|Year : 2018 | Volume
| Issue : 1 | Page : 30-37
Outcome of Couples with Reciprocal Translocation Carrier Undergoing the First Preimplantation Genetic Testing Cycles
Cai-Xia Lei1, Shuo Zhang1, Hai-Yan Sun1, Sai-Juan Zhu1, Jing Zhou1, Jing Fu1, Yi-Juan Sun1, Jun-Ping Wu1, Yue-Ping Zhang1, Xiao-Xi Sun2
1 Department of Genetics and IVF, Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
2 Department of Female Reproductive Endocrine Related Diseases, Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
|Date of Submission||23-Jan-2018|
|Date of Web Publication||21-May-2018|
588 Fangxie Road, Shanghai
Source of Support: None, Conflict of Interest: None
Background: Reciprocal translocation (RCP) causes male infertility and female recurrent pregnancy loss. Male and female carriers have different responses to meiotic disturbances. Gender difference in outcomes of the RCP couples undergoing preimplantation genetic testing (PGT) is unknown.
Methods: We conducted a retrospective analysis of 238 RCP couples (124 female and 114 male carriers) divided by gender of carrier from March 2014 to March 2017. Blastocysts were divided by day 5 and day 6. Females were divided into older (≥38 years) and younger (<38 years). Logistic regression was fitted for the relationship between gender of carriers and euploidy. Euploidy rate of each group, pregnancy rate, and live birth rate between different genders were analyzed.
Results: The sperm live rate, forward motile sperm rate, and normal morphology rate of serum in male RCP group were significantly decreased. The euploidy rate was 30.30% in female group and 34.90% in male group (P = 0.131); 34.50% in day 5 group and 27.50% in day 6 group (P = 0.039); 33.40% in age <38 years group and 22.40% in age ≥38 years group (P = 0.063). Day 5 (odds ratio [OR] = 1.388, 95% confidence interval [CI] = 1.012–1.904; P = 0.042) and younger age (OR = 1.753, 95% CI = 0.97–3.17; P = 0.063) were associated with euploidy. The clinical pregnancy rate (37.90% vs. 41.20%), ongoing pregnancy rate (33.10% vs. 37.70%), and live birth rate (25.80% vs. 31.60%) per initiated were not significantly different in two gender groups.
Conclusions: Although gender influence is not significant, couples with male carrier showed better clinical outcomes. The embryo growing rate and female age are important predictions estimating euploidy in RCP couples.
Keywords: In Vitro Fertilization; Intracytoplasmic Sperm Injection; Preimplantation Genetic Diagnosis; Preimplantation Genetic Screening; Preimplantation Genetic Testing-Aneuploidy; Single-Nucleotide Polymorphism
|How to cite this article:|
Lei CX, Zhang S, Sun HY, Zhu SJ, Zhou J, Fu J, Sun YJ, Wu JP, Zhang YP, Sun XX. Outcome of Couples with Reciprocal Translocation Carrier Undergoing the First Preimplantation Genetic Testing Cycles. Reprod Dev Med 2018;2:30-7
|How to cite this URL:|
Lei CX, Zhang S, Sun HY, Zhu SJ, Zhou J, Fu J, Sun YJ, Wu JP, Zhang YP, Sun XX. Outcome of Couples with Reciprocal Translocation Carrier Undergoing the First Preimplantation Genetic Testing Cycles. Reprod Dev Med [serial online] 2018 [cited 2021 Apr 14];2:30-7. Available from: https://www.repdevmed.org/text.asp?2018/2/1/30/232873
| Introduction|| |
Reciprocal translocation (RCP) is a class of common chromosome abnormality with the prevalence of 0.69%–5.96% in couples with recurrent pregnancy loss (RPL). During meiosis, a quadrivalent structure is formed to enable homologous chromosomes to pair which is prone to produce genetically unbalanced gametes as a result of abnormal segregation of the derivative chromosomes in RCP carriers. Males and females show very different responses to meiotic disturbances. In spermatogenesis, meiosis is generally arrested, and apoptosis ensues that may cause male factor infertility. During oogenesis, meiosis is generally not halted and may continue to form abnormal oocytes causing RPL  or primary ovarian insufficiency. RPL is an apparent trait of reduced fecundity which could be seen in RCP carriers of either sex, and aneuploidy is the leading cause. However, women experience that RPL might have other risk factors such as decreased endometrial receptivity  and aberrant maternal-fetal immune tolerance; the effects of preimplantation genetic testing-aneuploidy (PGT-A, also known in the literature as preimplantation genetic diagnosis [PGD] for aneuploidy screening) in these patients are controversial. Whether the euploidy rate of embryos, the pregnancy rate, and live birth rate in in vitro fertilization (IVF) cycles are differed in gender of RCP carriers is unknown. Many technologies including single-nucleotide polymorphism microarray (aSNP), comparative genomic hybridization microarray, and next-generation sequencing (NGS) are used for PGT. Among these, aSNP has a great advantage in detecting polyploidy  and uniparental diploidy (UPD) and has been used to improve the clinical outcomes.
The development rate of the embryo is a key predictor of the implantation potential during IVF. It is reported that day-5 and day-6 embryos show a similar aneuploidy rate in infertile patients of advanced maternal age. However, it is not clear if the growth rate of embryos of RCP couples are related with euploidy. The meiotic segregation pattern of quadrivalents may have significant effect than meiotic error in older age patients (≥38 years) targeted by PGT-A. It is hard to distinguish aged women with high frequency of aneuploidy in the population and age should not be the only prediction. The fourth session of the committee of Chinese Society of Reproductive Medicine has published a guideline for NGS-based PGD/PGS and suggested that women aged >38 years should be considered as advanced age and suitable for PGT-A.
In this study, our goal is to analyze the clinical outcome of the RCP couples and the influence of carrier gender, maternal age, and embryo growth rate on euploidy. The data are very helpful in the counseling of RCP couples who wish to pursue PGT-A in order to conceive babies using their own gametes.
| Methods|| |
The RCP couples recruited in this study should meet the following criterions: (1) the RCP couple was the first time to experience PGT in the IVF center; (2) only the first PGT cycle data were collected; (3) all embryos were frozen–thawed transferred (FET); and (4) the couple in the PGT cycle produced at least one blastocyst for biopsy. The couples started PGT cycles between March 2014 and March 2017, and the clinical outcome data were collected till October 2017 for most of the couples might have a clinical result. This study was approved by the Faculty of Ethics Committee of Shanghai JIAI Genetics and IVF institute, Obstetrics and Gynecology Hospital of Fudan University, China. The ethical approval number is JIAI E2017-23.
Intracytoplasmic sperm injection and trophectoderm biopsy
Standard techniques were used inIVF. Briefly, fertilized oocytes were produced using intracytoplasmic sperm injection (ICSI) and then were cultured postfertilization for 5–6 days in IVF laboratory to reach the blastocyst stage. Blastocysts were evaluated according to a grading system used widely recommended by Gardner et al., and 3–10 trophectoderm cells were biopsied and immediately transported to PGD laboratory of the same center for whole-genome amplification (WGA) and aSNP analysis. The day of trophectoderm biopsy was depended entirely on blastocyst development and was specifically recorded as day 5 or day 6. Blastocysts were cryopreserved immediately after biopsy procedure was finished.
Single-nucleotide polymorphism microarray analysis
WGA was performed using the REPLI-g Single Cell Kit (Qiagen, Hilden, Germany), following the manufacturer's recommendations. aSNP analysis was performed according to the Infinium Chip procedure (Illumina, Inc., San Diego, CA, USA). Briefly, the WGA product was amplified in an overnight isothermal reaction and then fragmented to a size of approximately 300–500 base pairs. After isopropanol precipitation and resuspension, the samples were hybridized to an Infinium Beadchip overnight for about 20 h. An automated Extension Staining (XStain) process was then performed. After staining, the Beadchips were read on an iScan reader. Genotype calls were made automatically by Illumina BlueFuse ® software, generating reports of the results.
Analysis of euploidy or aneuploidy of the embryo
All the aSNP data were analyzed and reported by two independent genetic technicians and then verified by senior genetic director in our laboratory. Embryos without any seen unbalance were described as euploidy (products resulted from alternate segregation). We categorized the abnormal embryos into five types: segmental aneuploidy (products resulted from adjacent-1 or adjacent-2 segregation which were commonly happened in quadrivalent segregation or randomly happened in duplication or deletion of one part of the arms of chromosomes), whole-chromosome aneuploidy (products mainly resulted from 3:1 or 4:0 segregation of the quadrivalent or randomly happened in meiosis I/II error), segmental plus whole-chromosome aneuploidy (both quadrivalent and meiosis error happened), mosaic only (mosaicism with only one or two chromosomes was found), and UPD (1-22, X)*2(comprehensive chromosome uniparental diploidy; and one or two chromosome uniparental isodisomy was not recorded).
Clinical outcome recording after frozen–thawed euploidy embryo transfer
The serum level of human chorionic gonadotropin (hCG) was measured 14 days after transfer, and a serial ultrasound was performed 5, 7, and 9 weeks after transfer. The clinical pregnancy was confirmed if an intrauterine gestational sac with fetal heart beat was visualized. Monochorionic–diamniotic (MCDA) twins or dichorionic–diamniotic (DCDA) twins were considered as one pregnancy cycle. Biochemical pregnancy number was recorded if the hCG level was positive, but no gestational sac was seen. Miscarriage was recorded if the fetal heart beat was no longer seen at the time of 7 or 9 weeks after transfer. The pregnancy status would be followed up once in the second trimester, and prenatal diagnosis would be done during this period. live birth number would be recorded when the babies were born.
Data were expressed as mean ± standard deviation or as percentages. The detailed algorithm of every clinical outcome was listed as follows: embryo implantation rate = gestational sacs with heart beat number/transfer embryo number; the biochemical pregnancy rate/embryo transfer (ET) = biochemical pregnancy number/frozen–thawed transfer cycles (FET); the clinical pregnancy rate/ET or initiated = clinical pregnancy number/FET or oocyte retrieval cycles; the ongoing pregnancy rate/ET or initiated = ongoing pregnancy number/FET or oocyte retrieval cycles; the live birth rate/ET or initiated = live birth number/FET cycles or oocyte retrieval cycles; the cumulative pregnancy rate or ongoing pregnancy rate or live birth rate = clinical pregnancy number or ongoing pregnancy number or live birth number/enrolled couple number; the cancellation rate = no ET cycles/oocyte retrieval cycles; and the miscarriage rate = miscarriage number/clinical pregnancy number. All statistical procedures were conducted with SPSS version 17.0 software (SPSS Inc., Chicago, IL, USA). Data were analyzed according to the gender of the carriers. Independent sample t-test and crosstab with Chi-squared distribution were performed, and P < 0.05 was considered statistically significant. Binary logistic regression was fitted for the relationship between gender of RCP carriers and the type of embryos (euploidy, abnormal, and failed). Potential confounders included gender of RCP carriers (female or male), the biopsied day (day 5 or day 6), and maternal age of the RCP couple (<38 years old or ≥38 years old). Odds ratios (OR s) with 95% confidence intervals (CI s) were calculated to assess the association. All the potential confounders were retained in the fitted adjusted models regardless of the significance based on literatures.
| Results|| |
Semen analysis was significantly differentiated between female and male reciprocal translocation group
From April 2014 to March 2017, a total of 238 couples met our criterions and the clinical data of these couples were collected and analyzed. Among these couples, 124 were female carriers and 114 were male carriers. The average female age (31.69 ± 4.10 vs. 31.52 ± 4.18; P = 0.743) and male age (33.65 ± 5.30 vs. 33.59 ± 6.53; P = 0.932) were not different. The miscarriage times of the couple before underwent PGT cycles ranged 0–7, and the average miscarriage times were not different (1.47 ± 1.45 vs. 1.18 ± 1.37; P = 0.112). No significant difference was found in the general information of the female: anti-Mullerian hormone (AMH, 5.65 ± 3.36 vs. 6.00 ± 4.06; P = 0.544), follicle-stimulating hormone (6.96 ± 1.68 vs. 7.16 ± 2.17; P = 0.436), and luteinizing hormone (5.02 ± 2.49 vs. 5.47 ± 4.32; P = 0.318). Female body mass index (BMI) (24.31 ± 3.51 vs. 23.89 ± 3.41; P = 0.352), male BMI (21.88 ± 2.81 vs. 21.74 ± 2.79; P = 0.685), and sperm density (106/mL) (46.69 ± 28.15 vs. 40.34 ± 29.58; P = 0.099) were not significantly different. However, sperm live rate (52.70 ± 21.05% vs. 42.32 ± 23.41%; P = 0.001), PR (forward motile sperm rate) (44.35% ± 19.33% vs. 34.96 ± 20.62%; P = 0.001), PR + NP (nonforward motile sperm rate) (52.27 ± 21.49% vs. 40.40 ± 24.52%; P = 0.001), and normal morphology rate (2.98% ± 1.33% vs. 2.50 ± 1.51%; P = 0.012) of men in male RCP group were significantly decreased compared with female RCP group [Table 1].
Day-3 cleaving embryo rate was higher in male reciprocal translocation carrier group
The data of the first PGT cycle of the two groups were collected. The mean number of retrieval oocytes (14.10 ± 6.60 vs. 13.78 ± 7.68; P = 0.727), MII oocytes (11.94 ± 5.85 vs. 11.70 ± 6.43; P = 0.769), two pronucleus zygotes (10.65 ± 5.61 vs. 10.34 ± 5.91; P = 0.678), cleavage zygotes (10.44 ± 5.40 vs. 10.15 ± 5.85; P = 0.687), day-3 cleaving embryos (8.39 ± 4.57 vs. 8.67 ± 5.29; P = 0.662), blastocysts biopsied (3.95 ± 2.78 vs. 4.46 ± 2.93; P = 0.167), normal embryos (1.66 ± 1.25 vs. 2.00 ± 1.34; P = 0.078), abnormal embryos (2.86 ± 2.12 vs. 3.06 ± 2.10; P = 0.486), and mosaic embryos (0.15 ± 0.36 vs. 0.18 ± 0.48; P = 0.767) was not significantly different between the female and male RCP groups. MII oocytes rate (85.09 ± 13.44% vs. 85.71 ± 13.95%; P = 0.726), fertilization rate (88.40 ± 14.44% vs. 88.32 ± 12.66%; P = 0.965), cleavage rate (98.18 ± 4.81% vs. 98.36 ± 5.69%; P = 0.788), blastocyst formation rate (50.30 ± 25.17% vs. 54.60 ± 22.33%; P = 0.166), and euploidy embryo rate (30.30 vs. 34.90%; P = 0.131) were not different. Significance was found in day-3 cleaving embryo rate (80.54 ± 19.63% vs. 85.35 ± 17.46%; P = 0.048 [Table 2]).
|Table 2: Data of the first COH, IVF, and PGT cycle of the female and male RCP carrier groups|
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Segmental aneuploidy was the largest proportion in abnormal embryos in reciprocal translocation couples
The total number of biopsied blastocysts was 999, and the results were described as euploidy, abnormal, and failed. The frequency of the three categories was 319 (31.93%), 658 (65.87%), and 22 (2.20%). Frequency of euploidy in different groups is as follows: the biopsied day (day 5 vs. day 6, 34.50% vs. 27.50%), gender of RCP carriers (female vs. male, 30.30% vs. 34.90%), and maternal age of the RCP couple (<38 years vs. ≥38 years, 33.40% vs. 22.40%) are shown in [Table 3]. We analyzed the proportion of the five types of abnormal blastocyst, and the results showed that segmental aneuploidy was the largest (67.48%). The second was the whole-chromosome aneuploidy (17.63%) and then was the segmental plus whole-chromosome aneuploidy (12.16%). The proportion of mosaic only was 1.98% and UPD (1-22, X)*2 was 0.76% [Figure 1].
|Table 3: Frequency of the euploidy and abnormal embryos in different groups|
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|Figure 1: The proportion of the five types of abnormal blastocyst. The segmental aneuploidy was the largest (67.48%). The second was the whole-chromosome aneuploidy (17.63%) and then was the segmental plus whole-chromosome aneuploidy (12.16%). The mosaic only and UPD(1-22, X)*2 were 1.98% and 0.76%, respectively. UPD: Uniparental diploidy.|
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Euploidy was related with biopsied day and maternal age
Day-5 biopsy was associated with euploidy embryos (OR = 1.388, 95% CI = 1.012–1.904; P = 0.042). Compared with female age ≥38 years old, female age <38 years old was associated with euploidy embryos at a borderline significance (OR = 1.753, 95% CI = 0.97–3.17; P = 0.063 [Table 4]).
Clinical outcome was not significantly different between the two reciprocal translocation groups
A total of 42 female and 33 male RCP couples had no euploidy embryos to transfer, which led the cancellation rate to 33.90% versus 28.90% [P = 0.414, [Table 5] and [Table 6]. Eighty female carrier couples underwent 95 FETs, and 75 male carrier couples underwent 93 FETs. The mean embryo number per ET was 1.04 (99/95) and 1.13 (105/93) in female and male carriers, respectively. We waited until all the outcomes of the FET cycles were collected in October 2017. Eight female RCP and nine male RCP ET cycles only observed hCG positive but no gestational sacs, resulting biochemical pregnancy rate/ET to 8.40% vs. 9.70% (P = 0.764). There was one ectopic pregnancy in each group. Fourty-five intrauterine gestational sacs with heart beat were observed in female carrier group and 52 were observed in male group (among these one MCDA in female group, one MCDA and four DCDAs in male group), henceforth the embryo implantation rate was 47.50% vs. 48.60% (P = 0.875), the clinical pregnancy rate/ET was 49.50% vs. 50.50% (P = 0.884), and clinical pregnancy rate/initiated cycle was 37.90% vs. 41.20% (P = 0.6), respectively. The cumulative pregnancy rate reached 58.80% vs. 62.70% (P = 0.618). The ongoing pregnancy rate per ET (43.20% vs. 46.20%; P = 0.671), per initiated (33.10% vs. 37.70%; P = 0.453), and cumulative ongoing pregnancy rate (51.30% vs. 57.30%; P = 0.447) were not significantly different. The miscarriage rate of female and male group was 12.80% versus 8.50% (P = 0.503). Till the end of collection of data, there were 16 ongoing pregnancy cycles (female/male, 9/7) and 68 live birth cycles (female/male, 32/36), leading the live birth rate per ET to 33.70% vs. 38.70% (P = 0.473), per initiated to 25.80% vs. 31.60% (P = 0.325), and the cumulative live birth rate to 40.00% vs. 48.00% (P = 0.316) in each group [Table 6]. The numbers of live borne boys and girls were 35 and 39, respectively [Table 5].
| Discussion|| |
This study aimed to analyze the clinical outcome of the first PGT cycles differed by the gender of the RCP carrier. Our data showed that the clinical outcomes such as embryo implantation rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate were higher in male RCP carrier group, but without significance. The miscarriage rate was lower in male RCP carrier group, but was not significantly different from female carrier group. Although the differences between the female and male carriers are not reached to the level of statistical significance, almost all clinical outcomes of PGT in the male group show better than those in the female group. The average live birth rate per initiated till data collection was 28.60%, which was similar to those reported earlier. The average miscarriage rate documented in the literatures ranged 0–33% after PGT,,, and our results showed 10.60%, which was within the range and similar as the miscarriage level in general population. It is known that more than 50% of early pregnancy loss is resulted from aneuploidy; however, when the times of pregnancy loss increases, the euploidy rate of the conceptus increases, which suggests that other factors such as aberrant maternal-fetal immune tolerance exist and cause unexplained early pregnancy loss. The women of the RCP couples might experience several times of pregnancy loss, whose uterine receptivity and maternal-fetal immune tolerance could be impaired, leading to higher miscarriage rate although the conceptus is euploidy.
It is well known that RCP will impair men's fecundity by decreasing the sperm quantity and quality. Our results showed that sperm live rate, forward motile sperm rate, and normal morphology rate were significantly decreased in male RCP carrier group compared with the counterparts in female RCP group, which was consistent with previous reports. It is assumed that the quality of sperm would impact embryo development, and the low-quality sperm might cause low fertilization rate, slow growth rate, high embryo aneuploidy rate,, and poor implantation rate during transfer procedure. Our results showed that the fertilization rate, cleavage rate, blastocyst formation rate, and euploidy embryo rate were not significantly different between the two groups; however, the day-3 cleaving embryo rate was significantly higher in male RCP group. This result indicated the major role of oocyte quality in regulating embryo growth. Although the sperms were impaired, the oocytes of the spouses of male carriers might be in a healthy state and eventually the fertilized eggs were developing in a regular pattern. However, the developmental ability of oocytes from female RCP carriers could be decreased, which might cause the slow growth rate in this group. Our results also showed that the blastocyst formation rate and the mean number of normal, abnormal, and mosaic embryos were not significantly different within the two gender carrier groups. The euploidy rate of embryos was significantly higher in day-5 embryos, indicating that the growth rate of embryo was a critical impactor of chromosome constitution in embryos of RCP carriers. Other studies showed that the growing rate of embryos was strongly predictive of euploidy rate  and clinical outcome. Our data confirmed that the growth rate of embryo was critical for evaluating euploidy rate of embryos of RCP carrier, while the gender effect was trivial. Although sperm quality was decreased in male RCP carriers, the growing rate of embryos was not affected, suggesting the principal role of oocytes in embryo development.
We specifically analyzed the constitution of all the abnormal embryos produced in this study and categorized the abnormal embryos into five types, which was described in material and methods. The results showed that the largest proportion was segmental aneuploidy, which reached 67.48%. The secondly share was whole-chromosome aneuploidy and then the third place was segmental plus whole-chromosome aneuploidy, which was also related with segregation error of quadrivalent. These data suggested that the quadrivalent segregation pattern overwhelmed the effect of older age in RCP carriers; however, the aneuploidies were not to be negligible in RCP carriers. Compared with older age (female age ≥38 years), younger age (female age <38 years) was associated with the increased rate of euploidy embryos at a borderline significance. Other study also showed 55–65% embryos with additional aneuploidies with or without translocation-related imbalances in RCP carriers. The high risk of recurrent miscarriage and live birth defects due to segmental or whole-chromosome aneuploidy made PGT is a reasonable choice for RCP couples. Compared with other platforms, aSNP is the only platform that distinguishes not only the segmental and whole-chromosome aneuploidy but also the polyploidy and UPD at the preimplantation stage,, resulting in the greatest decrease in miscarriage rate for couples suffered from RPL. The incidence of polyploidy and UPD detected by aSNP in miscarriage specimens could exceed 10%. As noted earlier, these can only be detected by aSNP. Our results showed that 0.76% whole-genome UPD was detected in abnormal embryos, which could result in a molar pregnancy if transferred. No polyploidy embryo has been reported in this study which is interesting and need further investigation for ICSI might reduce diandric fertilization but could not avoid the occurrence of polyploidy, and others have reported detection of polyploidy occurred at 4.17‰ in embryos. Therefore, aSNP might be a reasonable choice for patients such as RCP carriers pursuing PGT.
As concerned by RCP carriers and physicians, the high abnormal embryo rate caused cancellation cycles in IVF treatment, which was a disturbance for both sides. In our data, the cancellation rate of female and male carriers was 33.90% and 28.90%, respectively. Cancellation cycles are reported to occur in 19%–50% of cases.,, The fact that a great number of the RCP couples might have no chance to transfer a euploidy embryo in PGT cycles makes genetic counseling difficult for these couples. The minimum number of blastocysts was estimated to be 2–4 to obtain at least one normal/balanced embryo for RCP carriers, and this should also be discussed with RCP carriers. On the contrary, RCP couples underwent conventional IVF cycles without PGT could experience adverse pregnancy outcomes. A recently published study with a small size of RCP couples (n = 41) underwent conventional IVF procedure without PGT showed that by increasing embryos number transferred per cycle (2.6 ± 0.5), the clinical pregnancy rate (46.3%) and live birth rate (36.6%) per transfer were acceptable, but the miscarriage rate (21.1%) was higher compared with that of age-matched couples without RCP. Other studies discovered that without PGT, the miscarriage rate of RCP couples might be higher than 50% and the karyotype of miscarriage was abnormal in 90% of cases. Benefits and drawbacks of PGT for RCP couples should be discussed thoroughly before pursuing PGT.
In conclusion, we conclude that though gender influence is not significant, the clinical outcomes of couples with male RCP carriers show better in the first PGT cycles. Although sperm quality is decreased in male RCP carriers, the developing potential of embryo is not affected in this group, and the growing rate of embryo is a great prediction estimating euploidy rate in RCP carriers. Quadrivalent segregation pattern overwhelms the effect of older age in RCP carriers; however, the maternal age effect could not be neglected.
The authors thank Harvey J. Stern MD, PhD, Director, Reproductive Genetics Genetics and IVF Institute of the Genetics and IVF Institute, Fairfax, Virginia, for his help with proofreading of the draft of this manuscript.
Financial support and sponsorship
This work was sponsored by the Shanghai Municipal Commission of Health and Family Planning Project (No. 201640365).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]