Is PGD Safe? Embryo Development, Pregnancy Rates, and Children Born After PGD
Couples who wish to conceive with a healthy child want to know whether PGD affects the clinical outcome of IVF/ICSI. It is needless to say that any procedure performed on oocytes/embryos may damage a specific embryo. The experience of the assisted reproductive technology (ART) center in ovarian stimulation for IVF with PGD and in embryo micromanipulation, the technique used for biopsy, and the numbers of cells removed from the embryo may affect embryo development, implantation rate, and the pregnancy outcome.[30–33] The outcome of the study published by Mastenboek et al in 2007 raised similar concerns.[33,35]
Magli et al investigated implantation rates of embryos after combined polar bodies and embryo biopsies compared with blastomere only. They found similar implantation rates (26% versus 25%, respectively) regardless of the number of micromanipulations performed. We have looked at whether one, two, or three micromanipulations for PGD for polar bodies and/or blastomere biopsies affects blastocysts development rate. Comparing the development of 9925 embryos biopsied for PGD to 28,126 nonbiopsy ICSI embryos from the same time period revealed similar blastocysts development rates, irrespective of the number of biopsies performed. The PGD technique performed at our center was by mechanical breaching of the zona pellucida and by removing only one blastomere from day 3 embryos. Removing two cells from a day 3 embryo has been shown to affect embryo development significantly, and this practice should be stopped.[30–32] A recent prospective cohort study demonstrated that the live-birth rate was significantly higher after one-cell biopsy on day 3 compared with that of two-cell biopsy, as commonly performed in Europe. Whether the holes created in the zona pellucida for PGD increase the incidents of monozygotic twins was investigated by Verpoest et al. They found 1.5% monozygotic twins in the clinical pregnancies established in the PGD group (n = 1992 cycles) compared with 2.1% in the 2429 IVF/ICSI cycles (p = not significant [NS]). This demonstrates that multiple micromanipulations on oocytes and embryos can be performed safely for PGD at experienced centers.
PGD may, however, decrease the β-human chorionic gonadotropin (hCG) levels measured when patients conceive. Two groups have demonstrated initial lower β-hCG levels with pregnancies obtained after PGD compared with controls.[40,41] At the same time, the biochemical pregnancy rate, clinical miscarriage rate, and the take-home infant rate were similar in both groups. The lower β-hCG levels may result from the blastomere biopsy, which may decrease the β-hCG-producing activity of the trophoblast, especially at early pregnancy, or a delayed implantation that may occur in biopsied embryos. A delayed implantation may also be related to the type of controlled ovarian hyperstimulation (COH) used. Although this finding poses no significant clinical concern, a lower cutoff value of serum β-hCG level for predicting successful pregnancy outcome following PGD procedure may be clinically implemented.
The data collected by the European Society of Human Reproduction and Embryology (ESHRE) PGD consortium suggests a lower pregnancy rate for cycles with PGD compared with regular ART.[43,44] However, comparing their results to those of some centers in the United States demonstrate this is not necessarily the case.[45–47] During a 4-year period (November 2002 to November 2006), the author performed 166 consecutive oocyte retrievals for IVF for PGD for 51 different monogenic disorders (women ≤42 years of age) at IHR/RGI in Chicago.[46,47] The outcome of these cycles was compared with the outcome of the 520 oocyte retrievals from 45 centers reported by the PGD ESHRE consortium for 2004. The mean women's age was 33 years in both groups. The mean number of oocytes retrieved, the fertilization rate by ICSI, and the percentage of embryos biopsied out of those fertilized were all significantly higher at IHR/RGI in Chicago compared with those in Europe (15.7 versus 13.7, 81% versus 71%, and 95% versus 71%, respectively; p < 0.0001). The mean number of embryos transferred was comparable, 1.7 in Chicago versus 1.9 in Europe. The implantation rates were 35% in Chicago versus 16% in Europe, and the clinical pregnancy rates per oocyte retrieval and per embryo transfer (ET) were 38% and 47% in Chicago, compared with 20% and 26% in Europe, respectively (p < 0.0001). When comparing data from Chicago to three leading centers in Europe, the percentage of live births per ET, of cycles performed at a similar time period for patients of mean age 30 to 33 years, was 44% in Chicago, which was significantly higher than the 32% in Brussels,[48,49] 29% in London, and 23% in Paris. The percentage live birth per couple reached 52% in Chicago. These data suggest that a team of reproductive specialist experienced in IVF with PGD, together with skilled embryologists and PGD laboratory (including removal of only one cell from day 3 embryos), may obtain high pregnancy rates.
Most importantly, parents undergoing PGD should expect similar developmental outcomes for their children as seen in those born following IVF/ICSI without PGD.[11,51–54] Children born after PGD do not demonstrate a higher rate of malformation or neonatal problems.[11,55–60] In fact, because infertility has recently been shown to be an independent factor affecting children's health with or without ART, studies should investigate whether children born to couples who underwent PGD without infertility problems demonstrate an even lower rate of malformation or neonatal problems than IVF/ICSI-only children.
Several cohort studies demonstrated similar mental and psychomotor development at age 2 to 4 for children born after PGD compared with children born after natural conception or IVF/ICSI. No adverse effects of PGD/PGS on growth, congenital malformations, neonatal intensive care admissions, behavior, or mental and psychomotor development were found.[43,54,55,57–60,62,63] Middelburg et al demonstrated that although scores on all mental, psychomotor, and behavioral tests were within the normal range, PGS children showed an unexplained lower neurological optimality scores compared with the control children. An increased rate of stillbirths in multiple pregnancies following PGD was reported from one center that used to remove two cells for biopsy, which needs further attention. Long-term prospective follow-ups on PGD children should be continued.[11,60]
In summary, PGD in experienced laboratories seems to be safe, and couples may expect similar clinical outcomes as with regular ART. When biopsy is performed on day 3, only one cell should be removed for PGD/PGS. Embryo biopsy does not add risk factors to the health of singleton children born after PGD or PGS. Further prospective follow-up studies on biopsy safety and on children born should be encouraged.
Semin Reprod Med. 2012;30(4):309-322. © 2012 Thieme Medical Publishers