Newsletter - Issue 3, May 2012

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Diabetes and Pregnancy

Dr. Michael Dempsey photo

Michael Dempsey, M.D.
Endocrinologist in Rockville, MD

Diabetes is present in 2-6% of pregnant women in the United States; 88% of these women have gestational diabetes (GDM). This is a form of diabetes which appears during pregnancy, typically during the second or third trimester. The prevalence of GDM has increased due to the increased incidence of obesity in the US. The remaining 12% of pregnant women with diabetes have pre-existing type 1 or type 2 diabetes.

In all women who become pregnant, increased production of hormones by the placenta, such as human placental lactogen, causes resistance to insulin's action. Normal women are able to overcome this by increased production of insulin. Their sugar levels are thus maintained in the normal range.

Women with GDM, as well as pre-existing type 1 and type 2 diabetes, are unable to compensate for pregnancy associated insulin resistance. In type 1 diabetes, this is due to absence of insulin production. In GDM and type 2 diabetes this is due to pre-pregancy insulin resistance. Many of these women may also have defects in insulin production. Their inability to compensate for pregnancy related insulin resistance results in elevation of blood sugar levels.

If sugar levels are increased in women with pre-existing diabetes during the first weeks of pregnancy, there is an increased risk of spontaneous abortions and birth defects. If sugar levels remain elevated throughout their pregnancy, there is an increased risk of large babies and delivery associated injuries. There may also be an increased lifetime risk for obesity and/or diabetes in the child. Elevated sugar levels are also associated with an increased risk of high blood pressure and preeclampsia. High sugar levels in women with GDM are associated with similar risks.

Given the known association of high blood sugar levels with complications in the newborn and mother, good sugar control is important. Among women with pre-existing diabetes, every effort should be made to normalize blood sugar levels before conception.

Once pregnant, typical goals for sugar levels are morning fasting sugars of 70-90 mg/dl and 1 hour after meal sugars <120 mg/dl. HA1c levels should be as close to normal as possible. 70-80% of women with GDM will be able to achieve these goals with changes in their diet and light exercise. Consultation with a nutritionist is important.

If sugar goals are not achieved with lifestyle changes, medical therapy is initiated. In women with pre-existing diabetes, insulin is the most common therapy. Among women with GDM, treatment with oral diabetes agents such as Glyburide is another option.

Many endocrinologists (myself included) prefer insulin therapy due to lack of long-term safety data, as well as less dosing flexibility, with the oral agents. Sugar levels will return to pre-pregnancy values after delivery.

If nursing is planned, medication regimens should be reviewed with an obstetrician. Women with GDM are at a significantly increased risk for developing diabetes in the future. A glucose tolerance test is typically performed 6 weeks after delivery in GDM. Even if the test is normal, efforts should be made to maintain a healthy lifestyle and weight.

If sugar levels are managed carefully in pregnant women with diabetes, the chances for a healthy pregnancy and healthy child are similar to those reported in non-diabetic women. Future advances in management, as well as earlier diagnosis, should continue to improve the outlook for women with pregnancy and diabetes.

Dr. Dempsey is an endocrinologist in Rockville, Maryland, USA. His practice is dedicated to the careful, personalized management of people with hormonal disorders. He graduated from Harvard Medical School in 1983. In addition to his busy general medical practice, Dr. Dempsey has been actively involved in more than 40 diabetes related clinical trials since 2000. He is currently the Medical Liaison for Diabetes Education at Suburban Hospital, a physician for two community based endocrinology clinics for underserved patients in Montgomery County, and is the Chair of the Community Outreach Committee of the Montgomery County Medical Society. Follow him on Twitter @thediabetesdoc or visit the website of his practice https://sites.google.com/site/thediabetesdoc/

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The Kacey Rose Foundation

photo of Kacey Rose receiving her cord blood transplant, held by her parents

Glen & Kristina Mitchell are the parents of Kacey Rose.

The idea of forming our Foundation came as a result of not knowing what to do with our emotions after we lost our beautiful daughter to a very rare form of Leukemia known as AML-M7. With the help of family and friends it was decided to honor Kacey's life by helping other families that are battling childhood cancer.

During our daughter's 15 month fight, we witnessed many unfortunate consequences of a child being diagnosed with cancer. When Kacey relapsed shortly after completing the standard 5 rounds of chemo normally used to treat her disease, the only option left was for her to undergo a bone marrow transplant. We were relieved to have this treatment option. That feeling quickly went away when we found out that there was not a single match for Kacey in the entire world registry. We were devastated, how could this be?

We hosted a bone marrow drive and got over 500 new people into the registry, but a match still did not exist. Fortunately another option was offered to us - a cord blood transplant. We were vaguely aware of this option, and quickly became educated on the subject. A few months later Kacey underwent the process of heavy chemotherapy and full body radiation treatments meant to destroy the cancer cells in her body. The next step was to infuse her with the stem cells collected from a baby's umbilical cord that was wisely donated to a public cord blood bank 7 years earlier.

The transplant process was extreme but Kacey did come out the other end of it healthier than she had been in the previous year, and was cancer free. Unfortunately, her cancer relapsed and she passed away in our arms at home 7 months later.

Within weeks of her passing, we were compelled to do something to help others going through the same challenges. We quickly decided to provide public education about cord blood donation. We discovered that in the state of Connecticut there were very few resources for healthcare providers and expectant mothers who are interested in cord blood donation. In answer to this, the Kacey Rose Foundation and Lifeforce Cryobanks formed a partnership and have launched "Kacey's Cord Blood Program". We provide expectant mothers with cord blood collection kits that will enable them to mail in donations. Unlike private storage of cord blood, which can be very cost prohibitive, public donation is at no cost the donor and is available for public use.

It was not very long ago in history that the idea of using a donor's blood or organs to save another person's life was a very new and wild idea. Today both are proven and very successful treatment options for a variety of ailments. The success rate of cord blood transplants and number of diseases that can be treated continues to grow, but we need to add more units to the public registry so they are available to treat children and adults around the world. The more cord blood units in the public banks, the more treatment options are available to those in need.

"We are forever grateful to the wise mother who donated her cord blood. This gave Kacey another chance that she would not have otherwise had. If you are an expectant mother less than 34 weeks pregnant, please consider donating your cord blood." ~ Glen and Kristina Mitchell

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Cord Blood and Lithium Therapy of Spinal Cord Injury (SCI)

Dr. Wise Young photo

Wise Young, Ph.D. M.D.
Richard H. Shindell Chair in Neuroscience at Rutgers University

Umbilical cord blood (UCB) contains many stem cells per volume, more than adult bone marrow. In the past 20 years, UCB transplants have saved thousands of people suffering from disorders of the blood and immune system. Since 2005, UCB transplants are known to cure Krabbe's disease [1], a neurological disease that prevents myelination, and a variety of metabolic disorders [2]. Many researchers have reported that UCB may be beneficial for acquired neurological conditions such as stroke [3-4] and cerebral palsy [5-6].

Cord blood is stored in two types of banks: public or private (family). The former hold cord blood donated for the purposes of transplantation to other people, and are strictly regulated by the U.S. Food and Drug Administration (FDA). The latter are cord blood stored by families for private use by the donor. In general, the quality of privately banked cord blood is significantly lower in family banks [6]. On the other hand, autologous (self) cord blood units should have the best immunological match. Patients who did not store their own cord blood can utilize HLA-matched units from public banks.

UCB transplants improved recovery in rat [7-11] and dog [12-15] SCI models. UCB cells may help injured spinal cords through a variety of mechanisms [16-21], including stimulating myelination, suppressing inflammation, and preventing cell death. Studies have shown that various populations of stem cells in the UCB are all effective. These include unfractionated mono-nuclear cells in UCB [22-26], CD34+ cells [8, 27-29], multipotent cells cultured from UCB [10], mesenchymal stem cells [30-33], CD133+ pluripotent stem cells [34], and cultured neuron-like UCB cells [35], as well as UCB cells genetically modified to make neurons [36, 37] and to secrete growth factors [38, 39].

Lithium stimulates spinal cord regeneration [41-42] and stem cell proliferation in rats after SCI [43-44]. Lithium is the reference therapy for manic depression, taken by over 30 million people around the world. Lithium stimulates bone marrow and neural stem cells [44] to proliferate and to produce growth factors [45]. In humans, lithium significantly increases the brain's gray matter volume [46]. We therefore proposed that the UCB stem cells and lithium have synergistic effects on SCI recovery.

The China Spinal Cord Injury Network (ChinaSCINet) formed in 2006 to test promising SCI therapies. The network has 24 leading SCI centers in China, Hong Kong, and Taiwan. The clinical trials in the network are testing injections of UCB stem cells into the spinal cord and oral lithium treatment, individually and in combination, in patients with chronic (>1yr) and subacute (2day - 2week) SCI (Table 1). The UCB given to patients come from donors that match at least 4 out of 6 recipient HLA. These UCB are donated by the cord blood bank StemCyte.


Table 1. ChinaSCINet trials

Name SCI No. Treatment Groups Comments
CN101 >1yr 20 6w oral lithium carbonate (Li, titrated to 0.8-1.0 mM in serum) Phase 1 open label, adverse events
CN102A >1yr 40 Placebo vs. 6w of Li (0.8-1.2 mM serum levels) Phase 2 randomized double blind
CN102B >1yr 40 A-C: 4, 8, or 16 μl x4 (100,000 cells/ μl) UCB transplants; D. 16 μliter cells with MP; E. 16 μliter cells with MP + Li Phase 2 escalating dose, randomized, open label, ASIA motor/sensory scores
CN102C 2day- 2wk 40 A: Surgery; B: 6w of Li; C: 4x 16 μliters UCB; D: UCB +Li Phase 2 randomized double blind, ongoing
CN103 >1yr 400 UCB vs UCB + 6w oral Li (stratified ASIA A, B, C) Phase 3 randomized double blind, 2013

Legend: Oral lithium carbonate is increased every 3 days until serum Li >0.6 and <1.0 mM. Escalating doses of UCBMC (4, 8, or 16 μl of 100,000 cells/ μl) are injected into dorsal root entry zones above and below the injury site. MP is 30 mg/kg methylprednisolone given intravenously.

ChinaSCINet is conducting five clinical trials to establish the safety and feasibility of UCB and lithium treatments of SCI. CN101 showed that lithium is safe for patients with chronic SCI [47]. CN102A revealed no difference in neurological improvement between chronic SCI patients who received lithium or a placebo, but lithium reduced neuropathic pain [48]; a follow-up phase 3 trial is planned. CN102B has to date transplanted 28 patients (8 in Hong Kong, 20 in Kunming) and CN102C has randomized 30 subjects. CN103 is a phase 3 trial aimed at ascertaining whether UCB with or without lithium improves recovery.

In summary, the goal of ChinaSCINet is to conduct clinical trials of promising therapies for SCI. So far, UCB transplants appear to be safe and some subjects are regaining sensory and motor function. We plan to initiate phase 3 trials in 2013 in China, USA, Norway, and India. ChinaSCINet will continue to study promising therapies and compare them against the best therapy found in CN103.

Wise Young PhD MD is the Richard H. Shindell Chair of Neuroscience at Rutgers University in New Jersey. He founded and directs ChinaSCINet. He also serves as voluntary (unpaid) Global Medical Director of Stemcyte, Inc.

References

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