In this retrospective study, the utility of preimplantation genetic screening (PGS) in patients with advanced maternal age is evaluated. The patient population consisted of women aged 38–44years and included in a regular IVF programme with or without PGS analysis. Transfer rate, ongoing implantation rate and ongoing pregnancy rate were the main outcome parameters measured. A trend of better ongoing pregnancy rate per oocyte retrieval was observed in patients aged 38 and 39 years in the non-PGS group when compared with PGS groups, but better ongoing pregnancy rate per oocyte retrieval was observed in patients 41–44 years old in the PGS group. When patients with a low ovarian response accumulated oocytes in several stimulation cycles, clinical outcomes were comparable to those of normal-responder patients. These results show that, although PGS does not benefit patients less than 40 years of age, reproductive success increases more than two-fold in patients over 40 years, especially in patients with more than six metaphase II oocytes, as a result of a good ovarian response or gamete accumulation, suggesting a redefinition of advanced maternal age as indication for PGS.
In this retrospective study, the utility of preimplantation genetic screening (PGS) in patients with advanced maternal age is evaluated. Patient population consisted of women aged 38–44 years and included in a regular IVF programme with or without PGS analysis. Transfer rate, ongoing implantation rate and ongoing pregnancy rate were the main outcome parameters measured. A trend of better ongoing pregnancy rate per ovarian stimulation cycle was observed in patients aged 38–39 years in the non-PGS group when compared with PGS groups, but better ongoing implantation rate was observed in patients aged 41–44 years old in the PGS group. When patients with a low ovarian response (low number of oocytes available for the IVF cycle) accumulated oocytes in several stimulation cycles, their reproductive possibilities were comparable to those of normal-responder patients. These results show that, although PGS does not benefit patients less than 40 years of age, reproductive success increases more than 2-fold in patients over 40 years, especially in patients with more than six metaphase II oocytes, as a result of a good ovarian response or gamete accumulation, suggesting a redefinition of advanced maternal age as indication for PGS.
Introduction
Lifestyle changes now cause many women to delay motherhood until their thirties, when they are more psychologically and economically stable (Benzies et al., 2006, te Velde and Pearson, 2002). This new reproductive trend directly affects assisted reproduction centres, as most women erroneously believe that IVF can reverse the effects of ageing (Maheshwari et al., 2008). For example, a significant increase in advanced maternal age (AMA) patients attending the study clinic in recent years has been found compared with the years prior to 1995, shifting the mean age of patients from approximately 34 years to approximately 37 years.
Preimplantation genetic diagnosis (PGD) was initially developed as an option to conceive healthy children in couples with genetic disorders or with sex chromosome syndromes. The use of fluorescence in-situ hybridization (FISH) in PGD made the analysis of aneuploidies in embryos by preimplantation genetic screening (PGS) possible and, currently, the screening of aneuploidies by PGS covers a large number of patients visiting infertility centres all over the world. The inclusion of many of these patients under indications such as AMA, implantation failure and recurrent miscarriage is based on the high percentage of abortions cytogenetically studied from idiopathic miscarriages with chromosomal imbalances. Importantly, most of the embryos from patients with AMA, recurrent miscarriage and implantation failure are aneuploid (Baart et al., 2006, Bettio et al., 2008, Ferro et al., 2003, Findikli et al., 2006, Lathi et al., 2008, Munne et al., 2004, Munne et al., 2006, Pehlivan et al., 2003a, Pehlivan et al., 2003b, Rai and Regan, 2006, Rubio et al., 2005a, Stephenson et al., 2002, Wilding et al., 2004). These results gave rise to the logical but not sufficiently supported hypothesis that the selection of euploid embryos for a selected set of chromosomes (representative of the most common aneuploidies found in miscarriages) would increase reproductive success while reducing the number of aneuploid conceptions and subsequent miscarriages or terminations of pregnancy. Several retrospective studies in support of this hypothesis describe the selection of euploid embryos as producing, in most of them, clinical benefits (Colls et al., 2007, Garrisi et al., 2009, Grifo et al., 2007, Gianaroli et al., 1999, Gianaroli et al., 2005, Gianaroli et al., 2003, Montag et al., 2004, Munne et al., 2006, Munne et al., 1999, Munne et al., 2003, Obasaju et al., 2001, Pehlivan et al., 2003b, Platteau et al., 2005, Rubio et al., 2005b).
In patients with AMA, the availability of transferable embryos is affected by the low quantity and quality of oocytes retrieved after ovarian stimulation, which is closely related to the ovarian reserve (Broekmans et al., 2007). This problem is magnified in the case of patients included in PGS, where only those embryos that are properly developed and diagnosed as chromosomally normal are candidates for embryo transfer. Advances in technology, as well as new therapies for fertility preservation such as oocyte and embryo vitrification (Kuwayama, 2007, Cobo et al., 2008a, Cobo et al., 2008b, Cobo et al., 2008c) create promising new possibilities for those patients with reduced ovarian reserve, allowing them to reserve gametes for a fertility treatment with a higher number of oocytes.
The present study analysed the utility of PGS in patients with AMA considering both female age (in a year-by-year fashion) and the ovarian response. This approach has allowed us to observe trends for different clinical parameters according to the age of patients and the number of metaphase II (MII) oocytes retrieved, revealing a new subgroup of patients in which PGS provides the best reproductive option with one’s own gametes.
Section snippets
Study design
This retrospective study selected patients included in the study centre’s PGS programme with AMA as main medical indication ranging from 38–44 years and a normal karyotype. A written consent was compulsory to be included in the PGS programme. All patients within the same age range and attending the centre for regular IVF treatment without PGS or PGD within the same period of time were considered as the historical control group (non-PGS group). In the first part of this study, only cycles with
Results
This retrospective study have reviewed clinical outcomes for a total of 2253 IVF cycles (1848 patients) performed between January 2003 and May 2009. The study group included 1117 cycles (corresponding to 919 patients) in which PGS was performed on day 3. The non-PGS group comprised 1136 IVF cycles (corresponding to 929 patients). The infertility profile of all patients is shown in Table 1. Results were separated according to patient age at the time of treatment: (i) 38 years: 109 cycles (96
Discussion
During the last 2 years, several randomized controlled trials (RCT) have been conducted to analyse the effect of PGS on clinical outcome for poor prognosis IVF patients, including AMA. Studies vary widely in age of target population, as well as in technical approaches. This methodological variability precludes drawing clear conclusions about the utility of PGS and, most importantly, does not identify patient subpopulations that benefit most by being included in a well-established PGS programme.
Acknowledgements
The authors wish to thank the clinicians, IVF, Cryobiology and PGD embryologist and technicians of the IVI clinics for their co-operation in the development of the PGD programme. They are very grateful to Dr Marcos Messeguer and Dr Nicolás Garrido for statistical support.
Dr Miguel Milán graduated in science at the University of Valencia in 1999. He completed his PhD in Cell and Molecular Biology at the University of Valencia and in 2007 joined the Preimplantation Genetic Diagnosis Unit at the Instituto Universitario-IVI in Valencia. His current research interests are preimplantation genetic diagnosis for chromosomal abnormalities and chromatin structure.
