Reducing the Rate of Multifetal Pregnancies During Assisted Reproduction

Eric S. Surrey, M.D. and William B. Schoolcraft, M.D.
Colorado Center for Reproductive Medicine
Englewood, CO

Over the last several years, pregnancy rates from in vitro fertilization-embryo transfer (IVF-ET) procedures have increased in many centers. However, this has also been associated with relatively high multiple pregnancy rates. According to the most recent Society for Assisted Reproductive Technology/American Society for Reproductive Medicine registry for assisted reproductive techniques (ART) cycles performed during 1996 in the United States, 31.8% of all deliveries were twins, 6.5% were triplets, and 0.6% were greater than triplets.(1) These data underestimate the true incidence of multiple pregnancy since pregnancy losses and reduction procedures are not included. Although many couples aspire to multiple pregnancy, this outcome is associated with a significantly increased risk of pregnancy loss, preterm labor and premature birth. Similarly, multiple gestation increases the incidence of pregnancy complications for the mother as well (e.g., post-partum bleeding, pre-eclampsia, and gestational diabetes).

Several strategies have been proposed to reduce the number and extent of multiple gestations. Multifetal pregnancy reduction can be performed to decrease the extent of multiple pregnancy. However, this procedure, which is not in any way preventative, is associated with its own risks and may rarely result in the loss of the entire pregnancy. The psychological impact of this process may be significant and its use may be unacceptable to some patients.

When analyzing over 35,000 IVF cycles performed in the United States during 1996, Schieve and colleagues noted that multiple birth rates varied with maternal age and number of embryos transferred.(2) In women aged 30-34, a 20% multiple pregnancy rate was noted in those with two embryos transferred, whereas a 40% multiple birth rate was noted when 3 or more embryos were transferred. However, among women aged 40-44, the multiple birth rate was less than 25% when up to 5 embryos were transferred. A second approach is to arbitrarily limit the number of embryos to be transferred. In some countries, this number is limited by law. Although this approach does decrease the rate of multiple pregnancies, ongoing pregnancy rates are somewhat compromised. In one German study of 2573 consecutive transfer cycles, the multiple pregnancy was reduced by 7.9% in women with elective transfer of 2 embryos in comparison to those who had 3 embryos transferred.(3) However, the ongoing pregnancy rate in this group was only 22.0%.

A compromise alternative is to allow for individual variation based on each patient's age and embryo quality. It has been proposed by the American Society for Reproductive Medicine that limited numbers of embryos be transferred to women with an extremely favorable potential for conception (e.g., age <35 with high quality embryos) (4). The impact of these recommendations on lowering multiple pregnancy rates has not yet been demonstrated, although initial information should be available once the national outcomes data from 1999 and 2000 are analyzed.

Advances in the development of highly sophisticated culture media have allowed IVF laboratories to culture embryos to a more advanced stage of development - the blastocyst. A recent prospective randomized trial by Gardner and colleagues compared the outcome of transferring embryos at the 6-10 cell stage on the 3rd day of culture or at the blastocyst stage after 5 days of culture.(5) The pregnancy rates were equivalently high in the two groups (66% on day 3 and 71% on day 5), but significantly more embryos were transferred on day 3 (3.7) than on day 5 (2.2) to achieve this result. With the transfer of only 2 blastocysts, the incidence of triplet but not pregnancy can be virtually eliminated. These findings have been confirmed by other investigators.(6,7) In a recently submitted study of patients receiving donor oocytes, the transfer of 2 blastocysts resulted in an ongoing pregnancy and delivery rate of 79.5% with only a 2.6% triplet pregnancy rate which resulted from 2 cases of monozygotic or identical twins.(8) In contrast, patients receiving donated oocytes who underwent of a mean of 3.2 embryos after three days of culture experienced a 15.5% triplet pregnancy rate. Single blastocyst transfer may represent an ideal approach in the future for appropriate patients after completion of well-designed trials.

These data would suggest that the careful selection of limited numbers of high quality embryos or blastocysts can result in a significant reduction of high-order multiple pregnancies in the appropriate patient. Each IVF laboratory should develop its own criteria based on its own outcomes to enhance the process. There is no question that our ultimate goal of maintaining high pregnancy rates while drastically reducing the risks of multiple pregnancy can be achieved.