Newsletter - August 2012
Obesity and Pregnancy: A Dangerous Duo
The unfortunate "state of the weight" in the United States is that over the past 50 years, the number of Americans classified as overweight or obese has climbed from 13% to two-thirds. Of particular importance to women's health care practitioners is the fact that more than 40% of pregnant women are either overweight or obese.
The Body Mass Index (BMI) is a simple formula that combines an adult person's height and weight to determine if their body fat content is in the normal range (BMI of 18.5 - 24.9) or overweight (BMI of 25.0 - 29.9) or obese (BMI above 30, and BMI above 40 is extremely obese). The BMI categories overweight and obese are both associated with an increased risk for adverse health consequences.
Obesity has long been perceived as a risk factor in pregnancy. Research over several decades has demonstrated consistently that obese pregnant women are at risk for a multitude of adverse outcomes for the mother, the baby while it is in the womb, and the newborn baby. The recent rise in the U.S. maternal mortality rate has been attributed in part to the rise in obesity among pregnant women. In those states that have compiled data on this problem (Florida, Virginia), profound increases in the risk for maternal death have been associated with obesity.
While the mother is pregnant, obesity raises her risk for these pregnancy complications: gestational diabetes, high blood pressure during pregnancy, excessive and unhealthy growth of the baby in the womb, birth defects, prolonged labor, injuries to the baby during the birth process, the baby may get stuck trying to come out of the birth canal, the need to intervene in vaginal births to extract the baby with either forceps or vacuum extraction, the need to deliver the baby by C-section surgery, and post-delivery complications for the mother of excessive bleeding, blood clots in the legs, lungs and heart, and higher rates of infection.
Mounting evidence now suggests that the children of obese mothers are at greater risk for lifelong complications that include adult onset of diabetes, heart disease, and obesity. This is believed to occur through a mechanism called "in-utero programming" of the developing baby's metabolism.
Physicians encourage pre-natal counseling for women of reproductive age who are obese. They should be encouraged to lose weight and achieve a BMI in the normal range prior to conception. Daily intake of a multivitamin with a minimum of 400 mg of folic acid is also recommended for all women of reproductive age capable of achieving pregnancy, to reduce the risk of neural tube defects.
Unfortunately, many overweight and obese women do not prepare for pregnancy by losing weight. By the time their pregnancy is diagnosed, the baby has already been exposed to the potentially "toxic metabolic environment" that is seen in the womb when obesity and pregnancy go together. Moreover, the degree of weight loss required to substantially modify important health parameters (blood pressure, blood glucose and lipid levels) cannot occur safely in pregnancy without concern for the baby. It cannot be overstated that the ideal time for intervention is before conception.
In conclusion, the care of the obese pregnant woman can be extremely challenging and pregnancy outcomes are more often compromised. Achieving a normal BMI prior to pregnancy is highly recommended. For those women who are obese during pregnancy, especially those defined as extremely obese (BMI above 40), prenatal care with an obstetrician or Maternal-Fetal Medicine specialist with experience in the management of obesity in pregnancy is a necessity. Heightened surveillance for complications of pregnancy will hopefully achieve the very best pregnancy outcome possible under these circumstances. We have included a list of suggested reading for physicians.
As prevention is always the hallmark of the best medical approach to disease management, obese women contemplating pregnancy are encouraged to seek preconception counseling. This will give them the opportunity to make informed decisions regarding pregnancy based upon an individualized risk assessment. Patients should understand that the discussion of this somewhat sensitive topic is undertaken with the intent of improving the mother's health and that of her child; this is not an issue of aesthetics, but one of health status improvement. Hopefully the provider and patient will build a rapport that will allow for appropriate follow-up counseling on weight loss opportunities - be they behavioral, medical, or surgical. Truly, any impact made in this regard has the potential for tremendous health benefit not only in pregnancy, but over the entire life of the mother and her child.
Fanconi Anemia Research Fund
When Dave and Lynn Frohnmayer of Eugene, Oregon founded the Fanconi Anemia Research Fund, in 1989, little was known about Fanconi Anemia and few scientists were studying it. Three of the Frohnmayers' five children had been diagnosed with this rare genetic disease and they were looking for answers. They created the nonprofit Fanconi Anemia Research Fund to find effective treatments and a cure for Fanconi Anemia, and to provide education and support services to affected families worldwide.
Fanconi Anemia (FA) is a rare genetic disorder. Although considered primarily a blood disease, FA may affect all systems of the body. In the U.S., FA affects approximately one child out of 131,000 births each year. At least 25% of FA patients are born with abnormalities of the hands or arms. The current median lifespan is 24.7 years, with some patients living into their 30s, 40s, and 50s. Most FA patients develop bone marrow failure in childhood, and require a stem cell transplant. All FA patients are at an elevated risk of developing squamous cell carcinomas and other cancers. Moreover, these cancers can occur decades earlier than in the general population, and risk increases exponentially throughout the lifespan.
Due to the tireless efforts of the Frohnmayers, a core group of researchers, and some dedicated parents, the Fund soon found a foothold in the scientific community and interest in FA research emerged. Since its inception, the Fund has convened annual scientific symposia, inviting scientists and clinicians from around the globe. In 2011, the Fund's 23rd Annual Scientific Symposium was held in Barcelona, Spain and was attended by 300 researchers. Focused meetings on gene therapy and squamous cell carcinoma have also been held - all with the intention of enhancing treatment options and quality of life for FA patients.
The Fund developed the document Fanconi Anemia: Guidelines for Diagnosis and Management and provides this publication to clinicians and families at no charge. Family support is offered through newsletter publications, family support meetings, meetings for adults with FA, and a secure on-line forum.
To date, the Fanconi Anemia Research Fund has sponsored more than $14 million in research grants at 151 laboratories around the world. Fifteen genes involved in FA have been identified, five of which are also breast cancer susceptibility genes. Research supported by the Fund has resulted in significant improvements in bone marrow transplant survival rates for FA patients. Currently sponsored research projects include a gene therapy protocol for patients who do not have a donor for a stem cell transplant, and the development of an oral patch to help deliver medication to pre-cancerous areas in the mouth.
To learn more about Fanconi Anemia, or to contribute to the Fanconi Anemia Research Fund, please visit www.fanconi.org.
Gene Therapy for Fanconi Anemia
Fanconi anemia is an inherited disorder where patients have a defect in their ability to repair damaged DNA. It leads to progressively lower levels of blood cells and higher chances for developing acute leukemia or other cancers. The treatments available today include medications or transfusions to increase the patient's blood counts. The only potential cure for the low blood counts in Fanconi anemia is a bone marrow transplant from a person who does not carry the disorder. However, not all patients have a suitably matched donor for a bone marrow transplant, and the transplant is a very risky procedure for Fanconi anemia patients.
We have been developing a gene therapy clinical trial for patients with Fanconi complementation group A, the most common type of Fanconi anemia. Our study attempts to correct the patient's bone marrow stem cells by using a modified virus that can transfer the normal gene to the patient without causing an infection. The viruses used for this purpose previously were called gammaretroviruses, but we will use a new type of virus for Fanconi anemia gene therapy, called a lentivirus. The purpose of this study is to correct the defect in the patient's own bone marrow and blood cells.
The vector carrying the normal Fanconi A gene was constructed in Dr. Kiem's lab here at the Fred Hutchinson Cancer Research Center. A vector is a biological tool for delivering gene therapy. It consists of a virus carrying a normal gene that is designed to replace the patient's defective gene. Standard molecular biology methods are used to clone the normal gene and insert it into the viral backbone. All the modifications for gene expression, safety modifications, and other elements were performed here.
The patient begins the process by taking a growth factor called G-CSF which mobilizes blood-forming stem cells from the bone marrow into the blood. After receiving G-CSF injections for a few days, the patient has special IVs placed that connect via tubing to a machine for a procedure called leukapheresis. The patient's blood circulates into the machine, a portion of the white blood cells including the blood-forming stem cells is retained in a collection bag, and most of the other blood elements such as the red blood cells and platelets are returned to the patient. For patients age 18 and older, we will also use a second drug called plerixafor, which helps increase the yield of stem cells in the peripheral blood. For patients for whom we don't collect enough cells in this way, we may also aspirate bone marrow.
Once enough of the patient's stem cells have been harvested, they are treated in the laboratory to add the normal gene. First, the stem cells are selected from any other blood cells present by using magnetic bead separation techniques. Then the cells are incubated in low oxygen at body temperature, in combination with special factors and the lentivirus. The lentivirus combines with the patient's DNA and the normal gene for Fanconi type A remains in the DNA of the patient's cells, while the rest of the virus is degraded.
As soon as possible after the normal gene is inserted, the cells can be infused back into the patient like a regular blood transfusion. We will then see if the patient's blood counts improve after this treatment, and monitor the patient's blood and bone marrow for the presence of the gene corrected cells over a period of months to years.
This clinical trial is now open for adult patients, and we hope to open it in the future to children as well. Gene therapy has been used in clinical trials for other inherited conditions that affect the ability of blood-forming stem cells to develop into a normal blood and immune system. These include severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD), as well as others. For more information about this trial, please contact the research coordinator Jennifer Adair, PhD, at firstname.lastname@example.org
Suggested Reading about Obesity and Pregnancy:
- Perlow JH. Obesity in the Obstetric Intensive Care Patient. In: Obstetric Intensive Care Manual. 3rd ed. c. 2011. Published by McGraw-Hill
- Catalano PM. Management of obesity in pregnancy. Obstet Gynecol. 2007; 109:419-433.
- Alexander CI, Liston WA. Operating on the obese woman-a review. BJOG. 2006; 113:1167-1172.
- Perlow JH, Morgan MA. Massive obesity and perioperative cesarean morbidity. Am J Obstet Gynecol. 1994;170:560-565.
- American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Bariatric Surgery and Pregnancy. Number 105. June 2009.
- Wax JR. Risks and management of obesity in pregnancy: current controversies. Curr Opin Obstet Gynecol. 2009; 21:117-123.