LETTER TO THE EDITOR REPLY OF THE AUTHORS: Our article (1) not only tries to show our personal experience but also performs a review of the current literature on first-trimester Down syndrome screening in assisted conception. As summarized in Table 1, most previous series (and particularly the most recent ones with larger sample sizes) show a significant reduction of serum pregnancy-associated plasma protein A (PAPP-A) concentrations in pregnancies achieved by IVF and especially by intracytoplasmic sperm injection (ICSI). In our population, both IVF and ICSI pregnancies showed reduced maternal serum PAPP-A levels and increased false-positive rates in Down syndrome screening, but these were significant only in ICSI cycles. However, the sample size of our IVF cycles was quite small (n ¼ 328) compared with our ICSI cycles (n ¼ 1,364) and the most recent studies on IVF (n ¼ 2,115 in Kagan et al. [2]). As the latter showed significantly decreased PAPP-A levels in IVF cycles, we can infer that the reduction seen in our IVF group did not reach statistical significance probably due to the smaller sample size. Because of this, we also included the IVF cycles in our recommendation to perform adjustment of the PAPP-A levels in addition to ICSI cycles, in both cases when using own oocytes (nondonor cycles). In our opinion, the important message is that no adjustments are needed for the other low-rank assisted reproduction techniques (ART) or for free b-hCG levels. Regarding the two laboratory techniques used, caution was taken to check first the lack of differences between them before combining the entire set of biochemical data, as in previous publications (3). With respect to the type of gonadotropins used, we observed a reduction of serum PAPP-A concentrations in cycles in which only FSH was used for ovarian stimulation, but we have not found any reasonable explanation for it. We found that total doses of gonadotropins administered did not correlate with PAPP-A multiple of the median values and only marginally with free b-hCG MoM values (r ¼ 0.082;

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P¼ .027). Therefore, it seems that the influence of gonadotropin doses on serum PAPP-A concentrations is lacking. Concerning the effect of the ICSI technique on PAPP-A results and the theory suggested by our colleagues about the alteration of the constitution of the cytoplasm of the oocyte after ICSI, we agree that different unknown mechanisms may be responsible for the results obtained. But there is no doubt that in pregnancies achieved by ICSI serum, PAPP-A concentrations are more affected than in those achieved by IVF. The main difference between ICSI and IVF is the different degree of manipulation of the oocyte in the IVF laboratory, especially in our setting in which ICSI is performed more frequently than IVF, even in the absence of a severe male factor infertility. Further studies are needed to explore in depth the mechanisms involved. Jose Bellver, M.D. Vicente Serra, M.D. Instituto Valenciano de Infertilidad, Universidad de Valencia, Valencia, Spain December 19, 2013 http://dx.doi.org/10.1016/j.fertnstert.2013.12.037

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Bellver J, Casanova C, Garrido N, Lara C, Remohí 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. Kagan KO, Wright D, Spencer K, Molina FS, Nikolaides KH. First trimester screening for trisomy 21 by free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A: impact of maternal and pregnancy characteristics. Ultrasound Obstet Gynecol 2008;31:493–502. Gjerris AC, Loft A, Pinborg A, Christiansen M, Tabor A. First-trimester screening markers are altered in pregnancies conceived after IVF/ICSI. Ultrasound Obstet Gynecol 2009;33:8–17.

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