Recently, we did a routine ultrasound on a 16 year old in her first trimester to simply confirm her “dates” and found, incidentally, a baby with a large fluid collection on the back of its neck called a cystic hygroma. When this is identified in first trimester, more than 50% of the babies will be found to have a chromosomal abnormality. In the simplest terms possible, I tried to explain to her what that meant and how we could go about establishing the diagnosis. I knew I hadn’t gotten very far when her only question for me in the end was “Do you think the baby’s neck will look funny after it is born?” Since it was already late in the day, I asked her to think about things over night and return the next morning to talk with our genetic counselor. She did, and later that morning she had studies done that eventually confirmed the baby had an extra chromosome 21, or Down syndrome. Her own mother came with her after the diagnosis was made and could not understand how we could be correct because “My daughter isn’t 35 years’ old….”
Chromosomes contain the thousands of genes that orchestrate our growth, development, and biochemical functions. The normal human chromosomal complement is 46, or 23 pairs (22 pairs of ‘autosomes’ plus 2 ‘sex chromosomes’) with each parent contributing one chromosome per pair to the final genetic constitution of the baby. When a baby has too few or too many chromosomes, or even a small portion of a chromosome missing or extra, the baby is said to have a chromosomal abnormality, or aneuploidy. Most babies with an unbalanced amount of chromosomal material miscarry during the first trimester of pregnancy. Indeed, chromosomal abnormalities account for more than 50% of all spontaneous miscarriages in women who previously have had uncomplicated pregnancies. (Interestingly, they are NOT the most common cause of miscarriages in first pregnancies, a topic for a future post). Some babies with aneuploidy may be lost later in pregnancy and some will survive to be born.
There are a variety of ways by which a baby can end up with aneuploidy, and detailing all of these is not necessary for this post; however, the one that results in conditions with which the most people are familiar is an event called ‘nondisjunction.’ During the final step in gamete (egg or sperm) production, the 23 pairs of chromosomes must line up and then separate so that one of each pair is incorporated into the sperm or egg (oocyte), producing two gametes each with 23 chromosomes. When nondisjunction occurs, both chromosomes in a pair move together, resulting in one gamete with 24 chromosomes and one with 22 chromosomes. If one of these unbalanced gametes participates in the production of an embryo, assuming the correct number of 23 is contributed by the other parent, the baby will end up with a total of either 47 chromosomes or 45 chromosomes and be aneuploid, in this case with one entirely extra or too few chromosomes. Again, most of the time when this happens, the result is lethal, and the pregnancy ends spontaneously in miscarriage.
Examples of aneuploid babies that may survive through delivery with which many of you may be more or less familiar are an extra chromosome 21 (trisomy 21, or Down syndrome), an extra chromosome 18 (trisomy 18) or, rarely, an extra chromosome 13 (trisomy 13). Babies may also be born with missing or extra sex (X and Y) chromosomes (a normal female is XX and a normal male is XY). Common examples of this are, respectively, Turner’s syndrome (45 XO), affecting 1 in 2500 girls, and Klinefelter’s syndrome (47 XXY), affecting about 1 in 600 to 800 boys. Even most babies with any these chromosomal abnormalities are lost early in pregnancy.
Reasons for nondisjunction are poorly understood, but it is the event that is associated with increasing risk with increasing parental (especially maternal) age, and it is also the most common cause of aneuploidy at any age. In the case of Down syndrome, for example, the risk of delivering a baby with trisomy 21 is about 1 in 1250 for women at age 25, 1 in 1000 at age 30, 1 in 350 at age 35, 1 in 100 at age 40, and 1 in 25 at age 45. Risk for delivering a baby with any chromosomal abnormality is more than twice that for Down syndrome at any given age, i.e., 1 in 178 at age 35, 1 in 63 at age 40 and 1 in 18 at age 45. Because chromosomally abnormal babies can be lost throughout pregnancy, the chance of finding an aneuploid fetus is far greater earlier in pregnancy than at the time of delivery. For example, at age 35, the first trimester risk of finding a baby with trisomy 21 is 1 in 141 and in midtrimester it is only 1 in 270.
Discussions related to aneuploidy risks have become a daily routine in my practice because the trend over the past 30 years has been to delay childbearing until later in life. Data from the National Center for Health Statistics complied in 2002 demonstrated a drop in teenage birth rates to 43 births per 1000 (aged 15-19), a drop of 30% over the 10 year period from 1991; during the same time, birth rates for women aged 35-39 years increased to 41.4 per 1000, and for women aged 40-44, rose to 8.3 per 1000. These are the highest rates for women in these age categories ever recorded in the U.S. and the trend up seems to be continuing. So, in my next post, I will address issues related to aneuploidy screening….