple gestations has been reported to cause fetal bowel obstruction or atresia.^14,15 Fetal death also has been reported.¹⁶ Decades ago, indocyanine green, which is FDA approved to determine cardiac output, liver blood flow, and hepatic function, was reported to be useful to mark one sac of a twin gestation during amniocentesis.¹⁷ With modern ultrasonography technology, the need to rely on a dye to mark a sac of a twin has decreased significantly.

Our only option is to cope—effectively as possible Over decades, the medical community develops patterns of patient care that are critically dependent on the availability of key pharmaceuticals and devices. When a pharmaceutical or device suddenly becomes unavailable, it can disrupt important patterns of patient care. Imagine the impact on obstetrics practice if oxytocin became unavailable due to manufacturing shortages. Likely, both market forces and government regulation are the root cause of the shortfalls. Preventing the adverse consequences of the sudden loss of key pharmaceuticals and devices is an important priority to ensure optimal care of our patients.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Suddenly, indigo carmine is in short supply throughout the United States. One manufacturer has stopped production because of a raw materials shortage; another is experiencing manufacturing delays. Neither company can estimate a resupply or product return date.¹

Indigo carmine is approved by the US Food and Drug Administration (FDA) to localize ureteral orifices during cystoscopy and is commonly used in obstetrics and gynecology as a marker dye in the following additional situations:

• administered in a dilute solution via a catheter to back fill the bladder and test for bladder injury
• administered via a cannula in the uterine cavity to test the patency of the fallopian tubes
• injected into the amniotic fluid compartment to test for premature rupture of the membranes (PROM)
• injected into the amniotic fluid of a twin gestation to mark the amniotic fluid of one twin.

With this agent in short supply, we need to identify alternative marker dyes to use in our clinical practice. In this editorial, I provide a list of possible options to replace indigo carmine. Evidence supporting the use and safety of marker dyes in obstetrics and gynecology is based on small cohorts or case reports. The available evidence is of modest to low quality, and it is especially challenging to identify uncommon adverse effects. Consequently, expert opinion guides most practice recommendations.

Options to test the function of the ureters at cystoscopy
Given the lack of availability of indigo carmine, I recommend one of the following three options to test the function of the ureters at cystoscopy.

Partially fill the bladder with a solution of either sterile water or a 10% dextrose solution. (Experienced surgeons may prefer to use saline.) The turbulence of the interaction between the ureteral urine jet and instilled fluid in the bladder may permit visualization of the urine stream exiting the ureteral orifices as it swirls through the sterile water or dextrose solution. Both sterile water and a 10% dextrose solution offer a contrast in viscosity between the urine and the cystoscopy fluid, which may enhance the ability to detect the urine jet leaving the ureter.²

Administer IV methylene blue. Methylene blue is FDA approved for methemoglobinemia treatment. For this indication, it is administered intravenously at a dose of 1 to 2 mg/kgover 5 to 10 minutes. Paradoxically, when administered at a dose of >7 mg/kg, methylene blue can cause methemoglobinemia.³

Methylene blue often is provided as a 1% solution of 10 mg/mL in 10-mL vials. To use intravenous (IV) methylene blue to test ureteral function at cystoscopy, administer IV methylene blue 50 mg over 5 minutes. Use the cystoscope to view the colored urine exiting the ureteral orifices.^4,5 Administering a small dose of IV furosemide may accelerate the appearance of methylene blue in the urine.

When to use caution. Methylene blue blocks serotonin metabolism by inhibiting monoamine oxidase and may precipitate a serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs).

Common findings in the serotonin syndrome include: temperature above 38° C (100.4° F), anxiety, agitation, delirium, clonus, tremor, and hypertonia.⁶ I recommend that you DO NOT use IV methylene blue in patients taking these medications.^7,8

Great caution should be used before administering IV methylene blue in the presence of the following clinical situations:

• renal impairment  
• G6PD deficiency
• pediatric patients.

Methylene blue never should be given by a subcutaneous or intrathecal route. In pregnant women it should never be injected into the amniotic fluid compartment.

Use preoperative oral phenazo-pyridine. If the preoperative plan includes a cystoscopy procedure to test ureteral function, administering oral phenazopyridine in the preoperative holding area will result in colorization of the urine within 30 minutes, and it will persist for approximately 4 to 5 hours. To use this approach, administer one dose of phenazopyridine (Pyridium, Azo-Gesic), 100 mg or 200 mg orally, 30 minutes to 1 hour before the planned surgical start time, in the preoperative holding area.⁹ During cystoscopy, the urine from the ureteral jet will be colored orange.

When to use caution. Phenazo­pyridine should not be administered to patients with G6PD deficiency.

Option to test for bladder injury
Methylene blue. If methylene blue is used to test the integrity of the bladder, I recommend diluting 10 mg methylene blue in 1 L normal saline and then instilling the dilute solution through a catheter into the bladder.¹⁰

It is unlikely that this technique will be associated with sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs, and MAOIs.

Option to test patency of the fallopian tubes (chromopertubation)
Methylene blue. If methylene blue is used via a cannula in the uterine cavity to test the patency of the fallopian tubes, I recommend diluting 10 mg methylene blue in 150 mL normal saline and using the dilute solution to test tubal patency.

It is unlikely that this process will lead to sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs and MAOIs. However, if intrauterine injection of the dilute dye solution results in extravasation of the dye into the pelvic veins, a significant amount of dye can enter the circulation.¹¹ There are case reports of anaphylaxis following intrauterine injection of methylene blue to test tubal patency.^12,13

Options to diagnose PROM and to use for twin amniocentesis
None. Most experts recommend against the intra-amniotic injection of methylene blue to diagnose PROM or in twin amniocentesis procedures. Methylene blue injected into the intra-amniotic fluid during amniocentesis in multiple gestations has been reported to cause fetal bowel obstruction or atresia.^14,15 Fetal death also has been reported.¹⁶ Decades ago, indocyanine green, which is FDA approved to determine cardiac output, liver blood flow, and hepatic function, was reported to be useful to mark one sac of a twin gestation during amniocentesis.¹⁷ With modern ultrasonography technology, the need to rely on a dye to mark a sac of a twin has decreased significantly.

Our only option is to cope—effectively as possible Over decades, the medical community develops patterns of patient care that are critically dependent on the availability of key pharmaceuticals and devices. When a pharmaceutical or device suddenly becomes unavailable, it can disrupt important patterns of patient care. Imagine the impact on obstetrics practice if oxytocin became unavailable due to manufacturing shortages. Likely, both market forces and government regulation are the root cause of the shortfalls. Preventing the adverse consequences of the sudden loss of key pharmaceuticals and devices is an important priority to ensure optimal care of our patients.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Minimally invasive surgery utilizing laparoscopy for hysterectomy and myomectomy has become more common in women with gynecologic pathology. The benefits of this approach compared with laparotomy include decreased hospital stay, shorter recovery and, in experienced hands, significantly decreased morbidity.^1–3

Approximately 600,000 hysterectomies are performed annually in the United States—30% of which are performed laparoscopically.⁴ The primary indication for surgical intervention is uterine leiomyoma. This pathology accounts for 40% of procedures.⁵ During these surgeries, electromechanical morcellation (EMM), or open “power” morcellation, is commonly used to cut large tissue specimens into small pieces for removal and thereby avoid a larger incision. Concerns have been raised regarding the use of open power morcellation because of the risk of spreading an unrecognized malignancy.

Based on case reports and retrospective studies, the FDA issued a statement in April of this year discouraging the use of EMM for hysterectomy and myomectomy in women with uterine fibroids.⁶ The concern for inadvertent spread of an occult malignancy was the reasoning for the communication. Since that time, the FDA’s Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee held a public meeting in which the panel heard comments from patients, societies, and industry regarding their positions on the safety of laparoscopic power morcellation. The panel made several recommendations to the FDA but, at the time of this writing, the FDA has yet to issue a final decision.

Reaction to FDA’s action/inaction
The FDA’s “safety” communication was in response to the concern of a few who experienced a bad outcome believed to be secondary to open power morcellation of enlarged uteri or fibroid tumors. In its statement, the FDA estimated the risk of an occult sarcoma to be about 1 in 350 and stated that the risk of disseminating a sarcoma with morcellation is substantial. The FDA discouraged the use of the power morcellator during hysterectomy or myomectomy for uterine fibroids.

Many organizations, including the Society of Gynecologic Oncology, The American Association of Gynecologic Laparoscopists (AAGL), and the American College of Obstetricians and Gynecologists, issued less stringent statements regarding this technology.^7–9 These organizations stated generally that there were too few data to make a statement at that time, advocated the collection of more data, and encouraged detailed informed consent to be given to patients undergoing these procedures.

However, the FDA’s statement, and lack of a timely follow-up to clarify the role of the laparoscopic power morcellator in gynecologic surgery, has effectively stopped the use of this technology in its current form. In fact, in response to the statement, Ethicon Endosurgery has discontinued the distribution and sales of its power morcellator and many institutions have severely or completely restricted the use of this technology. The reason for these restrictions is that the medicolegal consequences of an adverse outcome would be very difficult to defend given the current, albeit premature, recommendations of the FDA. This statement makes it difficult to defend any adverse outcome that may occur in association with the use of the laparoscopic power morcellator. Furthermore, this statement by the FDA has largely prevented the medical community at large from collecting additional useful information to allow for a data-driven determination.

Power morcellation is not without risks. In fact, we outline them in this article. However, we believe that minimally invasive surgery should be allowed to continue to advance. In that vein, here we describe a technique of dual-port contained EMM. This surgical approach is performed under direct visualization—which solves the problem of poor visualization that hinders other contained EMM techniques.

Risks of power morcellation
The potential for inadvertent spread of occult malignancy is not the only risk of open EMM. Reports of disseminated leiomyomatosis, adenomyosis, and endometriosis also have been described from inadvertent tissue dispersion during open EMM with resulting ectopic reperitonealization.^10–12

The procedure itself is not without risks. A recent systematic review documented 55 major and minor complications from EMM.¹³ Multiple organ systems were injured including bowel, urinary, vascular, and others, resulting in six deaths from these complications. The investigators concluded that “laparoscopic morcellator–related injuries continue to increase and short- and long-term complications are emerging in both the medical literature and device-related databases. Surgeon inexperience is descriptively identified as one of the most common contributing factors.”

All of the above risks must be weighed against the known benefits of laparoscopic surgery and presented to each patient to assist in deciding which route of surgery should be performed.

Tissue extraction options for large specimens
Large specimen extraction options during gynecologic surgery include:

Vaginal coring. Delivery through the vagina or colpotomy during vaginal or laparoscopic hysterectomy uses the technique of coring, which has long been established in our field.

Manual morcellation through a single incision. Mini-laparotomy or laparoendoscopic single-site surgery (LESS) incisions provide another option of removal with manual morcellation after laparoscopic hysterectomy or myomectomy. One study revealed that specimens up to 22 weeks in size can be placed in a large EndoCatch bag and morcellated extracorporeally by circumferentially coring with a scalpel.¹⁴

Contained power morcellation through a single port. Finally, the technique of contained EMM was recently described.¹⁵ This technique uses a large containment bag placed through a LESS incision with EMM being performed in an artificially created pneumoperitoneum. This technique isolates the specimen so that it can be morcellated without risk of exposing the patient to any malignant cells that might be unrecognized within the specimen.

Each of these techniques allows many patients to consider a minimally invasive option for their surgery. However, the ability to safely morcellate a very large uterus or myoma may be limited by visualization, and the experience of the surgeon is often critical in the successful performance of these procedures.¹⁶

Therefore, at Washington Universitywe have developed a technique using dual ports, with isolation of the uterus or myomas to improve visualization and prevent spillage of malignant tumor or dispersion of other benign tissue.

Dual-port EMM: Technique, tips, and tricks
Our technique of dual-port contained EMM allows the removal of large fibroids or uteri much larger than 20 weeks in size safely under direct visualization through a 15-mm incision. The technique uses:

• Karl Storz Rotocut tissue morcellator with spacers (FIGURE 1)
• 15-mm trocar
• 5-mm balloon trocar
• 20320-inch containment bag (FIGURE 2).

Containment bag placement
Once the specimen is free, we place it to the right or left side of the abdomen. The 15-mm trocar is placed through the umbilicus while visualizing from a lateral trocar site. We then fan-fold the containment bag and introduce it through the 15-mm trocar, keeping the bag oriented with the opening anterior (FIGURE 3). The bag is then grasped at the opening along the drawstring with an atraumatic grasper.

Tip: Care must be taken when introducing the bag in order to avoid tearing or making a small hole in it.

The leading edge is then introduced into the deepest part of the pelvis, and the remainder of the bag (left outside of the abdomen) is then fed cephalad into the abdomen.

Once the bag is completely in the abdomen, we orient the bag with the opening as wide as possible. This allows placement of a very large specimen. Once the specimen is within the containment bag, the drawstring is pulled tight and the mouth of the bag is removed through the 15-mm trocar site at the umbilicus.

The abdominal lateral gas port is opened to allow the intra-abdominal pneumoperitoneum to escape. A 5-mm trocar is placed into the bag through the opening at the umbilicus and the containment bag is insufflated with carbon dioxide and the insufflation pressure is set to 30 mm. The laparoscope placed through this trocar allows the artificial pneumoperitoneum being created to be observed (VIDEO).

Vidyard Video

Tip: The containment bag covers the entire abdominal cavity and should be fully distended. If it does not distend fully, a hole in the bag may be present and the bag must be replaced.

At this point, we place a balloon trocar at the lateral trocar site and into the bag under direct visualization. The balloon tip is inflated and pulled up tightly against the bag and abdominal wall (FIGURE 4). This allows a tight seal so there is no gas leak or spillage of the morcellated specimen. The laparoscope is placed through this trocar and the insufflation tubing is moved to this port.

Morcellator insertion
The morcellator is introduced through the umbilicus under direct visualization using the short morcellator blade in most instances. Spacers are used to set the length of the morcellator within the containment bag. The tip of the morcellator should be approximately 3 cm to 4 cm within the bag but well away from the retroperitoneum. Remember, any bag will be cut easily by the morcellator and should be thought of as peritoneum only and not a tough barrier. Serious injuries could otherwise develop.

At this point, place the patient flat or out of Trendelenburg position. Morcellation may now proceed.

Tip: Morcellation is best performed with the morcellator perpendicular to the abdomen under direct visualization using a 30° laparoscope to optimize the view. Morcellation in this position uses gravity to facilitate “peeling” of the specimen during morcellation and allows for faster removal.

Before removing the morcellator, inspect the containment bag for any large pieces that may have been dispersed during the morcellation process and remove them. Once there are only small fragments remaining, remove the morcellator, allowing the carbon dioxide to escape. Deflate the balloon tip on the trocar.

Now the containment bag with the remaining specimen may be removed through the umbilicus, while simultaneously removing the balloon-tip trocar from the bag.

A safe minimally invasive approach
This technique has allowed us to safely remove specimens larger than 1,500 g while keeping them in a contained environment with no spill of tissue within the abdomen.

Tracking and adaptation needed
The FDA safety communication has severely limited the practice of morcellation in the minimally invasive gynecologic surgical setting. Many hospitals around the country have reacted by placing significant restrictions on the use of EMM or banned it outright. This action may reverse the national trend of increasing rates of laparoscopic hysterectomy and force many practitioners to return to open surgery.

Currently, it is unclear what the true risk of tissue extraction is whether it is performed via EMM or manually. Large national databases including the BOLD database from the Surgical Review Corporation, as well as AAGL, must be utilized to track these cases and their outcomes to guide therapy. In the meantime, in order to continue to offer a minimally invasive approach to gynecologic surgery, new techniques and instrumentation in the operating room will need to be modified to adapt to these new guidelines. This is vital to maintain or even reduce the rates of open hysterectomy and associated morbidity while diminishing the potential risks of inadvertent benign as well as malignant tissue dispersion with tissue extraction.

Share your thoughts on this article! Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com

Minimally invasive surgery utilizing laparoscopy for hysterectomy and myomectomy has become more common in women with gynecologic pathology. The benefits of this approach compared with laparotomy include decreased hospital stay, shorter recovery and, in experienced hands, significantly decreased morbidity.^1–3

Approximately 600,000 hysterectomies are performed annually in the United States—30% of which are performed laparoscopically.⁴ The primary indication for surgical intervention is uterine leiomyoma. This pathology accounts for 40% of procedures.⁵ During these surgeries, electromechanical morcellation (EMM), or open “power” morcellation, is commonly used to cut large tissue specimens into small pieces for removal and thereby avoid a larger incision. Concerns have been raised regarding the use of open power morcellation because of the risk of spreading an unrecognized malignancy.

Based on case reports and retrospective studies, the FDA issued a statement in April of this year discouraging the use of EMM for hysterectomy and myomectomy in women with uterine fibroids.⁶ The concern for inadvertent spread of an occult malignancy was the reasoning for the communication. Since that time, the FDA’s Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee held a public meeting in which the panel heard comments from patients, societies, and industry regarding their positions on the safety of laparoscopic power morcellation. The panel made several recommendations to the FDA but, at the time of this writing, the FDA has yet to issue a final decision.

Reaction to FDA’s action/inaction
The FDA’s “safety” communication was in response to the concern of a few who experienced a bad outcome believed to be secondary to open power morcellation of enlarged uteri or fibroid tumors. In its statement, the FDA estimated the risk of an occult sarcoma to be about 1 in 350 and stated that the risk of disseminating a sarcoma with morcellation is substantial. The FDA discouraged the use of the power morcellator during hysterectomy or myomectomy for uterine fibroids.

Many organizations, including the Society of Gynecologic Oncology, The American Association of Gynecologic Laparoscopists (AAGL), and the American College of Obstetricians and Gynecologists, issued less stringent statements regarding this technology.^7–9 These organizations stated generally that there were too few data to make a statement at that time, advocated the collection of more data, and encouraged detailed informed consent to be given to patients undergoing these procedures.

However, the FDA’s statement, and lack of a timely follow-up to clarify the role of the laparoscopic power morcellator in gynecologic surgery, has effectively stopped the use of this technology in its current form. In fact, in response to the statement, Ethicon Endosurgery has discontinued the distribution and sales of its power morcellator and many institutions have severely or completely restricted the use of this technology. The reason for these restrictions is that the medicolegal consequences of an adverse outcome would be very difficult to defend given the current, albeit premature, recommendations of the FDA. This statement makes it difficult to defend any adverse outcome that may occur in association with the use of the laparoscopic power morcellator. Furthermore, this statement by the FDA has largely prevented the medical community at large from collecting additional useful information to allow for a data-driven determination.

Power morcellation is not without risks. In fact, we outline them in this article. However, we believe that minimally invasive surgery should be allowed to continue to advance. In that vein, here we describe a technique of dual-port contained EMM. This surgical approach is performed under direct visualization—which solves the problem of poor visualization that hinders other contained EMM techniques.

Risks of power morcellation
The potential for inadvertent spread of occult malignancy is not the only risk of open EMM. Reports of disseminated leiomyomatosis, adenomyosis, and endometriosis also have been described from inadvertent tissue dispersion during open EMM with resulting ectopic reperitonealization.^10–12

The procedure itself is not without risks. A recent systematic review documented 55 major and minor complications from EMM.¹³ Multiple organ systems were injured including bowel, urinary, vascular, and others, resulting in six deaths from these complications. The investigators concluded that “laparoscopic morcellator–related injuries continue to increase and short- and long-term complications are emerging in both the medical literature and device-related databases. Surgeon inexperience is descriptively identified as one of the most common contributing factors.”

All of the above risks must be weighed against the known benefits of laparoscopic surgery and presented to each patient to assist in deciding which route of surgery should be performed.

Tissue extraction options for large specimens
Large specimen extraction options during gynecologic surgery include:

Vaginal coring. Delivery through the vagina or colpotomy during vaginal or laparoscopic hysterectomy uses the technique of coring, which has long been established in our field.

Manual morcellation through a single incision. Mini-laparotomy or laparoendoscopic single-site surgery (LESS) incisions provide another option of removal with manual morcellation after laparoscopic hysterectomy or myomectomy. One study revealed that specimens up to 22 weeks in size can be placed in a large EndoCatch bag and morcellated extracorporeally by circumferentially coring with a scalpel.¹⁴

Contained power morcellation through a single port. Finally, the technique of contained EMM was recently described.¹⁵ This technique uses a large containment bag placed through a LESS incision with EMM being performed in an artificially created pneumoperitoneum. This technique isolates the specimen so that it can be morcellated without risk of exposing the patient to any malignant cells that might be unrecognized within the specimen.

Each of these techniques allows many patients to consider a minimally invasive option for their surgery. However, the ability to safely morcellate a very large uterus or myoma may be limited by visualization, and the experience of the surgeon is often critical in the successful performance of these procedures.¹⁶

Therefore, at Washington Universitywe have developed a technique using dual ports, with isolation of the uterus or myomas to improve visualization and prevent spillage of malignant tumor or dispersion of other benign tissue.

Dual-port EMM: Technique, tips, and tricks
Our technique of dual-port contained EMM allows the removal of large fibroids or uteri much larger than 20 weeks in size safely under direct visualization through a 15-mm incision. The technique uses:

• Karl Storz Rotocut tissue morcellator with spacers (FIGURE 1)
• 15-mm trocar
• 5-mm balloon trocar
• 20320-inch containment bag (FIGURE 2).

Containment bag placement
Once the specimen is free, we place it to the right or left side of the abdomen. The 15-mm trocar is placed through the umbilicus while visualizing from a lateral trocar site. We then fan-fold the containment bag and introduce it through the 15-mm trocar, keeping the bag oriented with the opening anterior (FIGURE 3). The bag is then grasped at the opening along the drawstring with an atraumatic grasper.

Tip: Care must be taken when introducing the bag in order to avoid tearing or making a small hole in it.

The leading edge is then introduced into the deepest part of the pelvis, and the remainder of the bag (left outside of the abdomen) is then fed cephalad into the abdomen.

Once the bag is completely in the abdomen, we orient the bag with the opening as wide as possible. This allows placement of a very large specimen. Once the specimen is within the containment bag, the drawstring is pulled tight and the mouth of the bag is removed through the 15-mm trocar site at the umbilicus.

The abdominal lateral gas port is opened to allow the intra-abdominal pneumoperitoneum to escape. A 5-mm trocar is placed into the bag through the opening at the umbilicus and the containment bag is insufflated with carbon dioxide and the insufflation pressure is set to 30 mm. The laparoscope placed through this trocar allows the artificial pneumoperitoneum being created to be observed (VIDEO).

Vidyard Video

Tip: The containment bag covers the entire abdominal cavity and should be fully distended. If it does not distend fully, a hole in the bag may be present and the bag must be replaced.

At this point, we place a balloon trocar at the lateral trocar site and into the bag under direct visualization. The balloon tip is inflated and pulled up tightly against the bag and abdominal wall (FIGURE 4). This allows a tight seal so there is no gas leak or spillage of the morcellated specimen. The laparoscope is placed through this trocar and the insufflation tubing is moved to this port.

Morcellator insertion
The morcellator is introduced through the umbilicus under direct visualization using the short morcellator blade in most instances. Spacers are used to set the length of the morcellator within the containment bag. The tip of the morcellator should be approximately 3 cm to 4 cm within the bag but well away from the retroperitoneum. Remember, any bag will be cut easily by the morcellator and should be thought of as peritoneum only and not a tough barrier. Serious injuries could otherwise develop.

At this point, place the patient flat or out of Trendelenburg position. Morcellation may now proceed.

Tip: Morcellation is best performed with the morcellator perpendicular to the abdomen under direct visualization using a 30° laparoscope to optimize the view. Morcellation in this position uses gravity to facilitate “peeling” of the specimen during morcellation and allows for faster removal.

Before removing the morcellator, inspect the containment bag for any large pieces that may have been dispersed during the morcellation process and remove them. Once there are only small fragments remaining, remove the morcellator, allowing the carbon dioxide to escape. Deflate the balloon tip on the trocar.

Now the containment bag with the remaining specimen may be removed through the umbilicus, while simultaneously removing the balloon-tip trocar from the bag.

A safe minimally invasive approach
This technique has allowed us to safely remove specimens larger than 1,500 g while keeping them in a contained environment with no spill of tissue within the abdomen.

Tracking and adaptation needed
The FDA safety communication has severely limited the practice of morcellation in the minimally invasive gynecologic surgical setting. Many hospitals around the country have reacted by placing significant restrictions on the use of EMM or banned it outright. This action may reverse the national trend of increasing rates of laparoscopic hysterectomy and force many practitioners to return to open surgery.

Currently, it is unclear what the true risk of tissue extraction is whether it is performed via EMM or manually. Large national databases including the BOLD database from the Surgical Review Corporation, as well as AAGL, must be utilized to track these cases and their outcomes to guide therapy. In the meantime, in order to continue to offer a minimally invasive approach to gynecologic surgery, new techniques and instrumentation in the operating room will need to be modified to adapt to these new guidelines. This is vital to maintain or even reduce the rates of open hysterectomy and associated morbidity while diminishing the potential risks of inadvertent benign as well as malignant tissue dispersion with tissue extraction.

Share your thoughts on this article! Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com

Minimally invasive surgery utilizing laparoscopy for hysterectomy and myomectomy has become more common in women with gynecologic pathology. The benefits of this approach compared with laparotomy include decreased hospital stay, shorter recovery and, in experienced hands, significantly decreased morbidity.^1–3

Approximately 600,000 hysterectomies are performed annually in the United States—30% of which are performed laparoscopically.⁴ The primary indication for surgical intervention is uterine leiomyoma. This pathology accounts for 40% of procedures.⁵ During these surgeries, electromechanical morcellation (EMM), or open “power” morcellation, is commonly used to cut large tissue specimens into small pieces for removal and thereby avoid a larger incision. Concerns have been raised regarding the use of open power morcellation because of the risk of spreading an unrecognized malignancy.

Based on case reports and retrospective studies, the FDA issued a statement in April of this year discouraging the use of EMM for hysterectomy and myomectomy in women with uterine fibroids.⁶ The concern for inadvertent spread of an occult malignancy was the reasoning for the communication. Since that time, the FDA’s Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee held a public meeting in which the panel heard comments from patients, societies, and industry regarding their positions on the safety of laparoscopic power morcellation. The panel made several recommendations to the FDA but, at the time of this writing, the FDA has yet to issue a final decision.

Reaction to FDA’s action/inaction
The FDA’s “safety” communication was in response to the concern of a few who experienced a bad outcome believed to be secondary to open power morcellation of enlarged uteri or fibroid tumors. In its statement, the FDA estimated the risk of an occult sarcoma to be about 1 in 350 and stated that the risk of disseminating a sarcoma with morcellation is substantial. The FDA discouraged the use of the power morcellator during hysterectomy or myomectomy for uterine fibroids.

Many organizations, including the Society of Gynecologic Oncology, The American Association of Gynecologic Laparoscopists (AAGL), and the American College of Obstetricians and Gynecologists, issued less stringent statements regarding this technology.^7–9 These organizations stated generally that there were too few data to make a statement at that time, advocated the collection of more data, and encouraged detailed informed consent to be given to patients undergoing these procedures.

However, the FDA’s statement, and lack of a timely follow-up to clarify the role of the laparoscopic power morcellator in gynecologic surgery, has effectively stopped the use of this technology in its current form. In fact, in response to the statement, Ethicon Endosurgery has discontinued the distribution and sales of its power morcellator and many institutions have severely or completely restricted the use of this technology. The reason for these restrictions is that the medicolegal consequences of an adverse outcome would be very difficult to defend given the current, albeit premature, recommendations of the FDA. This statement makes it difficult to defend any adverse outcome that may occur in association with the use of the laparoscopic power morcellator. Furthermore, this statement by the FDA has largely prevented the medical community at large from collecting additional useful information to allow for a data-driven determination.

Power morcellation is not without risks. In fact, we outline them in this article. However, we believe that minimally invasive surgery should be allowed to continue to advance. In that vein, here we describe a technique of dual-port contained EMM. This surgical approach is performed under direct visualization—which solves the problem of poor visualization that hinders other contained EMM techniques.

Risks of power morcellation
The potential for inadvertent spread of occult malignancy is not the only risk of open EMM. Reports of disseminated leiomyomatosis, adenomyosis, and endometriosis also have been described from inadvertent tissue dispersion during open EMM with resulting ectopic reperitonealization.^10–12

The procedure itself is not without risks. A recent systematic review documented 55 major and minor complications from EMM.¹³ Multiple organ systems were injured including bowel, urinary, vascular, and others, resulting in six deaths from these complications. The investigators concluded that “laparoscopic morcellator–related injuries continue to increase and short- and long-term complications are emerging in both the medical literature and device-related databases. Surgeon inexperience is descriptively identified as one of the most common contributing factors.”

All of the above risks must be weighed against the known benefits of laparoscopic surgery and presented to each patient to assist in deciding which route of surgery should be performed.

Tissue extraction options for large specimens
Large specimen extraction options during gynecologic surgery include:

Vaginal coring. Delivery through the vagina or colpotomy during vaginal or laparoscopic hysterectomy uses the technique of coring, which has long been established in our field.

Manual morcellation through a single incision. Mini-laparotomy or laparoendoscopic single-site surgery (LESS) incisions provide another option of removal with manual morcellation after laparoscopic hysterectomy or myomectomy. One study revealed that specimens up to 22 weeks in size can be placed in a large EndoCatch bag and morcellated extracorporeally by circumferentially coring with a scalpel.¹⁴

Contained power morcellation through a single port. Finally, the technique of contained EMM was recently described.¹⁵ This technique uses a large containment bag placed through a LESS incision with EMM being performed in an artificially created pneumoperitoneum. This technique isolates the specimen so that it can be morcellated without risk of exposing the patient to any malignant cells that might be unrecognized within the specimen.

Each of these techniques allows many patients to consider a minimally invasive option for their surgery. However, the ability to safely morcellate a very large uterus or myoma may be limited by visualization, and the experience of the surgeon is often critical in the successful performance of these procedures.¹⁶

Therefore, at Washington Universitywe have developed a technique using dual ports, with isolation of the uterus or myomas to improve visualization and prevent spillage of malignant tumor or dispersion of other benign tissue.

Dual-port EMM: Technique, tips, and tricks
Our technique of dual-port contained EMM allows the removal of large fibroids or uteri much larger than 20 weeks in size safely under direct visualization through a 15-mm incision. The technique uses:

• Karl Storz Rotocut tissue morcellator with spacers (FIGURE 1)
• 15-mm trocar
• 5-mm balloon trocar
• 20320-inch containment bag (FIGURE 2).

Containment bag placement
Once the specimen is free, we place it to the right or left side of the abdomen. The 15-mm trocar is placed through the umbilicus while visualizing from a lateral trocar site. We then fan-fold the containment bag and introduce it through the 15-mm trocar, keeping the bag oriented with the opening anterior (FIGURE 3). The bag is then grasped at the opening along the drawstring with an atraumatic grasper.

Tip: Care must be taken when introducing the bag in order to avoid tearing or making a small hole in it.

The leading edge is then introduced into the deepest part of the pelvis, and the remainder of the bag (left outside of the abdomen) is then fed cephalad into the abdomen.

Once the bag is completely in the abdomen, we orient the bag with the opening as wide as possible. This allows placement of a very large specimen. Once the specimen is within the containment bag, the drawstring is pulled tight and the mouth of the bag is removed through the 15-mm trocar site at the umbilicus.

The abdominal lateral gas port is opened to allow the intra-abdominal pneumoperitoneum to escape. A 5-mm trocar is placed into the bag through the opening at the umbilicus and the containment bag is insufflated with carbon dioxide and the insufflation pressure is set to 30 mm. The laparoscope placed through this trocar allows the artificial pneumoperitoneum being created to be observed (VIDEO).

Vidyard Video

Tip: The containment bag covers the entire abdominal cavity and should be fully distended. If it does not distend fully, a hole in the bag may be present and the bag must be replaced.

At this point, we place a balloon trocar at the lateral trocar site and into the bag under direct visualization. The balloon tip is inflated and pulled up tightly against the bag and abdominal wall (FIGURE 4). This allows a tight seal so there is no gas leak or spillage of the morcellated specimen. The laparoscope is placed through this trocar and the insufflation tubing is moved to this port.

Morcellator insertion
The morcellator is introduced through the umbilicus under direct visualization using the short morcellator blade in most instances. Spacers are used to set the length of the morcellator within the containment bag. The tip of the morcellator should be approximately 3 cm to 4 cm within the bag but well away from the retroperitoneum. Remember, any bag will be cut easily by the morcellator and should be thought of as peritoneum only and not a tough barrier. Serious injuries could otherwise develop.

At this point, place the patient flat or out of Trendelenburg position. Morcellation may now proceed.

Tip: Morcellation is best performed with the morcellator perpendicular to the abdomen under direct visualization using a 30° laparoscope to optimize the view. Morcellation in this position uses gravity to facilitate “peeling” of the specimen during morcellation and allows for faster removal.

Before removing the morcellator, inspect the containment bag for any large pieces that may have been dispersed during the morcellation process and remove them. Once there are only small fragments remaining, remove the morcellator, allowing the carbon dioxide to escape. Deflate the balloon tip on the trocar.

Now the containment bag with the remaining specimen may be removed through the umbilicus, while simultaneously removing the balloon-tip trocar from the bag.

A safe minimally invasive approach
This technique has allowed us to safely remove specimens larger than 1,500 g while keeping them in a contained environment with no spill of tissue within the abdomen.

Tracking and adaptation needed
The FDA safety communication has severely limited the practice of morcellation in the minimally invasive gynecologic surgical setting. Many hospitals around the country have reacted by placing significant restrictions on the use of EMM or banned it outright. This action may reverse the national trend of increasing rates of laparoscopic hysterectomy and force many practitioners to return to open surgery.

Currently, it is unclear what the true risk of tissue extraction is whether it is performed via EMM or manually. Large national databases including the BOLD database from the Surgical Review Corporation, as well as AAGL, must be utilized to track these cases and their outcomes to guide therapy. In the meantime, in order to continue to offer a minimally invasive approach to gynecologic surgery, new techniques and instrumentation in the operating room will need to be modified to adapt to these new guidelines. This is vital to maintain or even reduce the rates of open hysterectomy and associated morbidity while diminishing the potential risks of inadvertent benign as well as malignant tissue dispersion with tissue extraction.

Share your thoughts on this article! Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com

Aspirin tablets

Credit: Sage Ross

Low-dose aspirin can decrease the risk of major vascular events among patients with venous thromboembolism (VTE), according to a study published in Circulation.

The study included more than 1000 patients who had completed initial anticoagulant therapy after their first VTE.

Patients who went on to receive a daily dose of aspirin had a lower incidence of recurrent VTE, myocardial infarction, stroke, and cardiovascular death, compared

to those who received placebo.

The effects were not as substantial as those typically observed with warfarin or newer anticoagulants, but the results suggest low-dose aspirin is a feasible option for patients who cannot receive long-term anticoagulant therapy.

“The study provides evidence that, after a first venous thrombosis or embolism, daily aspirin reduces the risk of another event, without causing undue bleeding,” said study author John Simes, MD, of the University of Sydney in New South Wales, Australia.

“This treatment is an alternative to long-term anticoagulation and will be especially useful for patients who do not want the inconvenience of close medical monitoring or the risk of bleeding. [Additionally,] aspirin will be ideal in the many countries where prolonged anticoagulant treatment is too expensive.”

For this study, Dr Simes and his colleagues evaluated data from the ASPIRE and WARFASA trials. ASPIRE included 822 patients who were followed for an average of 3 years. And WARFASA included 402 patients who were followed for at least 2 years.

The patients had completed initial treatment with heparin and warfarin or an equivalent anticoagulant regimen following a first, unprovoked VTE. They were randomized to receive placebo (n=608) or a 100 mg daily dose of aspirin (n=616).

The researchers evaluated the differences between these 2 groups with regard to bleeding, recurrent VTE, and major vascular events, which includes recurrent VTE, myocardial infarction, stroke, and cardiovascular death.

VTE recurred in 18.4% of patients in the placebo arm and 13.1% of patients in the aspirin arm. The annual rate of recurrent VTE was 7.5% and 5.1%, respectively. So aspirin reduced the risk of VTE by 32% (hazard ratio [HR]=0.68, P=0.008).

Aspirin reduced the risk of deep vein thrombosis by 34% (HR=0.66, P=0.01) and the risk of pulmonary embolism by 34% (HR=0.66, P=0.08).

Aspirin also reduce the risk of major vascular events by 34%. The annual rate of these events was 5.7% in the aspirin arm and 8.7% in the placebo arm (HR=0.66, P=0.002).

There was no significant difference between the treatment arms with regard to bleeding. The annual rate of bleeding was 0.7% in the placebo arm and 1.1% in the aspirin arm. The annual rate of major bleeding was 0.4% and 0.5%, respectively.

“Aspirin does not require laboratory monitoring and is associated with about a 10-fold lower incidence of bleeding compared with oral anticoagulants,” said study author Cecilia Becattini, MD, of the University of Perugia in Italy.

“We are convinced that it will be an alternative for extended prevention of venous thromboembolism after 6 to 12 months of anticoagulant treatment.”

The researchers stressed that aspirin will not be a substitute for anticoagulant therapy in all patients. But it is an option for patients who are stopping anticoagulant therapy or for patients in whom long-term anticoagulant therapy is unsuitable.

“Although less effective, aspirin is inexpensive, easily obtainable, safe, and familiar to patients and clinicians worldwide,” Dr Simes noted. “If cost is the main consideration, aspirin is a particularly useful therapy. The costs of treating future thromboembolic events is greater than the cost of the preventive treatment.”

Aspirin tablets

Credit: Sage Ross

Low-dose aspirin can decrease the risk of major vascular events among patients with venous thromboembolism (VTE), according to a study published in Circulation.

The study included more than 1000 patients who had completed initial anticoagulant therapy after their first VTE.

Patients who went on to receive a daily dose of aspirin had a lower incidence of recurrent VTE, myocardial infarction, stroke, and cardiovascular death, compared

to those who received placebo.

The effects were not as substantial as those typically observed with warfarin or newer anticoagulants, but the results suggest low-dose aspirin is a feasible option for patients who cannot receive long-term anticoagulant therapy.

“The study provides evidence that, after a first venous thrombosis or embolism, daily aspirin reduces the risk of another event, without causing undue bleeding,” said study author John Simes, MD, of the University of Sydney in New South Wales, Australia.

“This treatment is an alternative to long-term anticoagulation and will be especially useful for patients who do not want the inconvenience of close medical monitoring or the risk of bleeding. [Additionally,] aspirin will be ideal in the many countries where prolonged anticoagulant treatment is too expensive.”

For this study, Dr Simes and his colleagues evaluated data from the ASPIRE and WARFASA trials. ASPIRE included 822 patients who were followed for an average of 3 years. And WARFASA included 402 patients who were followed for at least 2 years.

The patients had completed initial treatment with heparin and warfarin or an equivalent anticoagulant regimen following a first, unprovoked VTE. They were randomized to receive placebo (n=608) or a 100 mg daily dose of aspirin (n=616).

The researchers evaluated the differences between these 2 groups with regard to bleeding, recurrent VTE, and major vascular events, which includes recurrent VTE, myocardial infarction, stroke, and cardiovascular death.

VTE recurred in 18.4% of patients in the placebo arm and 13.1% of patients in the aspirin arm. The annual rate of recurrent VTE was 7.5% and 5.1%, respectively. So aspirin reduced the risk of VTE by 32% (hazard ratio [HR]=0.68, P=0.008).

Aspirin reduced the risk of deep vein thrombosis by 34% (HR=0.66, P=0.01) and the risk of pulmonary embolism by 34% (HR=0.66, P=0.08).

Aspirin also reduce the risk of major vascular events by 34%. The annual rate of these events was 5.7% in the aspirin arm and 8.7% in the placebo arm (HR=0.66, P=0.002).

There was no significant difference between the treatment arms with regard to bleeding. The annual rate of bleeding was 0.7% in the placebo arm and 1.1% in the aspirin arm. The annual rate of major bleeding was 0.4% and 0.5%, respectively.

“Aspirin does not require laboratory monitoring and is associated with about a 10-fold lower incidence of bleeding compared with oral anticoagulants,” said study author Cecilia Becattini, MD, of the University of Perugia in Italy.

“We are convinced that it will be an alternative for extended prevention of venous thromboembolism after 6 to 12 months of anticoagulant treatment.”

The researchers stressed that aspirin will not be a substitute for anticoagulant therapy in all patients. But it is an option for patients who are stopping anticoagulant therapy or for patients in whom long-term anticoagulant therapy is unsuitable.

“Although less effective, aspirin is inexpensive, easily obtainable, safe, and familiar to patients and clinicians worldwide,” Dr Simes noted. “If cost is the main consideration, aspirin is a particularly useful therapy. The costs of treating future thromboembolic events is greater than the cost of the preventive treatment.”

Aspirin tablets

Credit: Sage Ross

Low-dose aspirin can decrease the risk of major vascular events among patients with venous thromboembolism (VTE), according to a study published in Circulation.

The study included more than 1000 patients who had completed initial anticoagulant therapy after their first VTE.

Patients who went on to receive a daily dose of aspirin had a lower incidence of recurrent VTE, myocardial infarction, stroke, and cardiovascular death, compared

to those who received placebo.

The effects were not as substantial as those typically observed with warfarin or newer anticoagulants, but the results suggest low-dose aspirin is a feasible option for patients who cannot receive long-term anticoagulant therapy.

“The study provides evidence that, after a first venous thrombosis or embolism, daily aspirin reduces the risk of another event, without causing undue bleeding,” said study author John Simes, MD, of the University of Sydney in New South Wales, Australia.

“This treatment is an alternative to long-term anticoagulation and will be especially useful for patients who do not want the inconvenience of close medical monitoring or the risk of bleeding. [Additionally,] aspirin will be ideal in the many countries where prolonged anticoagulant treatment is too expensive.”

For this study, Dr Simes and his colleagues evaluated data from the ASPIRE and WARFASA trials. ASPIRE included 822 patients who were followed for an average of 3 years. And WARFASA included 402 patients who were followed for at least 2 years.

The patients had completed initial treatment with heparin and warfarin or an equivalent anticoagulant regimen following a first, unprovoked VTE. They were randomized to receive placebo (n=608) or a 100 mg daily dose of aspirin (n=616).

The researchers evaluated the differences between these 2 groups with regard to bleeding, recurrent VTE, and major vascular events, which includes recurrent VTE, myocardial infarction, stroke, and cardiovascular death.

VTE recurred in 18.4% of patients in the placebo arm and 13.1% of patients in the aspirin arm. The annual rate of recurrent VTE was 7.5% and 5.1%, respectively. So aspirin reduced the risk of VTE by 32% (hazard ratio [HR]=0.68, P=0.008).

Aspirin reduced the risk of deep vein thrombosis by 34% (HR=0.66, P=0.01) and the risk of pulmonary embolism by 34% (HR=0.66, P=0.08).

Aspirin also reduce the risk of major vascular events by 34%. The annual rate of these events was 5.7% in the aspirin arm and 8.7% in the placebo arm (HR=0.66, P=0.002).

There was no significant difference between the treatment arms with regard to bleeding. The annual rate of bleeding was 0.7% in the placebo arm and 1.1% in the aspirin arm. The annual rate of major bleeding was 0.4% and 0.5%, respectively.

“Aspirin does not require laboratory monitoring and is associated with about a 10-fold lower incidence of bleeding compared with oral anticoagulants,” said study author Cecilia Becattini, MD, of the University of Perugia in Italy.

“We are convinced that it will be an alternative for extended prevention of venous thromboembolism after 6 to 12 months of anticoagulant treatment.”

The researchers stressed that aspirin will not be a substitute for anticoagulant therapy in all patients. But it is an option for patients who are stopping anticoagulant therapy or for patients in whom long-term anticoagulant therapy is unsuitable.

“Although less effective, aspirin is inexpensive, easily obtainable, safe, and familiar to patients and clinicians worldwide,” Dr Simes noted. “If cost is the main consideration, aspirin is a particularly useful therapy. The costs of treating future thromboembolic events is greater than the cost of the preventive treatment.”

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

An infusion of chimeric antigen receptor (CAR) T-cell therapy following chemotherapy can elicit responses in patients with non-Hodgkin lymphoma, a small study suggests.

However, patients also experienced significant acute toxicities, including fever, low blood pressure, focal neurological deficits, and delirium.

James N. Kochenderfer, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial was sponsored by the National Cancer Institute, but the CAR T-cell therapy being tested uses the same CAR construct as KTE-C19, which is being developed by Kite Pharma, Inc.

The study included 15 patients with advanced B-cell malignancies. The patients first received conditioning with cyclophosphamide and fludarabine.

A day later, they received a single infusion of the CAR T-cell therapy, which consists of T cells taken from each patient’s peripheral blood and modified to target CD19.

The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Response rates

Thirteen patients were evaluable for response. One patient was lost to follow-up because of noncompliance, and 1 died soon after treatment. The researchers said the cause of death was likely cardiac arrhythmia.

The overall response rate was 92%. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Three of the CRs are ongoing, with the duration ranging from 9 months to 22 months.

Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. All 3 CRs are ongoing, with the duration ranging from 14 months to 23 months.

Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR. The duration of the ongoing CR is 11 months.

Toxicity

As seen in other studies, the CAR T-cell therapy was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or IL-6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3  patients developed unexpected neurologic abnormalities.

One of these patients developed aphasia on day 5 after CAR T-cell infusion. It occurred intermittently for 7 days before resolving. The patient also experienced right-sided facial paresis that lasted approximately 20 minutes on day 8 after infusion.

Another patient developed aphasia 5 days after CAR T-cell infusion, but this was followed by confusion and severe generalized myoclonus. All symptoms resolved by 11 days after the infusion, except for a mild tremor that resolved over the next month.

A third patient developed aphasia 5 days after CAR T-cell infusion. This was followed by confusion, hemifacial spasms, apraxia, and gait disturbances. These effects varied in severity but dramatically improved 20 days after the infusion, according to the researchers.

Researcher in the lab

Credit: NIH

A new tool may help researchers sift through the scientific literature to discover hypothesis-generating information relevant to their own research.

The resource, called the Knowledge Integration Toolkit (KnIT), extracts relevant information from the literature, includes it in a network that can be queried, and

then attempts to use these data to generate reasonable and testable hypotheses that can help direct lab studies.

Researchers tested KnIT in a retrospective case study involving published data on p53 and found the tool could accurately predict the existence of proteins that modify p53.

Details from this study were published in the Association for Computing Machinery’s digital library.

Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas, is scheduled to discuss the study on August 27 at the 20th Annual Association for Computing Machinery’s Special Interest Group on Knowledge Discovery and Data Mining Conference in New York, New York.

“On average, a scientist might read between 1 and 5 research papers on a good day,” Dr Lichtarge noted.

“But, to put this in perspective with p53, there are over 70,000 papers published on this protein. Even if a scientist reads 5 papers a day, it could take nearly 38 years to completely understand all of the research already available today on this protein.”

Scientists formulate hypotheses based on what they read and know, but because they cannot read everything, their hypotheses may be biased, according to Dr Lichtarge.

“A computer certainly may not reason as well as a scientist,” he said, “but the little it can, logically and objectively, may contribute greatly when applied to our entire body of knowledge.”

With that in mind, Dr Lichtarge and his colleagues initiated a project to develop a knowledge integration tool that took advantage of existing text mining capabilities, such as those used by IBM’s Watson technology—cognitive technology that processes information more like a human than a computer.

And the team came up with KnIT. In the first test using KnIT, they sought to identify new protein kinases that phosphorylate p53.

There are more than 500 known human kinases and tens of thousands of possible proteins they can target. Thirty-three are currently known to modify p53.

The researchers used KnIT to mine the scientific literature up to 2003, when only half of the 33 phosphorylating protein kinases had been discovered.

Seventy-four kinases were extracted as potential modifiers. Of these, prior to 2003, 10 were known to phosphorylate p53, and 9 were discovered at a later date.

Of the 10 already known, KnIT accounted for them in reasoning as well as ranking the likelihood that the other 64 kinases targeted p53. Of the 9 found nearly a decade later, KnIT accurately predicted 7.

“This study showed that, in a very narrow field of study regarding p53, we can, in fact, suggest new relationships and new functions associated with p53, which can later be directly validated in the laboratory,” Dr Lichtarge said.

“Our long-term hope is to systematically extract knowledge directly from the totality of the public medical literature. For this, we need technological advances to read text, extract facts from every sentence, and to integrate this information into a network that describes the relationship between all of the objects and entities discussed in the literature.”

“This first study is promising, because it suggests a proof of principle for a small step towards this type of knowledge discovery. With more research, we hope to get closer to clinical and therapeutic applications.”

Researcher in the lab

Credit: NIH

A new tool may help researchers sift through the scientific literature to discover hypothesis-generating information relevant to their own research.

The resource, called the Knowledge Integration Toolkit (KnIT), extracts relevant information from the literature, includes it in a network that can be queried, and

then attempts to use these data to generate reasonable and testable hypotheses that can help direct lab studies.

Researchers tested KnIT in a retrospective case study involving published data on p53 and found the tool could accurately predict the existence of proteins that modify p53.

Details from this study were published in the Association for Computing Machinery’s digital library.

Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas, is scheduled to discuss the study on August 27 at the 20th Annual Association for Computing Machinery’s Special Interest Group on Knowledge Discovery and Data Mining Conference in New York, New York.

“On average, a scientist might read between 1 and 5 research papers on a good day,” Dr Lichtarge noted.

“But, to put this in perspective with p53, there are over 70,000 papers published on this protein. Even if a scientist reads 5 papers a day, it could take nearly 38 years to completely understand all of the research already available today on this protein.”

Scientists formulate hypotheses based on what they read and know, but because they cannot read everything, their hypotheses may be biased, according to Dr Lichtarge.

“A computer certainly may not reason as well as a scientist,” he said, “but the little it can, logically and objectively, may contribute greatly when applied to our entire body of knowledge.”

With that in mind, Dr Lichtarge and his colleagues initiated a project to develop a knowledge integration tool that took advantage of existing text mining capabilities, such as those used by IBM’s Watson technology—cognitive technology that processes information more like a human than a computer.

And the team came up with KnIT. In the first test using KnIT, they sought to identify new protein kinases that phosphorylate p53.

There are more than 500 known human kinases and tens of thousands of possible proteins they can target. Thirty-three are currently known to modify p53.

The researchers used KnIT to mine the scientific literature up to 2003, when only half of the 33 phosphorylating protein kinases had been discovered.

Seventy-four kinases were extracted as potential modifiers. Of these, prior to 2003, 10 were known to phosphorylate p53, and 9 were discovered at a later date.

Of the 10 already known, KnIT accounted for them in reasoning as well as ranking the likelihood that the other 64 kinases targeted p53. Of the 9 found nearly a decade later, KnIT accurately predicted 7.

“This study showed that, in a very narrow field of study regarding p53, we can, in fact, suggest new relationships and new functions associated with p53, which can later be directly validated in the laboratory,” Dr Lichtarge said.

“Our long-term hope is to systematically extract knowledge directly from the totality of the public medical literature. For this, we need technological advances to read text, extract facts from every sentence, and to integrate this information into a network that describes the relationship between all of the objects and entities discussed in the literature.”

“This first study is promising, because it suggests a proof of principle for a small step towards this type of knowledge discovery. With more research, we hope to get closer to clinical and therapeutic applications.”

Researcher in the lab

Credit: NIH

A new tool may help researchers sift through the scientific literature to discover hypothesis-generating information relevant to their own research.

The resource, called the Knowledge Integration Toolkit (KnIT), extracts relevant information from the literature, includes it in a network that can be queried, and

then attempts to use these data to generate reasonable and testable hypotheses that can help direct lab studies.

Researchers tested KnIT in a retrospective case study involving published data on p53 and found the tool could accurately predict the existence of proteins that modify p53.

Details from this study were published in the Association for Computing Machinery’s digital library.

Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas, is scheduled to discuss the study on August 27 at the 20th Annual Association for Computing Machinery’s Special Interest Group on Knowledge Discovery and Data Mining Conference in New York, New York.

“On average, a scientist might read between 1 and 5 research papers on a good day,” Dr Lichtarge noted.

“But, to put this in perspective with p53, there are over 70,000 papers published on this protein. Even if a scientist reads 5 papers a day, it could take nearly 38 years to completely understand all of the research already available today on this protein.”

Scientists formulate hypotheses based on what they read and know, but because they cannot read everything, their hypotheses may be biased, according to Dr Lichtarge.

“A computer certainly may not reason as well as a scientist,” he said, “but the little it can, logically and objectively, may contribute greatly when applied to our entire body of knowledge.”

With that in mind, Dr Lichtarge and his colleagues initiated a project to develop a knowledge integration tool that took advantage of existing text mining capabilities, such as those used by IBM’s Watson technology—cognitive technology that processes information more like a human than a computer.

And the team came up with KnIT. In the first test using KnIT, they sought to identify new protein kinases that phosphorylate p53.

There are more than 500 known human kinases and tens of thousands of possible proteins they can target. Thirty-three are currently known to modify p53.

The researchers used KnIT to mine the scientific literature up to 2003, when only half of the 33 phosphorylating protein kinases had been discovered.

Seventy-four kinases were extracted as potential modifiers. Of these, prior to 2003, 10 were known to phosphorylate p53, and 9 were discovered at a later date.

Of the 10 already known, KnIT accounted for them in reasoning as well as ranking the likelihood that the other 64 kinases targeted p53. Of the 9 found nearly a decade later, KnIT accurately predicted 7.

“This study showed that, in a very narrow field of study regarding p53, we can, in fact, suggest new relationships and new functions associated with p53, which can later be directly validated in the laboratory,” Dr Lichtarge said.

“Our long-term hope is to systematically extract knowledge directly from the totality of the public medical literature. For this, we need technological advances to read text, extract facts from every sentence, and to integrate this information into a network that describes the relationship between all of the objects and entities discussed in the literature.”

“This first study is promising, because it suggests a proof of principle for a small step towards this type of knowledge discovery. With more research, we hope to get closer to clinical and therapeutic applications.”

Overweight or obese adults at risk for cardiovascular disease should receive intensive behavioral counseling interventions, according to a recommendation statement by the U. S. Preventive Services Task Force.

After a comprehensive review of the current literature, the USPSTF concluded "with moderate certainty" that interventions promoting a healthful diet and increased physical activity have a moderate net benefit in this patient population, said Dr. Michael L. LeFevre, chair of the task force at the time the recommendation was finalized, and professor of family medicine at the University of Missouri, Columbia.

© Digital Vision/thinkstockphotos.com

The recommendation statement issued Aug. 25 is "an update and refinement" of the 2003 USPSTF recommendation on dietary counseling for at-risk adults, this time targeting overweight or obese patients who have additional CVD risk factors such as hypertension, dyslipidemia, impaired fasting glucose, or metabolic syndrome.

The group reviewed 74 trials assessing the effectiveness of behavioral counseling interventions of various intensities. Only 16 reported on direct health outcomes such as CVD events, mortality, or quality of life, the task force noted, so there is inadequate evidence about intensive behavioral counseling’s effect on such outcomes.

A total of 71 trials involving more than 32,000 participants focused on intermediate health outcomes such as lipid levels, blood pressure, glucose levels, weight, and medication use. Overall, intensive counseling interventions made "small but important changes" in these outcomes, with total cholesterol levels decreasing approximately 3-6 mg/dL, LDL cholesterol decreasing by 1.5-5.0 mg/dL, systolic blood pressure decreasing by 1-3 mm Hg, diastolic blood pressure decreasing by 1-2 mm Hg, and fasting glucose levels decreasing by 1-3 mg/dL.

In addition, weight decreased by a mean of approximately 3 kg, and the proportion of patients who participated in moderate-intensity exercise for 150 minutes per week rose from 10% to 25%. However, few of these studies followed patients for more than 1-2 years, so the evidence was inadequate to assess longer-term benefits.

Because very few and mostly minor adverse events were associated with these interventions, they yielded a moderate net benefit.

Most of the intensive behavioral counseling interventions that were assessed averaged 5-16 individual or group sessions during a period of 9-12 months. All included didactic education; in most programs, specially trained professionals (dietitians, nutritionists, physiotherapists, exercise professionals, health educators, and psychologists) provided monitoring and feedback for the participants, devised individualized care plans, and taught problem-solving skills. Many types and combinations of interventions were effective, and almost all were delivered outside the primary care setting.

The recommendation statement is in line with others published by the American Heart Association, the American College of Sports Medicine, and the American Academy of Family Physicians. The AAFP is updating its recommendations regarding behavioral counseling to prevent CVD, Dr. LeFevre and his associates noted.

The USPSTF, funded by but independent of the federal government, makes recommendations about the effectiveness of specific preventive-care services based on evidence of benefits and harms, without considering costs.

Do you refer overweight or obese patients with cardiovascular risk factors for intensive behavioral counseling? Take our Quick Poll on the Family Practice News homepage.

Overweight or obese adults at risk for cardiovascular disease should receive intensive behavioral counseling interventions, according to a recommendation statement by the U. S. Preventive Services Task Force.

After a comprehensive review of the current literature, the USPSTF concluded "with moderate certainty" that interventions promoting a healthful diet and increased physical activity have a moderate net benefit in this patient population, said Dr. Michael L. LeFevre, chair of the task force at the time the recommendation was finalized, and professor of family medicine at the University of Missouri, Columbia.

© Digital Vision/thinkstockphotos.com

The recommendation statement issued Aug. 25 is "an update and refinement" of the 2003 USPSTF recommendation on dietary counseling for at-risk adults, this time targeting overweight or obese patients who have additional CVD risk factors such as hypertension, dyslipidemia, impaired fasting glucose, or metabolic syndrome.

The group reviewed 74 trials assessing the effectiveness of behavioral counseling interventions of various intensities. Only 16 reported on direct health outcomes such as CVD events, mortality, or quality of life, the task force noted, so there is inadequate evidence about intensive behavioral counseling’s effect on such outcomes.

A total of 71 trials involving more than 32,000 participants focused on intermediate health outcomes such as lipid levels, blood pressure, glucose levels, weight, and medication use. Overall, intensive counseling interventions made "small but important changes" in these outcomes, with total cholesterol levels decreasing approximately 3-6 mg/dL, LDL cholesterol decreasing by 1.5-5.0 mg/dL, systolic blood pressure decreasing by 1-3 mm Hg, diastolic blood pressure decreasing by 1-2 mm Hg, and fasting glucose levels decreasing by 1-3 mg/dL.

In addition, weight decreased by a mean of approximately 3 kg, and the proportion of patients who participated in moderate-intensity exercise for 150 minutes per week rose from 10% to 25%. However, few of these studies followed patients for more than 1-2 years, so the evidence was inadequate to assess longer-term benefits.

Because very few and mostly minor adverse events were associated with these interventions, they yielded a moderate net benefit.

Most of the intensive behavioral counseling interventions that were assessed averaged 5-16 individual or group sessions during a period of 9-12 months. All included didactic education; in most programs, specially trained professionals (dietitians, nutritionists, physiotherapists, exercise professionals, health educators, and psychologists) provided monitoring and feedback for the participants, devised individualized care plans, and taught problem-solving skills. Many types and combinations of interventions were effective, and almost all were delivered outside the primary care setting.

The recommendation statement is in line with others published by the American Heart Association, the American College of Sports Medicine, and the American Academy of Family Physicians. The AAFP is updating its recommendations regarding behavioral counseling to prevent CVD, Dr. LeFevre and his associates noted.

The USPSTF, funded by but independent of the federal government, makes recommendations about the effectiveness of specific preventive-care services based on evidence of benefits and harms, without considering costs.

Do you refer overweight or obese patients with cardiovascular risk factors for intensive behavioral counseling? Take our Quick Poll on the Family Practice News homepage.

Overweight or obese adults at risk for cardiovascular disease should receive intensive behavioral counseling interventions, according to a recommendation statement by the U. S. Preventive Services Task Force.

After a comprehensive review of the current literature, the USPSTF concluded "with moderate certainty" that interventions promoting a healthful diet and increased physical activity have a moderate net benefit in this patient population, said Dr. Michael L. LeFevre, chair of the task force at the time the recommendation was finalized, and professor of family medicine at the University of Missouri, Columbia.

© Digital Vision/thinkstockphotos.com

The recommendation statement issued Aug. 25 is "an update and refinement" of the 2003 USPSTF recommendation on dietary counseling for at-risk adults, this time targeting overweight or obese patients who have additional CVD risk factors such as hypertension, dyslipidemia, impaired fasting glucose, or metabolic syndrome.

The group reviewed 74 trials assessing the effectiveness of behavioral counseling interventions of various intensities. Only 16 reported on direct health outcomes such as CVD events, mortality, or quality of life, the task force noted, so there is inadequate evidence about intensive behavioral counseling’s effect on such outcomes.

A total of 71 trials involving more than 32,000 participants focused on intermediate health outcomes such as lipid levels, blood pressure, glucose levels, weight, and medication use. Overall, intensive counseling interventions made "small but important changes" in these outcomes, with total cholesterol levels decreasing approximately 3-6 mg/dL, LDL cholesterol decreasing by 1.5-5.0 mg/dL, systolic blood pressure decreasing by 1-3 mm Hg, diastolic blood pressure decreasing by 1-2 mm Hg, and fasting glucose levels decreasing by 1-3 mg/dL.

In addition, weight decreased by a mean of approximately 3 kg, and the proportion of patients who participated in moderate-intensity exercise for 150 minutes per week rose from 10% to 25%. However, few of these studies followed patients for more than 1-2 years, so the evidence was inadequate to assess longer-term benefits.

Because very few and mostly minor adverse events were associated with these interventions, they yielded a moderate net benefit.

Most of the intensive behavioral counseling interventions that were assessed averaged 5-16 individual or group sessions during a period of 9-12 months. All included didactic education; in most programs, specially trained professionals (dietitians, nutritionists, physiotherapists, exercise professionals, health educators, and psychologists) provided monitoring and feedback for the participants, devised individualized care plans, and taught problem-solving skills. Many types and combinations of interventions were effective, and almost all were delivered outside the primary care setting.

The recommendation statement is in line with others published by the American Heart Association, the American College of Sports Medicine, and the American Academy of Family Physicians. The AAFP is updating its recommendations regarding behavioral counseling to prevent CVD, Dr. LeFevre and his associates noted.

The USPSTF, funded by but independent of the federal government, makes recommendations about the effectiveness of specific preventive-care services based on evidence of benefits and harms, without considering costs.

Do you refer overweight or obese patients with cardiovascular risk factors for intensive behavioral counseling? Take our Quick Poll on the Family Practice News homepage.

The American Heart Association has released its recommendations regarding the sale and usage of e-cigarettes, cautioning that the devices should be regulated to avoid enticing children to smoke while also saying that e-cigarettes could be used as a way to help some current smokers quit.

The guidelines, published online Aug. 24 in Circulation, state that clinicians "should not discourage" their patients from resorting to e-cigarettes if other approved forms of smoking cessation, such as the nicotine patch, have been exhausted. The AHA warned, however, that further studies are needed to fully understand the effects of e-cigarette usage, stressing that e-cigarettes have not been approved by the Food and Drug Administration as an acceptable smoking cessation device and could contain low amounts of toxic chemicals that would prove more harmful than helpful to patients in the long run.

©goldy/Thinkstockphotos.com

"E-cigarettes have caused a major shift in the tobacco-control landscape," Aruni Bhatnagar, Ph.D., lead author of the guidelines and chair of cardiovascular medicine at the University of Louisville, Ky., said in a statement. "It’s critical that we rigorously examine the long-term impact of this new technology on public health, cardiovascular disease, and stroke, and pay careful attention to the effect of e-cigarettes on adolescents."

For now, the AHA says that clinicians should tell their patients who use e-cigarettes to set a firm quit date, warning that any device that delivers nicotine into the body is harmful and likely lethal.

"Nicotine is a dangerous and highly addictive chemical no matter what form it takes – conventional cigarettes or some other tobacco product," Dr. Elliott Antman, AHA president, said in the statement. "Every life that has been lost to tobacco addiction" could have been saved, he noted.

To that end, the AHA also called for strong regulations regarding the potential marketability of e-cigarettes to youngsters. The group recommended a federal ban on the sale of e-cigarettes to minors, warning that the devices could become a gateway to actual cigarettes for young people who see e-cigarettes as "high-tech, accessible, and convenient," according to a JAMA Pediatrics study of 40,000 middle and high school students. The AHA also recommended that all existing rules and regulations in place for tobacco-related products should apply to e-cigarettes.

"We must protect future generations from any potential smokescreens in the tobacco product landscape that will cause us to lose precious ground in the fight to make our nation 100% tobacco-free," Dr. Antman said.

According to the AHA, 20 million Americans have lost their lives to tobacco over the last 50 years.

dchitnis@frontlinemedcom.com

The American Heart Association has released its recommendations regarding the sale and usage of e-cigarettes, cautioning that the devices should be regulated to avoid enticing children to smoke while also saying that e-cigarettes could be used as a way to help some current smokers quit.

The guidelines, published online Aug. 24 in Circulation, state that clinicians "should not discourage" their patients from resorting to e-cigarettes if other approved forms of smoking cessation, such as the nicotine patch, have been exhausted. The AHA warned, however, that further studies are needed to fully understand the effects of e-cigarette usage, stressing that e-cigarettes have not been approved by the Food and Drug Administration as an acceptable smoking cessation device and could contain low amounts of toxic chemicals that would prove more harmful than helpful to patients in the long run.

©goldy/Thinkstockphotos.com

"E-cigarettes have caused a major shift in the tobacco-control landscape," Aruni Bhatnagar, Ph.D., lead author of the guidelines and chair of cardiovascular medicine at the University of Louisville, Ky., said in a statement. "It’s critical that we rigorously examine the long-term impact of this new technology on public health, cardiovascular disease, and stroke, and pay careful attention to the effect of e-cigarettes on adolescents."

For now, the AHA says that clinicians should tell their patients who use e-cigarettes to set a firm quit date, warning that any device that delivers nicotine into the body is harmful and likely lethal.

"Nicotine is a dangerous and highly addictive chemical no matter what form it takes – conventional cigarettes or some other tobacco product," Dr. Elliott Antman, AHA president, said in the statement. "Every life that has been lost to tobacco addiction" could have been saved, he noted.

To that end, the AHA also called for strong regulations regarding the potential marketability of e-cigarettes to youngsters. The group recommended a federal ban on the sale of e-cigarettes to minors, warning that the devices could become a gateway to actual cigarettes for young people who see e-cigarettes as "high-tech, accessible, and convenient," according to a JAMA Pediatrics study of 40,000 middle and high school students. The AHA also recommended that all existing rules and regulations in place for tobacco-related products should apply to e-cigarettes.

"We must protect future generations from any potential smokescreens in the tobacco product landscape that will cause us to lose precious ground in the fight to make our nation 100% tobacco-free," Dr. Antman said.

According to the AHA, 20 million Americans have lost their lives to tobacco over the last 50 years.

dchitnis@frontlinemedcom.com

The American Heart Association has released its recommendations regarding the sale and usage of e-cigarettes, cautioning that the devices should be regulated to avoid enticing children to smoke while also saying that e-cigarettes could be used as a way to help some current smokers quit.

The guidelines, published online Aug. 24 in Circulation, state that clinicians "should not discourage" their patients from resorting to e-cigarettes if other approved forms of smoking cessation, such as the nicotine patch, have been exhausted. The AHA warned, however, that further studies are needed to fully understand the effects of e-cigarette usage, stressing that e-cigarettes have not been approved by the Food and Drug Administration as an acceptable smoking cessation device and could contain low amounts of toxic chemicals that would prove more harmful than helpful to patients in the long run.

©goldy/Thinkstockphotos.com

"E-cigarettes have caused a major shift in the tobacco-control landscape," Aruni Bhatnagar, Ph.D., lead author of the guidelines and chair of cardiovascular medicine at the University of Louisville, Ky., said in a statement. "It’s critical that we rigorously examine the long-term impact of this new technology on public health, cardiovascular disease, and stroke, and pay careful attention to the effect of e-cigarettes on adolescents."

For now, the AHA says that clinicians should tell their patients who use e-cigarettes to set a firm quit date, warning that any device that delivers nicotine into the body is harmful and likely lethal.

"Nicotine is a dangerous and highly addictive chemical no matter what form it takes – conventional cigarettes or some other tobacco product," Dr. Elliott Antman, AHA president, said in the statement. "Every life that has been lost to tobacco addiction" could have been saved, he noted.

To that end, the AHA also called for strong regulations regarding the potential marketability of e-cigarettes to youngsters. The group recommended a federal ban on the sale of e-cigarettes to minors, warning that the devices could become a gateway to actual cigarettes for young people who see e-cigarettes as "high-tech, accessible, and convenient," according to a JAMA Pediatrics study of 40,000 middle and high school students. The AHA also recommended that all existing rules and regulations in place for tobacco-related products should apply to e-cigarettes.

"We must protect future generations from any potential smokescreens in the tobacco product landscape that will cause us to lose precious ground in the fight to make our nation 100% tobacco-free," Dr. Antman said.

According to the AHA, 20 million Americans have lost their lives to tobacco over the last 50 years.

dchitnis@frontlinemedcom.com

Although there are some glimmers of hope that U.S. birthweights may be declining, the average infant birthweight has remained significantly tilted toward obesity. Moreover, and alarming number of infants, children, and adolescents are obese.

In 2007-2008, 9.5% of infants and toddlers were at or above the 95th percentile of the weight-for-recumbent-length growth charts. Among children and adolescents aged 2-19 years, 11.9% were at or above the 97th percentile of the body-mass-index-for-age growth charts; 16.9% were at or above the 95th percentile; and 31.7% were at or above the 85th percentile of BMI for age (JAMA 2010;303:242-9).

While more recent reports of obesity in children indicate a modest decline in obesity among 2- to 5-year-olds (JAMA 2014;311:806-14), an alarming number of infants and children have excess adiposity (roughly twice what is expected). In addition, cardiovascular mortality later in life continues to rise.

The question arises, have childhood and adult obesity rates remained high because mothers are feeding their children the wrong foods or because these children were born obese? One also wonders, with respect to cardiovascular mortality in adulthood, is the in utero environment playing a role?

Old lessons, growing relevance

More than 3 decades ago, the late British physician Dr. David Barker got us thinking about how a challenging life in the womb can set us up for downstream ill health. He studied births from 1910 to 1945 and found that the cardiovascular mortality of individuals born during that time was inversely related to birthweight. Smaller babies, he found, could have cardiovascular mortality risks that were double or even quadruple the risks of larger babies.

Dr. Barker theorized that, when faced with undernutrition, the fetus adapts by sending more blood to the brain and sacrificing blood flow to less essential tissues. His theory about how growth and nutrition before birth may affect the heart became known as the "Barker Hypothesis." It was initially controversial, but it led to an explosion of research – especially since 2000 – on various downstream effects of the intrauterine environment.

Investigators have learned that it is not only cardiovascular mortality that is affected by low birthweight, but also the risk of developing diabetes and being overweight. This is because the fetus makes less essential systems insulin resistant. Insulin resistance persists in the womb and after birth as well, predisposing individuals to insulin resistance and obesity, both of which are closely linked to the risk of metabolic syndrome – a group of risk factors that raises the likelihood of developing heart disease, stroke, and diabetes.

In fact, further research on cohorts of Barker children – individuals who had low birthweights – has shown that not only have they had higher rates of cardiovascular disease, but they have had higher blood sugars and higher rates of insulin resistance as well.

Today, we appreciate a fuller picture of the Barker data, one that shows a reversal of this trend when birthweights reach 4,000-4,500 grams. At this point, what was a progressively downward slope of cardiovascular mortality rates with increasing birthweight suddenly shoots upward again when birthweight exceeds 4,000 g.

It is this end of the curve that is most relevant – and most concerning – for ob.gyns. today. Our problem in the United States is not so much one of starving or growth-restricted newborns, as these babies account for 5% or less of all births. It is one of overweight and obese newborns who now represent as many as 1 in 7 births. Just like the Barker babies who were growth restricted, these newborns have high insulin levels and increased risk of cardiovascular disease as adults.

Changing the trajectory

Both maternal obesity and gestational diabetes get at the heart of the Barker Hypothesis, albeit a twist, in that excessive maternal adiposity and associated insulin resistance results in high maternal blood glucose, transferring excessive nutrients to the fetus. This causes accumulation of fat in the fetus and programs the fetus for an increased and persistent risk of adiposity after birth, early-onset metabolic syndrome, and downstream cardiovascular disease in adulthood.

Dr. Dana Dabelea’s sibling study of almost 15 years ago demonstrated the long-term impact of the adverse intrauterine environment associated with maternal diabetes. Matched siblings who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents, compared with the siblings born before their mothers were diagnosed with diabetes. In childhood, these siblings ate at the same table and came from the same gene pools (with the same fathers), but they experienced dramatically different health outcomes (Diabetes 2000:49:2208-11).

This landmark study has been reproduced by other investigators who have compared children of mothers who had gestational diabetes and/or were overweight, with children whose mothers did not have gestational diabetes mellitus (GDM) or were of normal weight. Such studies have consistently shown that, faced with either or both maternal obesity and diabetes in utero, offspring were significantly more likely to become overweight children and adults with insulin resistance and other components of the metabolic syndrome.

Importantly, we have evidence from randomized trials that interventions to treat GDM can effectively reduce rates of newborn obesity. While differences in birthweight between treatment and no-treatment arms have been modest, reductions in neonatal body fat, as measured by skin-fold thickness, the ponderal index, and birthweight percentile, have been highly significant.

The offspring of mothers who were treated in these trials, the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86), and a study by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009;361:1339-48), had approximately half of the newborn adiposity than did offspring of mothers who were not treated. In the latter study, maternal dietary measures alone were successful in reducing neonatal adiposity in over 80% of infants.

While published follow-up data of the offspring in these cohorts have covered only 5-8 years (showing persistently less adiposity in the treated groups), the offspring in the Australian cohort are still being monitored. Based on the cohort and case-control studies summarized above, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles into and through adulthood.

We know from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study that what were formerly considered mild and inconsequential maternal blood glucose levels are instead potentially quite harmful. The study showed a clear linear relationship between maternal fasting blood glucose levels, fetal cord blood insulin concentrations (a reflection of fetal glucose levels), and newborn body fat percentage (N. Engl. J. Med. 2008;358:1991-2002).

Interestingly, Dr. Patrick Catalano’s analysis of data from the HAPO study (Diabetes Care 2012;35:780-6) shows us more: Maternal obesity is almost as strong a driver of newborn obesity as is GDM. Compared with GDM (which increased the percentage of infant birthweights to greater than the 90th percentile by a factor of 2.19), maternal obesity alone increased the frequency of LGA by a factor of 1.73, and maternal obesity and GDM together increased LGA newborns by 3.62-fold.

In light of these recent findings, it is critical that we not only treat our patients who have GDM, but that we attempt to interrupt the chain of obesity that passes from mother to fetus, and from obese newborns onto their subsequent offspring.

A growing proportion of women across all race and ethnicity groups gain more than 40 pounds during pregnancy for singleton births, and many of them do not lose the weight between pregnancies. Increasingly, we have patients whose first child may not have been exposed to obesity in utero, but whose second child is exposed to overweight or obesity and higher levels of insulin resistance and glycemia.

The Institute of Medicine documented these issues in its 2009 report, "Weight Gain During Pregnancy: Reexamining the Guidelines." Data on maternal postpartum weights are not widely available, but data that have been collected suggest that gaining above recommended ranges is associated with excess maternal weight retention post partum, regardless of prepregnancy BMI. Women who gained above the range recommended by the IOM in 1990 had postpartum weight retention of 15-20 pounds. Among women who gained excessive amounts of weight, moreover, more than 40% retained more than 20 pounds, according to the report.

We must break the intergenerational transfer of obesity and insulin resistance by liberally treating GDM and optimizing glucose control during pregnancy. More importantly, we must emphasize to women the importance of having healthy weights at the time of conception. Recent research affirms that moderately simple interventions, such as dietary improvements and exercise can go a long way to achieving these goals. If we don’t – in keeping with the knowledge spurred on by Dr. Barker – we will be programming more newborns for life with insulin resistance, obesity, and disease.

Dr. Moore is a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego. He said he had no relevant financial disclosures.

Although there are some glimmers of hope that U.S. birthweights may be declining, the average infant birthweight has remained significantly tilted toward obesity. Moreover, and alarming number of infants, children, and adolescents are obese.

In 2007-2008, 9.5% of infants and toddlers were at or above the 95th percentile of the weight-for-recumbent-length growth charts. Among children and adolescents aged 2-19 years, 11.9% were at or above the 97th percentile of the body-mass-index-for-age growth charts; 16.9% were at or above the 95th percentile; and 31.7% were at or above the 85th percentile of BMI for age (JAMA 2010;303:242-9).

While more recent reports of obesity in children indicate a modest decline in obesity among 2- to 5-year-olds (JAMA 2014;311:806-14), an alarming number of infants and children have excess adiposity (roughly twice what is expected). In addition, cardiovascular mortality later in life continues to rise.

The question arises, have childhood and adult obesity rates remained high because mothers are feeding their children the wrong foods or because these children were born obese? One also wonders, with respect to cardiovascular mortality in adulthood, is the in utero environment playing a role?

Old lessons, growing relevance

More than 3 decades ago, the late British physician Dr. David Barker got us thinking about how a challenging life in the womb can set us up for downstream ill health. He studied births from 1910 to 1945 and found that the cardiovascular mortality of individuals born during that time was inversely related to birthweight. Smaller babies, he found, could have cardiovascular mortality risks that were double or even quadruple the risks of larger babies.

Dr. Barker theorized that, when faced with undernutrition, the fetus adapts by sending more blood to the brain and sacrificing blood flow to less essential tissues. His theory about how growth and nutrition before birth may affect the heart became known as the "Barker Hypothesis." It was initially controversial, but it led to an explosion of research – especially since 2000 – on various downstream effects of the intrauterine environment.

Investigators have learned that it is not only cardiovascular mortality that is affected by low birthweight, but also the risk of developing diabetes and being overweight. This is because the fetus makes less essential systems insulin resistant. Insulin resistance persists in the womb and after birth as well, predisposing individuals to insulin resistance and obesity, both of which are closely linked to the risk of metabolic syndrome – a group of risk factors that raises the likelihood of developing heart disease, stroke, and diabetes.

In fact, further research on cohorts of Barker children – individuals who had low birthweights – has shown that not only have they had higher rates of cardiovascular disease, but they have had higher blood sugars and higher rates of insulin resistance as well.

Today, we appreciate a fuller picture of the Barker data, one that shows a reversal of this trend when birthweights reach 4,000-4,500 grams. At this point, what was a progressively downward slope of cardiovascular mortality rates with increasing birthweight suddenly shoots upward again when birthweight exceeds 4,000 g.

It is this end of the curve that is most relevant – and most concerning – for ob.gyns. today. Our problem in the United States is not so much one of starving or growth-restricted newborns, as these babies account for 5% or less of all births. It is one of overweight and obese newborns who now represent as many as 1 in 7 births. Just like the Barker babies who were growth restricted, these newborns have high insulin levels and increased risk of cardiovascular disease as adults.

Changing the trajectory

Both maternal obesity and gestational diabetes get at the heart of the Barker Hypothesis, albeit a twist, in that excessive maternal adiposity and associated insulin resistance results in high maternal blood glucose, transferring excessive nutrients to the fetus. This causes accumulation of fat in the fetus and programs the fetus for an increased and persistent risk of adiposity after birth, early-onset metabolic syndrome, and downstream cardiovascular disease in adulthood.

Dr. Dana Dabelea’s sibling study of almost 15 years ago demonstrated the long-term impact of the adverse intrauterine environment associated with maternal diabetes. Matched siblings who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents, compared with the siblings born before their mothers were diagnosed with diabetes. In childhood, these siblings ate at the same table and came from the same gene pools (with the same fathers), but they experienced dramatically different health outcomes (Diabetes 2000:49:2208-11).

This landmark study has been reproduced by other investigators who have compared children of mothers who had gestational diabetes and/or were overweight, with children whose mothers did not have gestational diabetes mellitus (GDM) or were of normal weight. Such studies have consistently shown that, faced with either or both maternal obesity and diabetes in utero, offspring were significantly more likely to become overweight children and adults with insulin resistance and other components of the metabolic syndrome.

Importantly, we have evidence from randomized trials that interventions to treat GDM can effectively reduce rates of newborn obesity. While differences in birthweight between treatment and no-treatment arms have been modest, reductions in neonatal body fat, as measured by skin-fold thickness, the ponderal index, and birthweight percentile, have been highly significant.

The offspring of mothers who were treated in these trials, the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86), and a study by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009;361:1339-48), had approximately half of the newborn adiposity than did offspring of mothers who were not treated. In the latter study, maternal dietary measures alone were successful in reducing neonatal adiposity in over 80% of infants.

While published follow-up data of the offspring in these cohorts have covered only 5-8 years (showing persistently less adiposity in the treated groups), the offspring in the Australian cohort are still being monitored. Based on the cohort and case-control studies summarized above, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles into and through adulthood.

We know from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study that what were formerly considered mild and inconsequential maternal blood glucose levels are instead potentially quite harmful. The study showed a clear linear relationship between maternal fasting blood glucose levels, fetal cord blood insulin concentrations (a reflection of fetal glucose levels), and newborn body fat percentage (N. Engl. J. Med. 2008;358:1991-2002).

Interestingly, Dr. Patrick Catalano’s analysis of data from the HAPO study (Diabetes Care 2012;35:780-6) shows us more: Maternal obesity is almost as strong a driver of newborn obesity as is GDM. Compared with GDM (which increased the percentage of infant birthweights to greater than the 90th percentile by a factor of 2.19), maternal obesity alone increased the frequency of LGA by a factor of 1.73, and maternal obesity and GDM together increased LGA newborns by 3.62-fold.

In light of these recent findings, it is critical that we not only treat our patients who have GDM, but that we attempt to interrupt the chain of obesity that passes from mother to fetus, and from obese newborns onto their subsequent offspring.

A growing proportion of women across all race and ethnicity groups gain more than 40 pounds during pregnancy for singleton births, and many of them do not lose the weight between pregnancies. Increasingly, we have patients whose first child may not have been exposed to obesity in utero, but whose second child is exposed to overweight or obesity and higher levels of insulin resistance and glycemia.

The Institute of Medicine documented these issues in its 2009 report, "Weight Gain During Pregnancy: Reexamining the Guidelines." Data on maternal postpartum weights are not widely available, but data that have been collected suggest that gaining above recommended ranges is associated with excess maternal weight retention post partum, regardless of prepregnancy BMI. Women who gained above the range recommended by the IOM in 1990 had postpartum weight retention of 15-20 pounds. Among women who gained excessive amounts of weight, moreover, more than 40% retained more than 20 pounds, according to the report.

We must break the intergenerational transfer of obesity and insulin resistance by liberally treating GDM and optimizing glucose control during pregnancy. More importantly, we must emphasize to women the importance of having healthy weights at the time of conception. Recent research affirms that moderately simple interventions, such as dietary improvements and exercise can go a long way to achieving these goals. If we don’t – in keeping with the knowledge spurred on by Dr. Barker – we will be programming more newborns for life with insulin resistance, obesity, and disease.

Dr. Moore is a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego. He said he had no relevant financial disclosures.

Although there are some glimmers of hope that U.S. birthweights may be declining, the average infant birthweight has remained significantly tilted toward obesity. Moreover, and alarming number of infants, children, and adolescents are obese.

In 2007-2008, 9.5% of infants and toddlers were at or above the 95th percentile of the weight-for-recumbent-length growth charts. Among children and adolescents aged 2-19 years, 11.9% were at or above the 97th percentile of the body-mass-index-for-age growth charts; 16.9% were at or above the 95th percentile; and 31.7% were at or above the 85th percentile of BMI for age (JAMA 2010;303:242-9).

While more recent reports of obesity in children indicate a modest decline in obesity among 2- to 5-year-olds (JAMA 2014;311:806-14), an alarming number of infants and children have excess adiposity (roughly twice what is expected). In addition, cardiovascular mortality later in life continues to rise.

The question arises, have childhood and adult obesity rates remained high because mothers are feeding their children the wrong foods or because these children were born obese? One also wonders, with respect to cardiovascular mortality in adulthood, is the in utero environment playing a role?

Old lessons, growing relevance

More than 3 decades ago, the late British physician Dr. David Barker got us thinking about how a challenging life in the womb can set us up for downstream ill health. He studied births from 1910 to 1945 and found that the cardiovascular mortality of individuals born during that time was inversely related to birthweight. Smaller babies, he found, could have cardiovascular mortality risks that were double or even quadruple the risks of larger babies.

Dr. Barker theorized that, when faced with undernutrition, the fetus adapts by sending more blood to the brain and sacrificing blood flow to less essential tissues. His theory about how growth and nutrition before birth may affect the heart became known as the "Barker Hypothesis." It was initially controversial, but it led to an explosion of research – especially since 2000 – on various downstream effects of the intrauterine environment.

Investigators have learned that it is not only cardiovascular mortality that is affected by low birthweight, but also the risk of developing diabetes and being overweight. This is because the fetus makes less essential systems insulin resistant. Insulin resistance persists in the womb and after birth as well, predisposing individuals to insulin resistance and obesity, both of which are closely linked to the risk of metabolic syndrome – a group of risk factors that raises the likelihood of developing heart disease, stroke, and diabetes.

In fact, further research on cohorts of Barker children – individuals who had low birthweights – has shown that not only have they had higher rates of cardiovascular disease, but they have had higher blood sugars and higher rates of insulin resistance as well.

Today, we appreciate a fuller picture of the Barker data, one that shows a reversal of this trend when birthweights reach 4,000-4,500 grams. At this point, what was a progressively downward slope of cardiovascular mortality rates with increasing birthweight suddenly shoots upward again when birthweight exceeds 4,000 g.

It is this end of the curve that is most relevant – and most concerning – for ob.gyns. today. Our problem in the United States is not so much one of starving or growth-restricted newborns, as these babies account for 5% or less of all births. It is one of overweight and obese newborns who now represent as many as 1 in 7 births. Just like the Barker babies who were growth restricted, these newborns have high insulin levels and increased risk of cardiovascular disease as adults.

Changing the trajectory

Both maternal obesity and gestational diabetes get at the heart of the Barker Hypothesis, albeit a twist, in that excessive maternal adiposity and associated insulin resistance results in high maternal blood glucose, transferring excessive nutrients to the fetus. This causes accumulation of fat in the fetus and programs the fetus for an increased and persistent risk of adiposity after birth, early-onset metabolic syndrome, and downstream cardiovascular disease in adulthood.

Dr. Dana Dabelea’s sibling study of almost 15 years ago demonstrated the long-term impact of the adverse intrauterine environment associated with maternal diabetes. Matched siblings who were born after their mothers had developed diabetes had almost double the rate of obesity as adolescents, compared with the siblings born before their mothers were diagnosed with diabetes. In childhood, these siblings ate at the same table and came from the same gene pools (with the same fathers), but they experienced dramatically different health outcomes (Diabetes 2000:49:2208-11).

This landmark study has been reproduced by other investigators who have compared children of mothers who had gestational diabetes and/or were overweight, with children whose mothers did not have gestational diabetes mellitus (GDM) or were of normal weight. Such studies have consistently shown that, faced with either or both maternal obesity and diabetes in utero, offspring were significantly more likely to become overweight children and adults with insulin resistance and other components of the metabolic syndrome.

Importantly, we have evidence from randomized trials that interventions to treat GDM can effectively reduce rates of newborn obesity. While differences in birthweight between treatment and no-treatment arms have been modest, reductions in neonatal body fat, as measured by skin-fold thickness, the ponderal index, and birthweight percentile, have been highly significant.

The offspring of mothers who were treated in these trials, the Australian Carbohydrate Intolerance Study in Pregnant Women (N. Engl. J. Med. 2005;352:2477-86), and a study by Dr. Mark B. Landon and his colleagues (N. Engl. J. Med. 2009;361:1339-48), had approximately half of the newborn adiposity than did offspring of mothers who were not treated. In the latter study, maternal dietary measures alone were successful in reducing neonatal adiposity in over 80% of infants.

While published follow-up data of the offspring in these cohorts have covered only 5-8 years (showing persistently less adiposity in the treated groups), the offspring in the Australian cohort are still being monitored. Based on the cohort and case-control studies summarized above, it seems fair to expect that the children of mothers who were treated for GDM will have significantly better health profiles into and through adulthood.

We know from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study that what were formerly considered mild and inconsequential maternal blood glucose levels are instead potentially quite harmful. The study showed a clear linear relationship between maternal fasting blood glucose levels, fetal cord blood insulin concentrations (a reflection of fetal glucose levels), and newborn body fat percentage (N. Engl. J. Med. 2008;358:1991-2002).

Interestingly, Dr. Patrick Catalano’s analysis of data from the HAPO study (Diabetes Care 2012;35:780-6) shows us more: Maternal obesity is almost as strong a driver of newborn obesity as is GDM. Compared with GDM (which increased the percentage of infant birthweights to greater than the 90th percentile by a factor of 2.19), maternal obesity alone increased the frequency of LGA by a factor of 1.73, and maternal obesity and GDM together increased LGA newborns by 3.62-fold.

In light of these recent findings, it is critical that we not only treat our patients who have GDM, but that we attempt to interrupt the chain of obesity that passes from mother to fetus, and from obese newborns onto their subsequent offspring.

A growing proportion of women across all race and ethnicity groups gain more than 40 pounds during pregnancy for singleton births, and many of them do not lose the weight between pregnancies. Increasingly, we have patients whose first child may not have been exposed to obesity in utero, but whose second child is exposed to overweight or obesity and higher levels of insulin resistance and glycemia.

The Institute of Medicine documented these issues in its 2009 report, "Weight Gain During Pregnancy: Reexamining the Guidelines." Data on maternal postpartum weights are not widely available, but data that have been collected suggest that gaining above recommended ranges is associated with excess maternal weight retention post partum, regardless of prepregnancy BMI. Women who gained above the range recommended by the IOM in 1990 had postpartum weight retention of 15-20 pounds. Among women who gained excessive amounts of weight, moreover, more than 40% retained more than 20 pounds, according to the report.

We must break the intergenerational transfer of obesity and insulin resistance by liberally treating GDM and optimizing glucose control during pregnancy. More importantly, we must emphasize to women the importance of having healthy weights at the time of conception. Recent research affirms that moderately simple interventions, such as dietary improvements and exercise can go a long way to achieving these goals. If we don’t – in keeping with the knowledge spurred on by Dr. Barker – we will be programming more newborns for life with insulin resistance, obesity, and disease.

Dr. Moore is a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego. He said he had no relevant financial disclosures.

On Aug. 27, 2013, the field of obstetrics and gynecology suffered a great loss: the passing of Dr. David J.P. Barker. Dr. Barker was a visionary and leader whose hypothesis about the links between a mother’s health and the long-term health of her children was controversial when he first posed it in the late 1980s. However, after subsequent decades of maternal-fetal practice and research, his idea that preventing chronic disease starts with a healthy mother and baby, is embraced by the medical and science communities today.

I was just starting my career when Dr. Barker’s hypothesis, known then as the "fetal origins hypothesis" but subsequently referred to as the "Barker Hypothesis," was published. During my fellowship in maternal-fetal medicine at Yale University, I had the privilege of attending one of Dr. Barker’s lectures and meeting him. While my colleagues and I thought him an eloquent and impassioned speaker, Dr. Barker’s theory – that there was a relationship between a person’s birth weight and his or her lifetime risk for chronic disease – was highly contentious. He had based his hypothesis on large epidemiological studies conducted in Finland, India, the Netherlands, the United Kingdom, and the United States – all of which revealed that the lower a person’s birth weight, the higher his or her risk for developing coronary heart disease. In addition, he concluded that the lower a person’s birth weight, but the faster the weight gain after age 2 years, the higher a person’s risk for hypertension, stroke, and type 2 diabetes.

At that time, we did not fully realize the significance, gravity, and enormity of Dr. Barker’s contribution to the ob.gyn. field. I could not imagine the impact that his work would have on my professional path. Dr. Barker’s early papers often concluded with a section looking to the future, and in one of them he stated that "we now need to progress beyond epidemiologic associations [between in utero conditions and health later in life] to greater understanding of the cellular and molecular processes that underlie them"(Am. J. Clin. Nutr. 2000;71:1344s-52s). From my work as a physician with diabetic pregnant women to my scientific research devoted to understanding how, at the molecular level, maternal diabetes affects the developing fetus, I have a great appreciation and respect for Dr. Barker’s work.

Therefore, I am very pleased that this month’s Master Class is devoted to a discussion of how the Barker Hypothesis applies today. We have invited Dr. Thomas R. Moore, a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego, to give his reflection on how Dr. Barker’s once radical ideas revolutionized our field.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of the Master Class column. Contact him at obnews@frontlinemedcom.com.

On Aug. 27, 2013, the field of obstetrics and gynecology suffered a great loss: the passing of Dr. David J.P. Barker. Dr. Barker was a visionary and leader whose hypothesis about the links between a mother’s health and the long-term health of her children was controversial when he first posed it in the late 1980s. However, after subsequent decades of maternal-fetal practice and research, his idea that preventing chronic disease starts with a healthy mother and baby, is embraced by the medical and science communities today.

I was just starting my career when Dr. Barker’s hypothesis, known then as the "fetal origins hypothesis" but subsequently referred to as the "Barker Hypothesis," was published. During my fellowship in maternal-fetal medicine at Yale University, I had the privilege of attending one of Dr. Barker’s lectures and meeting him. While my colleagues and I thought him an eloquent and impassioned speaker, Dr. Barker’s theory – that there was a relationship between a person’s birth weight and his or her lifetime risk for chronic disease – was highly contentious. He had based his hypothesis on large epidemiological studies conducted in Finland, India, the Netherlands, the United Kingdom, and the United States – all of which revealed that the lower a person’s birth weight, the higher his or her risk for developing coronary heart disease. In addition, he concluded that the lower a person’s birth weight, but the faster the weight gain after age 2 years, the higher a person’s risk for hypertension, stroke, and type 2 diabetes.

At that time, we did not fully realize the significance, gravity, and enormity of Dr. Barker’s contribution to the ob.gyn. field. I could not imagine the impact that his work would have on my professional path. Dr. Barker’s early papers often concluded with a section looking to the future, and in one of them he stated that "we now need to progress beyond epidemiologic associations [between in utero conditions and health later in life] to greater understanding of the cellular and molecular processes that underlie them"(Am. J. Clin. Nutr. 2000;71:1344s-52s). From my work as a physician with diabetic pregnant women to my scientific research devoted to understanding how, at the molecular level, maternal diabetes affects the developing fetus, I have a great appreciation and respect for Dr. Barker’s work.

Therefore, I am very pleased that this month’s Master Class is devoted to a discussion of how the Barker Hypothesis applies today. We have invited Dr. Thomas R. Moore, a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego, to give his reflection on how Dr. Barker’s once radical ideas revolutionized our field.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of the Master Class column. Contact him at obnews@frontlinemedcom.com.

On Aug. 27, 2013, the field of obstetrics and gynecology suffered a great loss: the passing of Dr. David J.P. Barker. Dr. Barker was a visionary and leader whose hypothesis about the links between a mother’s health and the long-term health of her children was controversial when he first posed it in the late 1980s. However, after subsequent decades of maternal-fetal practice and research, his idea that preventing chronic disease starts with a healthy mother and baby, is embraced by the medical and science communities today.

I was just starting my career when Dr. Barker’s hypothesis, known then as the "fetal origins hypothesis" but subsequently referred to as the "Barker Hypothesis," was published. During my fellowship in maternal-fetal medicine at Yale University, I had the privilege of attending one of Dr. Barker’s lectures and meeting him. While my colleagues and I thought him an eloquent and impassioned speaker, Dr. Barker’s theory – that there was a relationship between a person’s birth weight and his or her lifetime risk for chronic disease – was highly contentious. He had based his hypothesis on large epidemiological studies conducted in Finland, India, the Netherlands, the United Kingdom, and the United States – all of which revealed that the lower a person’s birth weight, the higher his or her risk for developing coronary heart disease. In addition, he concluded that the lower a person’s birth weight, but the faster the weight gain after age 2 years, the higher a person’s risk for hypertension, stroke, and type 2 diabetes.

At that time, we did not fully realize the significance, gravity, and enormity of Dr. Barker’s contribution to the ob.gyn. field. I could not imagine the impact that his work would have on my professional path. Dr. Barker’s early papers often concluded with a section looking to the future, and in one of them he stated that "we now need to progress beyond epidemiologic associations [between in utero conditions and health later in life] to greater understanding of the cellular and molecular processes that underlie them"(Am. J. Clin. Nutr. 2000;71:1344s-52s). From my work as a physician with diabetic pregnant women to my scientific research devoted to understanding how, at the molecular level, maternal diabetes affects the developing fetus, I have a great appreciation and respect for Dr. Barker’s work.

Therefore, I am very pleased that this month’s Master Class is devoted to a discussion of how the Barker Hypothesis applies today. We have invited Dr. Thomas R. Moore, a perinatologist who is chair of the department of reproductive medicine at the University of California, San Diego, to give his reflection on how Dr. Barker’s once radical ideas revolutionized our field.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of the Master Class column. Contact him at obnews@frontlinemedcom.com.