Getting Older Women Pregnant Contemporary Thought

Authors: Gautam N Allahbadia

Publish Date: 2015/11/13

Volume: 66, Issue: 5, Pages: 305-309

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Abstract

For women of advanced age with abnormally increased FSH levels standardized hormonal stimulation often represents a costintensive procedure with a low success rate It is well established now that with mild ovarian stimulation there is a greater percentage of goodquality eggs although a smaller number than with higherdose conventional stimulation Mild stimulation protocols reduce the mean number of days of stimulation the total amount of gonadotropins used and the mean number of oocytes retrieved The proportion of highquality and euploid embryos seems to be higher compared with conventional stimulation protocols and the pregnancy rate per embryo transfer is comparable Moreover the reduced costs the better tolerability for patients and the less time needed to complete an IVF cycle make mild approaches clinically and costeffective over a given period of time The low number of embryos available for transfer poses a great challenge in the management of older women going in for IVF A potential management of these older women is to create a sufficient pool of embryos by accumulating vitrified goodgrade embryos over several minimal stimulation and natural cycles At the end of the accumulation process these embryos can be subjected to a preimplantation genetic screening using nextgeneration sequencing and then the pool would have only chromosomal normal embryos with maximal chances of implantation This would potentially make the chances of success for older women similar to normal responders This management however is unthinkable without an outstanding vitrification program The option of accumulating embryos has become a promising reality with the advent of vitrification technologiesGautam N Allahbadia is the EditorinChief of the Journal of Obstetrics Gynecology of India as well as the IVF Lite Journal of Minimal Stimulation IVF and Medical Director of RotundaThe Center for Human Reproduction Bandra and RotundaBlue Fertility Clinic and Keyhole Surgery Center Parel Mumbai IndiaIglesias et al 1 investigated differences in ovarian reserve markers antimüllerian hormone AMH and antral follicle count AFC in Indian and Spanish women The mean age of women undergoing their first or second IVF cycle was significantly higher in Spanish than in Indian women 375 ± 33 vs 315 ± 38 years Despite this 6year age gap AFCs were similar 95 ± 47 vs 99 ± 46 as were day3 FSH levels 75 ± 45 vs 69 ± 23 IU/L AMH levels were slightly lower in Spanish women 16 ± 17 vs 25 ± 16 ng/mL Multivariate regression analysis showed that being Indian decreased AFC by 23 such that AFC in Indian women was similar to that in Spanish women 63 years older 95  CI 339–110 Similar ovarian reserve markers and ovarian response were observed in women with a 6year age difference in favor of the Spanish suggesting ethnic differences in ovarian aging Further research is needed to understand whether these differences are genetically induced or are caused by other variables such as nutrition 1 The number of women attempting to conceive between the ages of 36 and 44 has increased significantly in the last decade While it is well established that women’s reproductive success dramatically declines with age the underlying physiological changes responsible for this phenomenon are not well understood With assisted reproductive technologies it is clear that oocyte quality is a likely cause since women over 40 undergoing in vitro fertilization IVF with oocytes donated by younger women have success rates comparable to young patients Till a few years ago apart from oocyte donation there was no known intervention to improve the pregnancy outcome of older patients Today with the widespread use of the IVF Lite protocol 2 3 4 and the advent of nextgeneration sequencing NGS technology to screen embryos 5 6 we have pregnancy rates that have almost doubled in older women from a decade backGoldman et al 7 set up a randomized clinical trial to determine the optimal infertility therapy for women at the end of their reproductive potential The study included couples with ≥6 months of unexplained infertility female partner aged 38–42 years who were randomized to treatment with two cycles of clomiphene citrate CC and intrauterine insemination IUI follicle stimulating hormone FSH/IUI or immediate IVF followed by IVF if not pregnant They randomized 154 couples to receive CC/IUI N = 51 FSH/IUI N = 52 or immediate IVF N = 51 140 909  couples initiated treatment The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI FSH/IUI or immediate IVF were 216 173 and 490  respectively After all treatments 110 714  of 154 couples had conceived a clinically recognized pregnancy and 461  had delivered at least one liveborn baby 842  of all liveborn infants resulting from treatment were achieved via IVF There were 36  fewer treatment cycles in the IVF arm compared with either COH/IUI arm and the couples conceived leading to a live birth after fewer treatment cycles This randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF 7 Success rates for women aged 40 or over with clomiphene IUI IUI with FSH are all extremely low at 1  live birth per cycle However IVF offers a success rate of around 137  per cycle Attempting treatments other than IVF will delay conception unnecessarily 8In many IVF centers it is a common practice to consider the day3 FSH value as an end marker for the patient selection procedure Most centers hold a day3 FSH value of 10–15 IU/L as the upper limit to decide whether to provide IVF treatment or not since one of the largescale studies evaluated a day3 FSH 15 IU/L and demonstrated a decrease in pregnancy rate 9 Many patients having high day3 FSH are denied IVF treatment quoting reduced ovarian reserve and low success rate and pushed toward donor egg IVF The high baseline FSH concentration that is usually observed with older women due to lower ovarian reserve simply indicates the need for an IVF Lite protocol with no downregulation and banking of embryos with backtoback mild stimulation alternating with natural IVF cycles In Zhang’s series patients were not denied treatment based on their day3 FSH value or ovarian reserve 10 Yet very acceptable pregnancy rates were achieved 20  for fresh embryo transfers ETs and 41  for cryopreserved ETs These results strengthen the argument for an IVF Lite protocol 2 3 4 11 12 as an alternative to standard conventional IVF stimulation protocolsIn the era before vitrification Weghofer et al 13 reported on 84 IVF cycles using minimal ovarian stimulation and 85 cycles with a standard longstimulation protocol in women aged 40 and above who had slightly increased FSH levels Minimal stimulation cycles resulted in a clinical pregnancy rate of 82  per started cycle and 10  per ET whereas the control group yielded a clinical pregnancy rate of 106  per started cycle and of 107  per ET not statistically significant In women aged 40 and above with abnormal FSH levels minimal stimulation protocol achieves similar pregnancy rates to a standard protocol and thus represents a costeffective alternative 13A retrospective cohort study was performed in private infertility center to evaluate the embryological and clinical results of a large exclusive SET program according to patient age lower or equal 29 30–34 35–39 40–44 and equal to or higher than 45 years 14 A total of 7244 infertile patients underwent 20244 cycles with a clomiphenebased minimal stimulation or naturalcycle IVF protocol during 2008 Following oocyte retrieval fertilization and embryo culture a total of 10401 fresh or frozen singleET procedures were performed involving cleavagestage embryos or blastocysts Successful oocyte retrieval rate 780  showed no agedependent decrease until 45 years Fertilization 803  and cleavage 911  rates were not significantly different between age groups Blastocyst formation 701–228  and overall live birth rates LBR 359–2  showed an agedependent decrease Vitrified frozenthawed blastocyst transfer BT cycles gave the highest chance of live birth per ET 413–61  High fertilization and cleavage rates were obtained regardless of age whereas blastocyst formation and LBR showed an agedependent decrease An elective singleET program based on a minimal ovarian stimulation protocol yielded acceptable LBR per ET in infertile patients up until their mid40s 14 However in very advanced age patients equal to or higher than 45 years old success rates fall below 1 IVF–ET with intracytoplasmic sperm injection ICSI was performed for a 45yearold woman with a peak serum FSH level of 29 mIU/mL and a history of failing to conceive in five previous IVF–ET cycles at a younger age A minimal FSH stimulation protocol was used 15 A fresh transfer of a sevencell embryo was performed on day 3 A successful pregnancy and delivery ensued This case report establishes a precedent that a successful pregnancy following IVF–ET is possible in a woman whose serum FSH is 15 mIU/mL and age is 45 Of course there is no implication that accomplishing this again in another woman with similar circumstances would be likely 15

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