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FMR1 CGG trinucleotide repeat expansions are associated with Fragile X syndrome (full mutations) and primary ovarian insufficiency (premutation range); the effect of FMR1 on the success of fertility treatment is unclear. The effect of FMR1 CGG repeat lengths on IVF outcomes after ovarian stimulation was reviewed. PubMed was searched for studies on IVF-related outcomes reported by FMR1 trinucleotide repeat length published between 2002 and December 2017. For women with CGG repeats in the normal (<45 CGG), intermediate range (45–54 CGG), or both, research supports a minimal effect on IVF outcomes, including pregnancy rates; although one study reported lower oocyte yields after IVF stimulation in women with lower CGG repeat lengths and normal ovarian reserve. Meta-analysis revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates (summary OR 1.0, 95% CI 0.87 to 1.15). Premutation carriers (CGG 55–200) may have reduced success with IVF treatment (lower oocyte yield) than women with a normal CGG repeat length or a full mutation, although findings are inconsistent. Direct implications of the repeat length on inheritance and the risk of Fragile X syndrome have been observed. Patients may require clinical and psychological counselling, and further preimplantation genetic testing options should be considered. Thus, there are clinical and psychological counseling implications for patients and potential further patient decisions regarding preimplantation genetic testing options.
]) in children, and this is more common among sons than daughters. A full mutation (>200 CGG trinucleotide repeat in the FMR1 gene) leads to hypermethylation, suppression of FMR1 transcription and decreased FMR protein levels in the brain (
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.
Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study–preliminary data.
Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.
American Journal of Medical Genetics.1999; 84: 300-303
), alternatively termed primary ovarian insufficiency (POI). Research suggests that the risk of primary ovarian failure (POF) and POI may be highest for repeat sizes between 59 and 99, whereas, it declines within the range of 100–200 CGG repeats (
). The odds ratio for experiencing premature ovarian failure, which clinically presents as a cessation of menses before age 40 and postmenopausal gonadotropin levels, among women who carry the premutation was estimated to be 5.4 (95% CI 1.7-17.4) (
The question remains whether or not the FMR1 gene is associated with diminished ovarian reserve (separately from POI and POF) and, if it is, which repeat length confers the greatest risk. On the basis of the National ART Surveillance System guidelines and in the Federal Register Notice, diminished ovarian reserve (DOR) is diagnosed by abnormal ovarian reserve testing (elevated but not menopausal basal FSH levels >10 mIU/ml, failed clomiphene citrate challenge test, anti-Müllerian hormone <1.0 ng/ml or low antral follicle count) in women who have regular periods (
on behalf of the ESHRE working group on Poor Ovarian Response Definition ESHRE consensus on the definition of ‘poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.
), DOR differs from POI and POF. Some reports, using various case definitions and different comparison populations, have suggested an association between DOR or, more broadly, infertility. These include women with low normal CGG repeat lengths (often defined as ≤26 CGG) (
); a combination of high normal repeat lengths (often defined as 35–44 CGG repeats) and/or intermediate repeat lengths (about 45 to 54 CGG) and/or premutation repeat lengths (
Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study.
). Relatedly, many investigators have compared reproductive endocrine results, which are used to measure ovarian reserve, by FMR1 repeat length.
Further details on the FMR1 distribution in the general population and a review of existing population data from Asia, Europe and North America in the range of fewer than 45 CGG FMR1 repeat lengths have been published elsewhere (
The increase in expanded carrier screening and advances in reproductive endocrinology and infertility genetics has prompted our group to propose the research question: Is there an influence of FMR1 CGG repeat length on IVF outcomes after taking preparatory ovarian stimulation medication? One can argue, especially for premutation carriers, that FMR1 may influence IVF outcomes owing to a potentially lower baseline, (i.e., without medication) ovarian reserve, hence there is a theoretical basis for such research. The present review aims to synthesize reports on the effect, if any, of the FMR1 trinucleotide repeat length distribution on any IVF outcome after the ovarian stimulation process has started. Our clinical timeframe spans oocyte retrieval in the prospective mother to the end of pregnancy, if conception has occurred.
Materials and methods
Search strategy
This systematic literature review includes summary meta-analyses of published data. A structured approach to identifying and reviewing studies was taken. The PubMed database was searched for studies on IVF-related outcomes that were reported in detail by FMR1 trinucleotide repeat length. PubMed reports spanned from 1950 to December 2017; however, we chose to start the present search strategy from 2002 owing to changes in IVF technology over the past 15 years.
When searching PubMed, controlled vocabulary Medical Subject Headings (MeSH) were used. The search term strategy was as follows: • (FMR1 OR [fragile x] OR (CGG repeats) OR (Trinucleotide repeats/genetics* [MESH term]) OR (‘Fragile X syndrome/genetics’[Mesh]) OR ('Fragile X mental retardation protein’[Mesh]) OR [Fragile X syndrome]) AND • (Fertilization in vitro/trends* [Mesh term]) OR IVF OR (assisted reproductive technology [MeSH Terms]) OR (assisted reproduction).
The strategy above yielded 102 articles, of which 93 were available in English. Abstracts of all identified articles were reviewed for eligibility independently by two authors (LP and BM). Any discrepancies were resolved by discussion until consensus was achieved. Those publications immediately deemed eligible were read in their entirety for further eligibility review. Sixteen publications met our criteria.
Data collected from each article included study design and analysis methods, study sample characteristics, with special attention to FMR1 CGG repeat lengths and primary findings relevant to IVF. Selected article features were entered onto a spreadsheet and subsequently re-designed into its final form of tables for this manuscript. A forest plot (Review Manager 5.3,
) was created for outcomes within FMR1 strata when published details for graphing purposes and consistency in the reported CGG ranges and outcomes for meta-analysis purposes were sufficient. A summary odds ratio was calculated along with a test of the overall effect of the CGG repeat length on the outcome of interest.
Results
A review of published research on the FMR1 gene and its effect on IVF outcomes yielded 16 articles (
Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
). Eleven of the 12 reports that focused on the normal range of CGG repeats (some of which included intermediate size repeats) were from the USA (one of which was a collaboration with an Austrian research group [
). All four of the articles that primarily investigated premutation carriers, full mutation individuals, or both, were conducted in Israel.
Our observations, summarized below, and corresponding tables, are subdivided by the trinucleotide repeat range of interest in each publication.
FMR1 within the normal range (<45 CGG), intermediate range (45–54 CGG), or both, and IVF outcomes
The earliest research on IVF outcomes within the normal range of repeats, primarily published between 2008 and 2012, reported a potential association between either low normal or high normal CGG repeats and a less favourable IVF outcome (Table 1). Specifically, in 2009
reported that, among women aged younger than 38 years, fewer oocytes were retrieved from those with 35–54 CGG compared with women with 34 or fewer CGG (P = 0.006). Three subsequent studies (Table 1) identified low normal rather than high normal repeats as having poorer IVF outcomes (
) reported that having a low-normal repeat (<26 CGG; n = 94) is associated with a reduced chance of becoming pregnant with IVF compared with women with both alleles in the 26–34 CGG range (n = 183) after adjusting for maternal age (P < 0.02). Additionally,
found lower embryo quality (assessed by cleavage stage embryos and fragmentation) in women with fewer than 26 CGG (n = 48; 73 cycles) compared with women with 26–54 CGG (n = 77; 95 cycles) undergoing an IVF cycle (P < 0.03).
Table 1Studies reporting IVF outcomes in patients with FMR1 trinucleotide repeat lengths of fewer than 55 CGG
Normal and low: 41; high: 14 (sample size by age strata not reported).
In women younger than 38 years, those with fewer than 35 repeats produced significantly more oocytes than women with 35 repeats or more (P = 0.006). In women younger than 38 years, retrieved oocytes were inversely related to repeats, adjusted for gonadotrophin dosage (P = 0.03). No associations with FMR1 were observed in women over the age of 38 years.
Normal and normal: n = 183; normal and low: n = 94; normal and high: n = 62.
IVF pregnancy rates were significantly higher in women with both alleles 26–34 CGG (38.6%) than with one low normal allele (22.2%; P = 0.001), and this remained after maternal age adjustment (P < 0.02).
Normal and normal: n = 183 normal and low: n = 94 normal and high: n = 62
Women with one low normal allele were less likely to have a clinical pregnancy from IVF compared with women with 26–34 repeats (OR 0.44; 95% CI 0.23 to 0.85; P = 0.014); no difference was found for high normal repeats. FMR1 was no longer significant in a model that included age, BMI, race-ethnicity and AMH.
91 consecutive infertility patients with premature ovarian ageing, undergoing first IVF cycle
Normal and normal: n = 47; at least one allele less than 26 or greater than 34: n = 43.
Total androgen concentrations were not associated with pregnancy; however, in women with an allele <26 or >34 CGG, higher free testosterone significantly increased clinical pregnancy potential (P = 0.03).
Higher FSH per oocyte retrieved was associated with reduced chance of pregnancy in women with both alleles 26–34 CGG (P < 0.05), but not among women with normal and low or normal and high alleles.
217 first IVF cycles in women over the age of 40 years.
Normal and normal: n = 126; normal and low: n = 56; normal and high: n = 35
Overall, oocyte yield did not differ by FMR1 repeat length. Among those with poorer ovarian reserve (AMH <1.05 ng/ml), women with normal and high alleles had higher oocyte yields (5.0 ± 3.8) than those with normal and low alleles (3.1 ± 2.5; P = 0.03), confirmed after log conversion and age adjustment.
Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
Normal and normal: n =106; normal and low: n = 58; normal and high: n =38; low and low, low and high, and high and high: n = 11
Pregnancy rate did not differ by CGG repeat length (details not contained in the article).
Efficacy of androgen supplementation with DHEA varied depending on female age and FMR1 repeat length (P ≤ 0.02): normal and high women converted androgens significantly better than normal and low women.
Three sub-studies with varying sample sizes: n = 125 (168 cycles) in embryo morphology analysis; 149 cycles for aneuploidy analysis; n = 352 infertile patients (younger than age 38 years) versus n = 179 egg donor-recipient cycles in analysis of clinical pregnancy from IVF
Data shown for analysis of clinal pregnancy only; format is ‘donor cycle women, non-donor cycle women’); normal and normal: n = 90, n = 217; normal and low: n = 51, n = 63; normal and high: n = 17, n = 55; low and low: n = 5, n =10; low and high: n = 7, n = 4; high and high: n = 9, n =3
A low FMR1 allele (CGG < 26) is associated with significantly poorer clinical pregnancy chance (P = 0.015).
The aneuploidy rate did not differ by FMR1 repeats (as measured with PGS and FISH). A low FMR1 allele (CGG < 26) is associated with significantly poorer morphologic embryo quality (based on cleavage stage embryos, number arrested or % fragmented, P < 0.03)
Normal and normal: n = 1754; normal and low: n = 737; normal and high: n = 338; (‘high’ defined as 35–45 CGG); low and low: n = 89; low and high: n = 64; high and high: n = 24.
The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield (R2 < 0.002).
The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups.
Numbers are approximate from the article's Supplementary Figure 1, and the percentages and high/high count were reported in the text. AMH, anti-Müllerian hormone; BMI, body mass index; DHEA, dehydroepiandrosterone; DOR, diminished ovarian reserve; FISH, fluorescence in-situ hybridization; PGS, preimplantation genetic screening.
: n = 2500 (54%); normal and low: n = 1200 (25%); normal and high: n = 700 (14%); low and low: n =200; low and high: n = 200; high and high: n = 4.
Very weak association of FMR1 and oocyte yield (R2 ≤ 0.002).
The FMR1 repeat length was not associated with embryo quality (SART system, measured at cleavage and blastocyst stage) or live birth in adjusted models.
a Suggests that two premutation carriers were excluded from the analysis.
b Numbers are approximate from the article's Supplementary Figure 1, and the percentages and high/high count were reported in the text.AMH, anti-Müllerian hormone; BMI, body mass index; DHEA, dehydroepiandrosterone; DOR, diminished ovarian reserve; FISH, fluorescence in-situ hybridization; PGS, preimplantation genetic screening.
Between 2012 and 2013, several published studies included larger samples (between 200 and 550 women), which suggested overall that FMR1 repeat lengths were not directly associated with oocyte yield (
Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
). These are also presented in Table 1. For example, in a 2012 study of egg donors, those with high normal or intermediate repeat lengths (n = 63) had a similar oocyte yield and pregnancy success as, and required lower gonadotropin doses than, the comparison group of n=141 women with <35 CGG (
, however, examined a cohort of patients (n = 3006) all of whom had normal range CGG repeats and were undergoing their first IVF cycle. They reported no differences between low normal, high normal and 26–34 CGG repeat lengths in the number of mature oocytes retrieved after IVF stimulation, euploidy rates after comprehensive chromosomal screening, nor cycle cancellation owing to poor ovarian response (as defined elsewhere [
on behalf of the ESHRE working group on Poor Ovarian Response Definition ESHRE consensus on the definition of ‘poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.
, with 3290 patients (4690 IVF cycles in total), found no association between low normal repeat lengths (<26 CGG) compared with 26–34 CGG repeats and with high normal and intermediate repeats (35–54 CGG) in embryo quality or IVF live birth rate. Embryo quality was measured at both the cleavage and blastocyst stage by the simplified SART system (
, however, reported an unadjusted association between a lower oocyte yield with lower FMR1 repeats (P = 0.02) for the shorter allele and P = 0.04 for the longer allele, which corresponded to one additional oocyte retrieved for every increase of 14 to 20 FMR1 CGG repeats. In adjusted generalized estimating equation models, linear regression models and receiver operating curves, the effect of the FMR1 repeat length was far less than the effect of anti-Müllerian hormone (AMH) and antral follicle count (AFC). Those investigators further disclosed that the unadjusted association between the FMR1 repeat length and lower oocyte yield may be an assessment of the biologic function of FMR1. Although both these studies would not have included patients who used donor eggs,
presented data adjusted for age, AMH, AFC and FSH.
Meta-analysis revealed no association between repeat length within the normal range and pregnancy outcomes (Figure 1). Current research indicates no association of FMR1 repeat length with pregnancy rates when women with 26–35 CGG repeat lengths are compared with the low normal and high normal repeat groups (summary odds ratio 1.0, 95% CI 0.87 to 1.15). The test of overall effect supports no association with pregnancy rates (P = 1.0). Without the large report by
, the summary odds ratio still indicates no association (OR 0.80, 95% CI 0.63 to 1.03), although the test of overall effect would be considered borderline (P = 0.08; data not shown).
Figure 1Research on successful IVF (measured by pregnancy rates) for women with low normal and high normal relative to normal FMR1 CGG repeat length.
FMR1 in the premutation (about 55 to 200 CGG), full mutation ranges (>200 CGG), or both, and IVF outcomes
In general, reports suggest that premutation carriers may have reduced success with IVF treatment as measured by a lower oocyte yield than women with either a normal CGG repeat or a full mutation, although findings are inconsistent (Table 2).
were the first to suggest that lower CGG repeat lengths within the premutation range might be related to fewer oocytes after IVF stimulation and greater dose of gonadotrophin needed for adequate ovulatory response, although the sample size was small (18 women all within the premutation range).
found no difference in the pregnancy rate (>12 weeks of gestation), live birth rate or oocyte yield between premutation (n = 22), full mutation (n = 5) (total cycles 79) and controls (<40 CGG; n = 33; 108 cycles).
expanded the analysis on this topic by investigating the potential effect of the specific CGG repeat length within the premutation range, and by exploring granulosa cells. The number of oocytes retrieved in each IVF cycle was lower, and the corresponding gonadotrophin dose needed was higher in premutation carriers (n = 25, most especially for 80–120 CGG) than women with normal or intermediate range repeats (n = 15) (
). Further analysis within the premutation range, in addition to a separate evaluation of IVF parameters among women with a full mutation, was reported by
. They found premutation carriers (n = 51) had fewer oocytes retrieved after IVF stimulation than full mutation carriers (n = 21; P = 0.005); Full mutation carriers had a normal response to IVF stimulation, and three modelling techniques did not identify any significant relationship between any IVF outcome assessed and the exact CGG repeats within the premutation range.
Table 2Studies reporting IVF outcomes in patients with FMR1 trinucleotide repeat lengths in the premutation (about 55 to 200 CGG), full mutation ranges (>200 CGG), or both
Oocytes retrieved, number of two-pronuclear zygotes, dose of gonadotrophins.
Positive correlation found between number of CGG repeats and number of retrieved oocytes (P = 0.007) and two-pronuclear zygotes (P = 0.009), and an inverse correlation with the dose of gonadotrophins (P < 0.0001), all adjusted for maternal age.
<55 repeats: n =15 with male infertility factor (age matched to cases); 55–200 repeats: n = 21.
Oocytes retrieved, pregnancy rate from IVF .
Premutation carriers had fewer retrieved oocytes compared with those with <55 repeats and required a greater gonadotrophin dose (P = 0.04). In FMR1 premutation carriers, a significant non-linear association was found between the number of CGG repeats and the number of retrieved oocytes (P < 0.0001). The fewest retrieved oocytes were seen in women with mid-size CGG repeats (80–120). A significant negative linear correlation was observed between the granulosa cells FMR1 mRNA levels and the number of retrieved oocytes (R square linear = 0.231; P = 0.02).
60–200 repeats: n = 22; 300–2000 repeats: n = 5; 640 repeats (control, carried either a maternal autosomal or X-linked disease): n = 33.
Pregnancy rate, live birth rate, gonadotrophin dose; oocytes retrieved.
Patients with Fragile X syndrome (premutations and full mutations + full mutations) required higher doses of gonadotrophins (P < 0.001) but had lower peak serum oestradiol levels (P = 0.03) and fewer oocytes retrieved (P = 0.01). The cancellation rate (unsatisfactory ovarian response) was higher in the Fragile X syndrome group than in the control group (13 versus 1%; P < 0.001). When embryos were transferred, ongoing pregnancy and live birth rates per transfer were similar (29 versus 36%; P = 0.54).
Premutation carriers had fewer oocytes retrieved after IVF stimulation than full mutation (P = 0.005). Full mutation carriers had a normal response to IVF stimulation. Gonadotrophin dose required was not significantly different between premutation and full mutation (P = 0.10). Modelling of the exact CGG repeats within the premutation range did not identify any significant relationship with oocyte yield, fertilization rate, cleavage rate or embryo quality (as measured by rate of biopsy for PGD). No significant difference in fertilization rate was found between premutation carriers and full mutation carriers. No correlation was found between the number of repeats in the premutation carriers and the number of oocytes retrieved, oestradiol levels or fertilization rate.
This review includes reports on IVF outcomes across the entire trinucleotide range. Most studies, however, focused on the normal genotype (<45 CGG) with or without inclusion of the intermediate zone (45–54 CGG). Early research on IVF within the normal FMR1 trinucleotide range suggested poorer outcomes among women with a low normal repeat (<26 CGG), but more recently in 2016, two large studies each with more than 3000 participants reported fewer differences between low normal, high normal (35–44 CGG) and 26–34 CGG repeat lengths in various IVF outcomes (
). No association between the FMR1 repeat length and pregnancy rates was found overall, whereas, the results are inconsistent between the two largest studies (
). Older age influences multiple reproductive outcomes and has an interactive effect with FMR1 through an increased rate of expansion from premutations to full mutations to the offspring with increasing maternal age (
). Therefore, it could be argued that the egg donor findings should be age-adjusted.
In three out of four studies, it was suggested that premutation carriers may have reduced success (oocyte yield, pregnancy rate and live birth rate) with IVF treatment compared with women with either a normal CGG repeat or a full mutation (
). Future studies that provide additional data will be beneficial in helping counsel patients with premutations before moving forward with ovarian stimulation for IVF. Because commercially available expanded carrier screening panels are becoming more widespread in use, providers now encounter more scenarios in which an infertility patient planning IVF has an incidental finding of a FMR1 premutation or intermediate range allele.
Our review mainly encompasses studies from the USA, Israel, Spain and Austria. As of 2015, the mean age of childbearing in the USA is 28.4 years compared with 31.6 years in Spain, and 30.4 years in Israel and Austria (
). This difference in childbearing age also translates to higher age during assisted reproductive technology cycles, with European registries reporting that 49.1% of all IVF and intracytoplasmic sperm injection cycles initiated in Spain are in women between the ages of 35 and 39 years, whereas, in the USA, that percentage is lower at 40.4% for ages 35–40 years (
). Israel has yet to establish a national registry of assisted reproductive technology outcomes; however, data from their second largest fertility centre reports that about 28% of women undergoing IVF are aged between 35 and 39 years (
). This variability in IVF patient ages may influence the direct comparability between some of the studies in this review given the maternal age and FMR1 interactive effect on repeat expansion risk previously mentioned (
The FMR1 gene is inherited in an X-linked dominant fashion; female carriers transmit it to 50% of their offspring, whereas males transmit the premutation to all of their daughters and none of their sons. For all clinical scenarios in which women are found to have the Fragile X intermediate zone, premutation or full mutation, genetic counselling is recommended to help calculate the risk of having offspring with the full expansion resulting in Fragile X syndrome (
). Through genetic testing of embryos, preimplantation genetic testing for monogenic/single gene defects (PGT-M) provides parents with embryo-specific information on whether it is not affected (<55 CGG), a carrier of the premutation or affected with the full mutation. Genetic testing companies vary in the level of detail on CGG repeat length and whether AGG interruptions data are also provided, and such differences will continue to alter and evolve over time in response to provider–patient expectations and technological advances. Prospective patients can also consider using preimplantation genetic screening (chromosomal test) to identify and select a female embryo for IVF embryo transfer, given the milder phenotype in most of the females with a full mutation. Young women with the premutation and a family history of Fragile X syndrome should undergo ovarian reserve testing and consider moving forward with fertility preservation, such as oocyte cryopreservation, if they have decreased ovarian reserve for their age or if they are not ready to proceed with IVF and immediate family building.
The stability of the CGG repeat length when transmitted to the next generation is further dependent on the presence of AGG trinucleotide interruptions within the allele. Interrupting AGG trinucleotides, which typically occur once between a sequence of nine to 10 CGG repeats, were first described in the early 1990s (
developed a model that mapped the risk of expansion to a full mutation based on three factors (longer total repeat length, fewer AGG interruptions, older age), each of which increased the risk of expansion to a full mutation. All alleles greater than 110 CGG expanded to a full mutation, and the full mutation risk was unrelated to ethnicity (
). Recent articles on AGG interruptions potentially have genetic testing and genetic counselling inheritance implications. It can benefit a person with an intermediate or premutation CGG repeat length between 45/50–90 to be assessed for AGG interrupters, because having one, two or three AGG interrupters reduces the risk of instability (either expansion or contraction) in the next generation. On a practical note, however, the AGG test is not readily available (only one test manufacturer), although some preimplantation genetic testing labs now include that test option, will incur an additional cost and may not be covered by insurance, and may further delay IVF treatment or natural conception attempts. It is also complicated for clinicians and counsellors to discuss the concept of a protective effect of AGG with patients in terms of inheritance over and above the complication of the inheritance implications of patients’ allelic CGG repeat lengths.
For individual patients considering preimplantation genetic testing (PGT), multiple pros and cons should be considered, which include financial and emotional costs. A recent review on actual (as opposed to hypothetical) PGT-M patient decision-making (
) highlighted five themes. Although the themes reported thus far are likely seen within the patient population considering the use of PGT-M for FMR1 embryo testing, little research on patient PGT-M decision-making focusing specifically on FMR1 testing has been published.
reported their experience with PGT for FMR1 among 14 patients (excluding four patients with premature ovarian failure and either a premutation or full mutation repeat). In a total of 47 PGT cycles (mean 3.4 preimplantation genetic diagnosis cycles per couple, day-3 biopsies), 4% of the embryos had various sex chromosome abnormalities, and one-half of the remaining embryos were not affected with either the premutation or full mutation allele. Seven clinical pregnancies from unaffected embryos resulted from 39 of the 46 PGT cycles. Although this sample size is small, such data can be informative for patients and clinicians in setting realistic expectations of IVF cycle results for those using PGT for FMR1 risk management. In a recent report (
), 37 out of 175 (21%) pregnant women at high risk of passing on a FMR1 full mutation in Israel opted for IVF with PGT-M. The key predictors for selecting IVF with PGT-M were previous termination for an affected fetus and an advanced maternal age, whereas women with a history of IVF failure were more likely to choose to conceive naturally and to use prenatal genetic diagnosis testing (
). Further research is needed in this area. For discussion of FMR1-specific reproductive decision-making unrestricted to PGT, the reader is referred to the research of
on women without a family history of Fragile X syndrome undergoing FMR1 testing in reproductive, endocrinology and infertility clinics.
To the best of our knowledge, this is the first review on the relationship between the FMR1 gene and IVF outcomes. These reports suggest that women who carry the FMR1 premutation should be informed that they may have reduced success with IVF, e.g. fewer retrieved oocytes after ovulatory stimulation regimens, whereas it does not seem to have any detrimental effect on IVF outcomes associated with FMR1 repeat lengths fewer than 55 CGG or more than 200 CGG. A possible exception is that fewer oocytes are retrieved with fewer CGG lengths, albeit the effect of FMR1 seems to be secondary to the larger effect from AMH levels and antral follicle count (
). With the growing existence of clinical databases of thousands of patients with some genotype detail and some IVF outcomes, it is possible now to analyse potential associations with greater efficiency than previously possible. A limitation of large retrospective database analyses is that patients in large IVF centres may be selected to have normal ovarian reserve and, therefore, patients who have decreased ovarian reserve may be under-represented.
Areas for future research include outcomes that are not readily captured in such databases, e.g. patient decision-making considerations, or that have been rarely reported, e.g. few articles reported miscarriage or live birth rates or PGT-M outcomes; research that includes individuals who are not patients of fertility clinics, e.g. families with Fragile X syndrome who are not seeking medical intervention for reproduction; research that includes all patients seeking fertility treatment before IVF to further characterize the FMR1 gene's biologic effect on ovarian reserve; and genetic counselling tools or approaches that reduce the counselling complexity, e.g. tools to increase patient understanding or to assist practitioners to counsel patients on the health effects from their FMR1 genotype.
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Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study–preliminary data.
Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study.
Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.
American Journal of Medical Genetics.1999; 84: 300-303
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.
Lisa Pastore is an Associate Professor at the Department of Obstetrics and Gynecology at Stony Brook University, New York, USA. She was awarded four National Institutes of Health grants, three of which investigated FMR1 and diminished ovarian reserve. Her masters and doctoral degrees (epidemiology) are from the University of North Carolina at Chapel Hill. Her research spans female infertility, genetics, genetic counselling and psychology.
Key message
Published research suggests that women who carry the FMR1 premutation (about 55 to 200 CGG) may have reduced success with IVF, e.g. fewer retrieved oocytes after ovulatory stimulation regimens. A meta-analysis has revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates.
Article info
Publication history
Published online: December 10, 2018
Accepted:
November 29,
2018
Received in revised form:
August 13,
2018
Received:
March 19,
2018
Declaration: The authors report no financial or commercial conflicts of interest.
Lisa Pastore is an Associate Professor at the Department of Obstetrics and Gynecology at Stony Brook University, New York, USA. She was awarded four National Institutes of Health grants, three of which investigated FMR1 and diminished ovarian reserve. Her masters and doctoral degrees (epidemiology) are from the University of North Carolina at Chapel Hill. Her research spans female infertility, genetics, genetic counselling and psychology.
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