California Pacific Currents 2002
Leading a Team That's Advancing the Diagnosis & Treatment of Birth Defects
Thomas J. Musci, M.D.
Unbiased and impartial in effecting morbidity and mortality, birth defects occur among children of mothers from all age groups, income brackets, races, cultures, and occupations. Complex birth defects cause one-third of the deaths among newborns in the U.S. Birth defects are also responsible for serious illness and can leave infants and children unable to walk, hear, think, or even fight off disease.
The etiology of birth defects is complex. But Thomas J. Musci, MD, and his team here at California Pacific Medical Center intend to spearhead research into the prenatal diagnosis of birth defects. Other areas of emphasis will be advanced diagnostic techniques and intrauterine interventions to correct birth defects or reduce their severity. Musci, a clinical geneticist and perinatologist, accepted the new position as Director of Perinatal Research at California Pacific Medical Center this spring. “In creating the position, we intend to enhance our clinical research activities in the areas of perinatal medicine and genetics at the Medical Center,” comments Warren Browner, MD, MPH, Scientific Director of the Research Institute.
“California Pacific delivers more babies than any other hospital in San Francisco, and there is a wealth of information to be analyzed about the outcomes of pregnancies and births. In addition, many high-risk patients are referred to the perinatologists here. This provides us with a great deal of information about at-risk deliveries and how to achieve the best outcomes,” says Dr. Browner.
Prior to joining the medical and research staffs at California Pacific, Musci was Associate Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine where he spent the last 19 years practicing and conducting research in maternal-fetal medicine (also called perinatology) and clinical genetics.
In addition to research, Musci is also a practicing physician who has worked with other clinical geneticists and perinatologists to diagnose and even ameliorate a small number of birth defects in utero. “However, most birth defects still are managed most effectively by medical and surgical care after delivery. It is rare that birth defects can be fixed in utero or even after the baby has been born. What we need to understand is how to prevent the birth defect from ever occurring. We need to understand what went wrong in the first place.”
And what can and does go wrong is all too common. According to the California Birth Defect Monitoring Program, one out of every 33 babies is born with a birth defect. This translates into more than more than 150,000 babies each year nationwide. According to the March of Dimes, more than 4,500 different birth defects have been identified. While the causes of about 60% of them are unknown, the good news is that infant deaths due to birth defects have been cut in half since 1960.
In addition to reduced mortality from birth defects, sophisticated imaging techniques, such as ultrasound and MRI, give researchers and clinicians better anatomical information and can help detect suspected abnormalities such as brain developmental defects. Advances in diagnostic testing — such as chorionic villus sampling and direct fetal blood sampling from the umbilical cord — have made many genetic diseases detectable before birth.
Why Do Birth Defects Occur?
In the majority of cases, researchers cannot be certain, but there are clues. For example, environmental toxins have been implicated in the occurrence of certain birth defects.
In other cases, such as spina bifida — a condition in which the spinal column is not entirely enclosed within the body, resulting in increased rates of infection, paralysis, and later bladder and bowel problems — researchers and clinicians have identified a lack of folic acid in the mother’s diet as a potential contributor to the disorder. “With adequate amounts of folic acid given to women at the beginning of their pregnancies, we can lower the incidence of spina bifida,” says Dr. Musci.
Environmental contaminants such as drinking water polluted with pesticide runoff, occupational exposures to chemicals, and certain prescription medications taken in the early weeks of pregnancy are other factors to consider when looking for causative agents.
Additionally, there are certain women who are at a higher risk. This population includes women who have a family history of birth defects, birth defects among first-degree relatives (parents or siblings), or a woman who has already delivered a child with a birth defect, especially one with a congenital heart defect. A woman with uncontrolled or poorly controlled diabetes is also at increased risk.
The Mystery of Cell Differentiation
At the core of these potential causative agents lies the basic cellular differentiating process. This process — how a small cluster of nonspecific embryonic cells turns into skin, bone, muscle, or organs — presents as many questions to genetic researchers and scientists as it does answers. Regardless of the type of being, from insects to frogs to humans, the same developmental process is at the basis of transforming undifferentiated cells into cells with specific architecture and function. Investigations into this process on both the molecular and cellular levels have occupied Musci for the last 14 years.
But for mothers of babies with birth defects, the developmental process was somehow subject to interference. It did not proceed normally, and when the signaling process in cell differentiation is abnormal, the result can be one of many thousands of different types of birth defects. “By better understanding normal embryonic development, we will begin to identify, and some day intervene, when fetal development is abnormal,” explains Dr. Musci. “But many questions about fundamental developmental processes remain. Understanding these processes is critical before the research community can develop preventive therapies for birth defects or develop therapies to cure serious human genetic diseases.” Additionally, an understanding of how the various tissues and organs of the embryo develop will ultimately help researchers solve the mysteries of how normal cells differentiate into cancerous cells.
Specific Research Initiatives
Musci is involved in several research initiatives focusing on the diagnosis of fetal chromosomal abnormalities (such as Downs Syndrome, also known as Trisomy 21), fetal genetic disease, and fetal anomalies/abnormalities. For example, Musci and his collaborators here at California Pacific Medical Center are participating in the early stages of a national, multi-center study on the possible use of ultrasound to better predict which patients are carrying Downs Syndrome fetuses. The use of ultrasound will hopefully reduce the number of women who need to undergo invasive testing, such as amniocentesis or chorionic villus sampling, and thus will prevent unnecessary fetal losses.
One of Musci’s primary areas of research is in “Fragile X Syndrome,” which causes a wide range of mental impairment, from mild learning disabilities to severe mental retardation. It is the most common cause of genetically inherited mental impairment, with the full mutation (the most serious form of the disease) appearing in approximately 1 in 3,600 males and 1 in 4,000 to 6,000 females. In addition to mental impairment, Fragile X Syndrome is associated with a number of physical and behavioral characteristics.
Musci and his colleagues are working to better understand the molecular aspects of Fragile X Syndrome and to establish comprehensive, prenatal testing programs for those at risk. They are also instituting a cost-effectiveness analysis on the implementation of widespread, prenatal screening for Fragile X.
There are several tests available to determine if someone has the disorder and if family members can potentially transmit the gene. Research that Musci conducted on animal models is aimed at uncovering the causes of the syndrome and unraveling the complexities of how the disease is inherited.
Along with a team of California Pacific prenatal diagnostic specialists, Musci will study the clinical implementation of offering Fragile X DNA mutation tests to women undergoing prenatal genetic counseling and diagnostic procedures such as amniocentesis and chorionic villus sampling. “On the clinical side, we will study how to best educate and counsel patients about this disorder. Our research initiative will help us to determine how many women should undergo testing and ultimately reveal the exact percentage of women in our northern California population who are at risk of transmitting the Fragile X Syndrome to their offspring,” says Dr. Musci.
Applying Research Findings to Prevent Preterm Labor
“We have Dr. Michael Katz in our group who is an expert in preterm labor and in performing ‘cervical cerclage’ for women with a disorder known as incompetent cervix.” Cervical cerclage is a procedure in which a suture is placed around the cervix of women who have lost a pregnancy before the infant can live on its own outside of the womb (known as a previable state). With the large number of patients referred to Dr. Katz and the Medical Center for this procedure, outcomes data can and will be collected and analyzed in order to discover improved methods of management and treatment of incompetent cervix.
Bringing Research Findings to the Patient Encounter
“The role of the clinical geneticist is to diagnose, treat, and to counsel. We want to give parents as much information as we possibly can so that they can make informed decisions about their current pregnancy and/or to better care for their infant as soon as it is born,” explains Dr. Musci.
Enhanced patient care, improved outcomes, and more definitive, less invasive diagnostic procedures are the overarching goals of the program. “My role as a clinical geneticist and perinatologist will be to spearhead these efforts, organize, and ultimately obtain more funds to carry out these and other research initiatives, the results of which, we hope, will ultimately reduce the number and severity of infants born with birth defects,” concludes Dr. Musci.