To bring those of you just jumping into this discussion up to speed, in our last two regular posts on the subject of “Chromosomal Abnormalities in Multiple Gestations,” we presented a case in which a 40 year old woman, who conceived twins by IVF after a long (and expensive) history of infertility, presented at 20 weeks for a ‘targeted’ ultrasound and was found to have one of the babies with multiple congenital anomalies. Subsequently, it was determined by amniocentesis that the baby with abnormalities had trisomy 18, confirming our initial clinical suspicion. Despite recommendations by her infertility doctors and her regular physicians, she had declined any assessment of the babies for chromosomal abnormalities earlier in the pregnancy. The other baby appeared perfectly normal and did not have chromosomal studies done. Her case is presented, because as the number of women delaying childbirth increases, as does the dependence of older women on infertility services for conception, this situation is becoming much more common. To have waited so long, and been through so much for a pregnancy, to have shared the excitement of a multiple gestation with friends and family, and then to be put in the position of having to deal with the emotions, and sometimes hard decisions, related to one “normal” baby and one baby with complications, can be extraordinarily difficult and at times quite devastating.
In the current case, our patient was told the baby had trisomy 18 on the basis of the rapid (FISH) studies that were done, but she elected to wait until the final fetal karyotype, based on the standard culture technique, was completed before she returned to discuss “where do we go from here.” At the time of that return visit, she was now about 23 weeks. Before performing another ultrasound, we reviewed the poor prognosis for babies with trisomy 18 – many will die in utero and most who don’t, succumb shortly after delivery. She asked if there was anything we could do to help the baby at this point, or to improve his chances for survival and quality of life and we told her that there wasn’t. She asked if this baby was lost in utero if that could deleteriously affect the outcome for the other baby and, without going into details here, she was told that it could, but that the prognosis for the healthy baby should be fairly good, if that occured, because the twins were dizygotic (from completely different eggs) and had completely separate placentas.
In the same breath, however, I told her that sometimes survival of an abnormal baby in multiple gestations actually jeopardizes the pregnancy. She looked at me quizzically and I went on to explain with several examples of women under similar circumstances (advanced maternal age; infertility; IVF pregnancies; multiple gestations) who had twins (or more) with one or more babies with chromosomal abnormalities in which the healthy babies were put at risk as the result of complications arising due to the abnormal babies. Babies with Down syndrome, for example, often have upper bowel obstructions, such as duodenal atresia, that result in the inability of the baby to return fluid wastes to the mother for disposal. As the result, excessive amniotic fluid accumulates around the baby (polyhydramnios), the uterus becomes overdistended, and premature labor and/or premature rupture of membranes can ensue. Similarly, babies that are severely growth restricted (whether or not they are chromosomally abnormal) increase the mother’s risk of developing preeclampsia that may also necessitate early delivery, thereby putting an otherwise healthy sibling at risk for complications of prematurity.
At that point, it was clear we had hit a nerve. “Oh,” she said, “I guess that would be a good reason to consider finding out early with twins if one of the babies has a chromosome problem ...” “That’s one reason,” I said, “and there are lots of others…Some people use the information to prepare for pregnancy complications and to gather information and support for their deliveries, some elect to have ‘selective termination’ of the chromosomally abnormal fetus, and others elect to terminate their entire pregnancies. What I have found is that most people do NOT know what they would do with the information before they actually have it! No matter what they bring to the table, they just do not know…and you know what? We don’t tell them what to do either…”
With regard to this discussion, recently, I received the following comment from a reader…
Thanks for putting so much effort into a fascinating and endlessly informative blog!
How reliable is the screening for multiple gestations? Isn't beta-HCG elevated in that case? Or is there sufficient info in the database on twins, triplets, etc. that the differences can be taken into account and reliable estimates of risk can still be made?
The query above is about the usefulness of first trimester screening for aneuploidy in the evaluation of multiple gestations. Its timing coincides nicely with the clinical situation we have been discussing and, indeed, was a point of conversation between the patient and me when she finally returned for follow-up and it was another impetus for this brief series on chromosomal abnormalities in multiple gestations.
As we have discussed previously, the basic approach to first trimester screening for aneuploidy involves a risk calculation based on a combination of fetal measurements (crown-rump length and nuchal translucency-NT), maternal serum screening for free beta hCG (pregnancy hormone) and PAPP-A (pregnancy-associated plasma protein-A), and pertinent ‘demographic’ information that is generated by comparison to a large database of other patients. Using this, the overall detection of Down syndrome (trisomy 21) and trisomies 18 and 13 in singleton pregnancies is in the range 90% with a false-positive rate of about 5%. Other chromosomal abnormalities may also be detected using this approach, but not as reliably. Thus, one shortcoming of first trimester screening is that it does not alert us to the risk of all chromosomal abnormalities. When cystic hygromas are found during the course of this evaluation, more than 50% will have some form of chromosomal abnormality.
Spencer in 2000 (Prenat Diagn 2000;20:91-5) analyzed the distribution of free beta-hCG and PAPP-A in 159 twin pregnancies and compared that to 3466 singleton pregnancies and found “on average free beta-hCG values are 2.099 times greater in twins than in singletons and PAPP-A some 1.86 times greater.” Using NT measurements and these results to provide statistical correction for these biochemical markers in the risk calculations for twin pregnancies, he estimated detection rates for Down syndrome in the range of 80%, which was higher than for using the NT measurements alone. In a subsequent study (Prenat Diagn 2001;21:715-7), he demonstrated the validity of the risk correction algorithm in both monochorionic and dichorionic twin gestations. In a summary of studies to date, Bush and Malone (Clin Perinatol 2005;32:373-86) concluded that “the best available data (based on modeling) show approximately 75-85% detection rates for Down syndrome, with a false-positive rate of 5%.” Thus, in the case of twins, it would appear that combined first trimester screening can be used reliably to assist women in their decisions regarding the options for additional fetal evaluation (screening and diagnostic). At this point, there is probably insufficient data to extend that reliability to higher order multiples, but fortunately, we do not have to deal with them that often as our Reproductive Endocrinology colleagues have become more efficient (and more cautious) in their efforts to achieve fertility!