Bethany Weathersby remembers when she stopped feeling her daughter Lucy inside her in 2013. At about 18 weeks' gestation, she had an intrauterine blood transfusion to try to save her baby. She never felt Lucy after that, and days later Lucy had died.
Lucy had a hemolytic disease of the fetus called Kell alloimmunization. It's a mismatch of blood types between the mother and the baby.
Clinical trials on a medication that shows promise to treat this mismatch are being done at Dell Children's Medical Center and being led by Dr. Kenneth Moise Jr., a maternal fetal medicine specialist and co-director of the Dell Children's Comprehensive Fetal Care Center.
The fetal care center, which officially began in May 2021, has attracted patients from throughout the country and from Europe, who are now coming to Austin for care. The center brought in Moise and co-director Dr. Michael Bebbington, as well as support staffers such as genetic counselors, sonographers and nurse navigators. Other fetal-maternal health physicians, obstetricians, neonatologists and a palliative medicine specialist also work with the center's patients.
It's part of a $700 million expansion at Dell Children's, which includes building a fourth tower to the main hospital and adding a second hospital in North Austin, both of which will open in November.
In Kell alloimmunization, a mother has developed the anti-Kell antigen from a previous pregnancy or from a blood transfusion. If her baby's blood type is Kell positive, those antibodies then attack the baby's red blood cells, causing severe anemia.
In Weathersby's case, her husband's blood was positive for Kell and she was negative. Her first baby, Liam, 13, might have had her Kell status or her husband's (they don't know), but if he had her husband's, she was not exposed to his Kell blood during birth. Her second son, Asher, 11, had her husband's Kell status. She was exposed to Asher's blood while giving birth, which caused her to then begin making anti-Kell antibodies.
It's much like the more well-known Rh disease, another hemolytic disease, in which a mother has a negative blood type and the baby has a positive blood type. In Rh disease, the mothers are given an injection of RhoGAM, an immune globulin medication, during the second trimester and the mother's antibodies no longer try to attack the fetus's blood.
It's not that simple with Kell alloimmunization or other types of hemolytic disease of the fetus and newborn, at least not yet.
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Investigating a new treatment
Moise has been leading a global study of a monoclonal antibody known as M281 for use in hemolytic disease of the fetus and newborn.
During the trial, which is in phase two out of three, the medication is given weekly as an IV infusion to stop the mother's antibodies from attacking the fetus's blood. It is then stopped at about 35 weeks and an infusion of intravenous immune globulin is given to help the fetus make its own antibodies. Then the baby is delivered between 37 and 38 weeks.
M281 is thought to prevent the need for multiple intrauterine blood transfusions, which have been the standard of care in hemolytic disease. Without any intervention, these fetuses die before birth.
Transfusions, though, come with big risks. Prior to 22 weeks' gestation, an intrauterine blood transfusion has about a 20% to 30% rate of fetal death, even in the most experienced hands, Moise said. A needle is put through the mother's abdomen and into a vein in the umbilical cord. "These are tiny babies, weighing half a pound or less," Moise said.
These babies also need five to six transfusions during the course of a pregnancy, each coming with its own risk and each raising the mother's anxiety level, Moise said.
"We need to stop this craziness," he said.
The hope is that a weekly IV infusion, which can be given at any infusion center or specialized doctor's office, could make a treatment more available and prevent more fetal deaths. Eventually, it might be delivered in a weekly injection that a mom can give herself.
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How M281 might work
M281 already has been used in treating autoimmune diseases. In pregnant women, it is thought to work in two ways: It stops the antibodies from crossing into the placenta, and it lowers the amount of the antibody the mother has.
The drug was originally created by Momenta Pharmaceuticals, which was then bought out by Johnson & Johnson.
Moise, who has been working with Momenta and then Johnson & Johnson for eight years on these clinical trials, also will lead the third phase after phase two is done. "It's a slow process with the FDA," he said. "If I'm realistic, a final approval is at least three years away."
Moise first started working on this trial when he was in Houston, leading the fetal care center at Children's Memorial Hermann Hospital. He came to Austin to start the Comprehensive Fetal Care Center in July 2020.
The M281 trial is being done at 14 centers around the United States and the Netherlands, Ireland, Australia, Spain, German and Sweden. In phase two, the participants had to be "the sickest of the sick" and had to have already lost a baby to hemolytic disease of the fetus and newborn, Moise said. The trial also got slowed by COVID-19.
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Helping save another baby
After losing Lucy, Weathersby didn't feel like her family was complete and wanted to have another baby. She knew, though, that anti-Kell was a 50% possibility in any babies she might conceive.
She found a study about hemolytic disease of the fetus and newborn that had Moise mentioned in it. She printed a copy of it and kept it with her.
"Just the presence of that in my pocket gave me hope," Weathersby said.
One day, she reached out to Moise by email, and he called her back 45 minutes later.
"I couldn't believe it," she said. "I couldn't believe that he was that generous. He didn't know who I was. He truly cared about me."
Weathersby became pregnant with daughter Nora two years after Lucy. Through the routine blood test, it was confirmed that Nora also was Kell positive and would be at risk of dying without intervention.
This time under Moise's guidance. Weathersby got an initial infusion of intravenous immune globulin infusion and plasmapheresis to help her fetus not be exposed to as many of her Kell antibodies and delay the need for blood transfusions.
At 17 weeks into her pregnancy, Weathersby drove from her home in Tuscaloosa, Alabama, and moved to the Ronald McDonald House in Houston, to be seen by Moise until the baby was born. He did five intrauterine blood transfusions on Nora to keep her healthy.
Nora was born healthy in July 2015 and is now 6.
Weathersby went on to have two more sons, Callum, 4, and August, 1, all of whom were born healthy but were Kell positive. By then, Weathersby was willing to try a center closer to home in Atlanta. Moise consulted on those pregnancies as well.
For August's pregnancy, Weathersby was hoping she could be part of Moise's M281 study, but a blood test disqualified her.
"It would have been amazing to have a healthy baby without all the intervention," she said. "It would have been a different experience."
The research into this new medication possibility has been fascinating, Moise said. "We have very few FDA-approved drugs in pregnancy. Doing pregnancy research is so difficult."
The first patient he treated with M281 is now 2½ and doing well, Mosie said.
Weathersby has created a foundation to prevent fetal death from hemolytic disease of the fetus and newborn called Allo Hope Foundation. Each year on Feb. 9, the family recognizes Lucy's birthday, sometimes with a cake, but she's always remembered.
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