LETTER TO THE EDITOR First-trimester Down syndrome screening after assisted conception TO THE EDITOR: We would like to comment on the article written by Bellver et al. (1) regarding the need for adjustments of first-trimester Down syndrome screening parameters after assisted conception. Although we greatly appreciate their work, which confirms earlier data in the field, we would like to issue some additional remarks. The Bellver et al. (1) study suggests a reduced maternal serum pregnancy-associated plasma protein A (PAPP-A) and increased false-positive rates in singleton pregnancies achieved by IVF and intracytoplasmic sperm injection (ICSI), compared with naturally conceived pregnancies. However, the latter showed to be significant when including only ICSI cycles using nondonor oocytes. Bellver et al. (1) discuss several other groups according mode of conception (IUI with partner or donor sperm, IVF, nondonor vs. donor oocytes, fresh vs. frozen ET), which veils the main message of the article, namely that (at least in their cohort) only in ICSI nondonor cycles serum PAPP-A level at first-trimester Down screening is significantly different from that seen in natural pregnancies. In their article Bellver et al. (1) describe a ‘‘diminished’’ PAPP-A level, even in cases where these levels are not significantly different, which is confusing. Although Bellver et al. (1) state that no significant differences were observed between the used laboratory techniques, the fact that dosages and calculations were performed with two different technologies during two successive time periods warrants caution when interpreting the combined results. Bellver et al. (1) mention some interesting data relating to the ovarian stimulation protocol and its influence on the firsttrimester Down screening biochemical markers. However, some details lack, such as the doses of gonadotropins/hormones used. Also, the finding that cycles in which only FSH was administered presented a significant reduction in PAPP-A MoM values, whereas this was not the case for FSHþLH regimens, needs additional discussion. We agree with Bellver et a. (1) on the hypothesis that ovarian stimula-

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tion may alter first-trimester biochemical screening parameters, as we found that decreased PAPP-A levels after IVF or ICSI were strongly correlated with the E2 level at ovulation triggering (2). However, we tend to disagree with the hypothesis that the ICSI technique adds an insult to the zona pellucida (ZP) of the oocytes, which in turn leads to altered serum PAPP-A levels by the placenta. If so, this effect should also be found in donor ICSI cycles. Another hypothesis might be that ICSI alters the constitution of the cytoplasm of the oocyte (and further downstream the origin of the placenta), rather than the ZP solely. The placenta does not originate from the ZP, but from the trophectoderm of the blastocyst. Finally, we agree with Bellver et al. (1) that studies investigating first-trimester biochemical markers should be performed in the scope of their correlation with complications in ART pregnancies. Frauke Vanden Meerschaut, M.D., Ph.D.a Claude Giorgetti, Ph.D.b Petra De Sutter, M.D., Ph.D.a a Centre for Reproductive Medicine, University Hospital Ghent, Ghent, Belgium; and b Institute of Reproductive Medicine, Marseille, France December 12, 2013 http://dx.doi.org/10.1016/j.fertnstert.2013.12.036

REFERENCES 1.

2.

Bellver J, Casanova C, Garrido N, Lara C, Remohi J, Pellicer A, et al. Additive effect of factors related to assisted conception on the reduction of maternal serum pregnancy-associated plasma protein A concentrations and the increased false-positive rates in first-trimester Down syndrome screening. Fertil Steril 2013;100:1314–20. Giorgetti C, Vanden Meerschaut F, De Roo C, Saunier O, Quarello E, Hairion D, et al. Multivariate analysis identifies the estradiol level at ovulation triggering as an independent predictor of the first trimester pregnancyassociated plasma protein-A level in IVF/ICSI pregnancies. Hum Reprod 2013;28:2636–42.

VOL. 101 NO. 3 / MARCH 2014