David R. Meldrum, MD
The Meldrum quads
People have often asked whether it makes me more conservative in managing infertile couples to have had quadruplets myself. There’s no simple answer, but that’s probably somewhat true. Everyone who gets through a multiple pregnancy without a major complication should be very thankful. Twins usually do well, and no question, it’s “two for the price of one”. But even twins can be delivered early enough so one or both offspring doesn’t survive or could have a major impairment such as cerebral palsy, brain damage, or other major or minor handicap. Twins are also a major stress for your relationship and divorce has been shown to occur more often. When all of the pluses and minuses are considered, it’s actually better to undergo more expense to have each baby one at a time. Recent studies have even shown that when more than one embryo is transferred and a second sac shrinks away, or even if there is no sign of another implantation, a resulting singleton pregnancy will have more complications than when only one embryo is transferred. This is presumably because of inflammation associated with another implantation that fails to develop. It is also why it is not a good strategy to add a poor embryo to the transfer just because it formed and would otherwise be discarded. It could cause complications of a pregnancy resulting from the good quality embryo.
So how can you have one embryo transferred and still keep your success rate high and the process as efficient as possible? First, for women under age 35, transfer of a single day 5 embryo (a blastocyst) of good quality will give a high chance of pregnancy. With current cryopreservation by vitrification the survival of that additional embryo will be so high that your overall success rate will be unchanged. You just have to accept a bit higher chance of having to undergo the inconvenience and expense of transfer of that second embryo. For women over age 35 and particularly over age 38, you can have a single embryo transferred while maintaining a high chance of pregnancy, but it requires additional expense and an adjustment of expectations and some patience. It can be accomplished in women anticipated to have a good response and a good number of embryos by sampling each embryo on day 5 to verify that all chromosomes are normal using many thousands of genetic probes (above), followed by cryopreservation and transfer of a single normal embryo in a later cycle. By transferring only chromosomally normal embryos the process becomes much more efficient, requiring fewer embryo transfers. Transferring in a cycle where the endometrium has not been stimulated has recently been shown to also result in a higher chance of implantation. The technique is called “trophectoderm biopsy”, meaning that a small hole is made in the egg shell of the day 5 embryo using a laser, and when cells destined to become the placenta start hatching, a few cells are trimmed off, again using the laser. The cells are then sent to a special lab to determine whether every chromosome is normal. (Incidentally, that also will tell you which embryos will be boys or girls.) The chance of miscarriage, which is usually due to a chromosome abnormality, will be lower. As well, the chance of an ongoing pregnancy being chromosomally abnormal, such as Down’s syndrome, where there is an extra chromosome 21 (right), will also be much lower, reducing the chance of needing a pregnancy termination or having a chromosomally abnormal newborn. However, even with the excellent techniques used today, you should still realize that the chance of a chromosomally abnormal fetus is not reduced to zero, because the technique is not perfect. Also, there is a very small (in the range of 1-3%) chance that the sex determination could be wrong. However, if you factor in the lower risk of pregnancy complications and miscarriage (understanding that those are generally covered by your insurance), the additional expense (about $6,000) is easily justified. It is unfortunate that insurance doesn’t cover both infertility and these other medical costs. In some countries in Europe the government mandates the transfer of a single embryo under most circumstances with initial IVF attempts, realizing that the overall cost will be lower. We do understand that when IVF expenses are out of pocket, as is often the case in this country and the expenses for complications are covered by insurance, couples can be swayed toward transferring more embryos. Still, to my mind, the decision is trumped by reducing the chance, however unlikely, of having a seriously impaired offspring, with the obvious lifelong difficulties and expense.
Notice that I said above “in women anticipated to have a normal response”. Most of the experience to date has been in such women and it is entirely possible that lesser outcomes could occur for women whose ovaries do not respond well. There is more to implantation success than just having all of the chromosomes being normal. It is well known that two day 5 embryos (blastocysts) can be equally high in quality but have differing metabolism and implantation potential. Unfortunately women vary in the quality of their ovarian function and egg quality. For those with lower ovarian quality and response, transfer of multiple embryos will be necessary until there is some reliable metabolic test to determine which embryo is likely to implant. Also some embryos, particularly in such women, may implant better when transferred on day 3 or even day 2, allowing more time for them to “talk” to the uterine lining, and for the uterine lining to help boost their metabolism. In the future there likely will be tests that can be done at an earlier stage that will not adversely affect the embryo. Recent studies suggest that the cells surrounding the egg might reveal the egg/embryo’s potential by their gene activities or metabolism. Other studies have shown that a sophisticated technique using time-lapse video pictures of each embryo during its early developmental stages can help to predict which one has the potential to implant.
So, in summary, if you are under 35 and have good quality blastocysts, you should strongly consider single embryo transfer. If you are over 35 and anticipated to have a normal response, you can consider testing of each embryo on day 5 and transfer of a single normal embryo after cryopreservation, either as an initial approach or if routine IVF is not successful.
I did mention sex selection, which deserves further comment. Because on average half of the embryos will be of the “deselected” sex, and usual success rates are based on being able to choose the best embryo/s from all available embryos, sex selection will reduce your chance of success (let’s estimate that effect as a one-third decrease until enough data is gathered). For couples with normal fertility the reduction might be small and not significant, but for a couple struggling with infertility, any sizable reduction probably won’t be tolerable. Of course there are variations on that decision. A couple could decide if there are two embryos of equal quality to try transferring the desired sex first. Or they could transfer each reasonable embryo of the desired sex followed later by the initially deselected sex if they are unsuccessful.
So how did the Meldrum quads do? They delivered at 34 weeks and did well. It was certainly very difficult, but Claudia is incredibly well-organized and our marriage was strengthened by all of the challenges. However, I have seen enough instances over the years where things did not go well that we consider ourselves extremely fortunate.