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Advanced age: Implantation problems and miscarriages
Sesh Sunkara Guy’s and St Thomas’ NHS Trust, London
King’s College London
Background
• Embryo implantation is complex involving – Maturational events in the embryo
– Endometrium
– Maternal hormonal changes and immune responses
• IVF provides a unique opportunity in understanding factors influencing embryo implantation
Maternal age and miscarriage
• Danish prospective register linked study
• All women with reproductive outcome from 1978 – 1992
• 634 272 women with 1 221 546 pregnancy outcomes
Maternal age and fetal loss: population based register linkage study Anne-Marie Nybo Andersen, Jan Wohlfahrt, Peter Christens, Jorn Olsen, Mads Melbys RMJ Volume 320 24 JUNE 2000
Maternal age and miscarriage
Maternal age and miscarriage
Age and miscarriage following IVF
Outcomes of 124,351 pregnancies following IVF
Sunkara et al., ASRM 2012
Age 1 ≤34 years 2 35 – 37 years 3 38 – 39 years 4 40 – 42 years 5 43 – 44 years 6 ≥45 years
Miscarriage following ART
• Outcome of 62,228 clinical pregnancies following ART US between 1996 – 1998
• Spontaneous miscarriage rates following ART compared with miscarriage rates from a population-based survey of US women aged 15 – 44 years
Spontaneous Abortion Among Pregnancies Conceived Using Assisted Reproductive Technology in the United States
Laura A. Schieve, PhD, Lilith Tatham, DVM, MPH, Herbert B. Peterson, MD, MPH, James Toner, MD, Phd and Gary Jeng, PhD Vol. 101, NO.5, PART 1, MAY 2003
Miscarriage following ART
Patients oocytes
Donor oocytes
Schieve et al., AJOG 2000
Miscarriage following ART
Miscarriage rate over time
Sunkara et al., ASRM 2012
Cause of miscarriage
• Cytogenetic analysis of products of conception (POC) following spontaneous miscarriage
• 133 POC following ART and 144 from infertile couple following natural conception
Chromosomal abnormalities in miscarriages after different assisted reproduction procedures D. Bettio, A. Venci, P.E. Levi Setti Placenta, 29 (2008) S126-S128
Chromosomal abnormalities
NC natural conception
Chromosomal abnormalities as a major cause of miscarriage
Maternal age and aneuploidy
• 258 blastocysts from 51 cycles analysed after biopsy and microarray
• 43.4% euploid and 56.6% aneuploid embryos
• Aneuploid rates significantly higher in older women
– 44.2% (<35 years); 43.9% (35-37years); 56.4% (38-40 years); 82% (≥41 years)
DNA Microarray reveals that high proportions of human blastocysts from women of advanced maternal age are aneuploid and mosaic. Jianqiao Liu, Weihua Wang, Xiaofang Sun, Lian Liu, Man Li, Craig Witz, Dan Williams, Jason Griffith, Josh Skorupski, Gus Haddad and Jimmy Gill BIOLOGY OF REPRODUCTION (2012) 87 (6):148, 1-9
Maternal age and aneuploidy
Retrospective study of 353 miscarriages karyotyped and grouped according to number of miscarriages and maternal age
The effect of maternal age on chromosomalanomaly rate and spectrum in recurrent miscarriage Maribel Grande, Antoni Borrel, Raul Garcia-Posada, Virginia Borobio, Myriam Munoz, Montserrat Creus, Anna Soler, Aurora Sanchez, and Juan Balash Human Reproduction, Vol. 27, No. 10 pp.3109-3117, 2012
Mastenbroek et al., Hum Reprod Update 2011
LBR significantly lower in PGS group (18%) compared to controls (26%)
Role of PGS?
CCS for embryo assessment
Molecular Human Reproduction Vol.14, No.12 pp. 703-710, 2008 Advance Access publication on November 28, 2008
New Research Horizon Use of Comprehensive chromosomal screening for embryo assessment: microarrays and CGH Dagan Wells, Samer Alfarawati and Elpida Fragouli
CCS in advanced age
• Study group (n=30) frozen blastocyst transfer with euploid embryos tested by CCS
• Control group (n=30) fresh blastocyst transfer; embryos selected based on morphology – IR 40.9% vs 60.8% (p<0.05)
– Miscarriage rate 0% vs 20% (p<0.01)
Comprehensive chromosome screening (CCS) with vitrification results in improved clinical outcome in women > 35 years : randomized control trial W.B. Schoolcraft, E. Surrey, D. Minjarez, R.L. Gustofsonm R.T. Scott, Jr., M.G. Katz-Jaffe
Conclusion
Poor oocyte quality cause of reduced implantation
Chromosomal anomalies cause for increased miscarriages
Role of CCS using CGH need to be evaluated in larger RCTs
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