Uterine Transplantation: Scientific Impact Paper No. 65 April 2021.

A uterine transplant, or womb transplant, provides a potential treatment for women who cannot become pregnant or carry a pregnancy because they do not have a womb, or have a womb that is unable to maintain a pregnancy. This is estimated to affect one in 500 women. Options for those who wish to start a family include adoption and surrogacy, but these are associated with legal, cultural, ethical and religious implications that may not be appropriate for some women and their families. A womb transplant is undertaken when the woman is ready to start a family, and is removed following the completion of their family. Womb transplants have been performed all over the world, with more than 70 procedures carried out so far. At least 23 babies have been born as a result, demonstrating that womb transplants can work. While the procedure offers a different option to adoption and surrogacy, it is associated with significant risks, including multiple major surgeries and the need to take medications that help to dampen the immune system to prevent rejection of the womb. To date there has been a 30% risk of a transplant being unsuccessful. Although the number of transplants to date is still relatively small, the number being performed globally is growing, providing an opportunity to learn from the experience gained so far. This paper looks at the issues that have been encountered, which may arise at each step of the process, and proposes a framework for the future. However, long term follow-up of cases will be essential to draw reliable conclusions about any overall benefits of this procedure.

The vaginal microbiome in uterine transplantation.

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.

Human uterine transplantation: a review of outcomes from the first 45 cases.

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.

Psychological assessment tool for patients diagnosed with absolute uterine factor infertility and planning to undergo uterine transplantation.

Uterine transplantation (UTn) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI) and who are willing to bear their own child. AUFI renders a woman 'unconditionally infertile'. For AUFI women in general, UTn may offer a way to re-discover their own femininity through the restoration of fertility. Thus, when faced with a patient who may undergo UTn, the 'holistic approach' takes on an extra meaning. This is because the psychological element is two-sided for these patients. On one side lies the psychology of infertility, and on the other and equally important, is the substantially higher prevalence of psychiatric disorders in transplant candidates and recipients than in the general population. However, the psychology of a potential recipient of a uterine graft in order to bring about fertility has not been adequately explored or reviewed scientifically. We have presented here an outline of the areas which should be included in a psychological assessment for patients wishing to undergo UTn.

Patient selection criteria for blastocyst culture in IVF/ICSI treatment.

BACKGROUND: The development and refinement of blastocyst media in recent years has allowed embryos to be cultured in-vitro for 5 or 6 days post oocyte retrieval and has been established as an effective selection tool to aid embryo selection for IVF treatment. It is generally accepted that blastocyst culture is not an appropriate option for all patients but the criteria for patient selection varies between clinics. Our blastocyst culture programme started in February 2005; the patient criteria was set at a minimum of 4 oocytes retrieved, a minimum of 4 2PN pronuclear embryos and at least 4 8-cell embryos of any quality on Day 3 where the female patient was 34 years and under. In the female age group of 35 years and over the criteria was at least 6 oocytes retrieved, a minimum of 6 2PN pronuclear embryos and at least 6 8-cell embryos of any quality on day 3. Improvements in pregnancy rates demonstrated the effectiveness of blastocyst transfer and clinical opinion was that the criteria should be adjusted to allow this option to be available to an increased patient population. From February 2007 the blastocyst patient selection criteria was changed to at least 4 oocytes retrieved, at least 4 2PN pronuclear embryos and at least 2 8-cell and 2 6-cell or 7-cell embryos of top quality on Day 3 in women 38 years and under. For women 39 years and over the criteria was lowered to at least 5 eggs retrieved, at least 5 2PN and at least 3 8-cell embryos and 2 6-cell embryos of top quality on Day 3. METHODS: Retrospective statistical analysis was carried out to determine the pregnancy rates, live birth rates and twin rate for the period under the initial criteria and to examine the impact that lowering the criteria for patient selection for blastocyst culture had on these parameters. RESULTS: There was an overall fall in the ongoing pregnancy/live birth rate from 50.9% under the old criteria to 45.0% under the new criteria. However, the patients who had blastocyst culture under the new criteria but would have had day-3 embryo transfer under the initial criteria had a significantly increased live birth/ongoing pregnancy rate from 22.7% to 40.7%. There is an increase in the number of blastocyst culture cycles from 26.4% under the old criteria to 39.1% with the refined criteria. The twin pregnancy rate was reduced from 25.2% to 17.5%. CONCLUSION: The result of this cohort study revealed that lowering the blastocyst selection criteria may lead to a lower overall clinical live birth rate from blastocyst culture; however, it will benefit a specific group of patients to achieve a better pregnancy and live birth rate. Furthermore, it increases the number of patients who will benefit from the blastocyst culture programme and also reduces multiple pregnancy rate.

Elevated basal FSH and embryo quality: lessons from extended culture embryos: raised FSH and blastocyst quality.

BACKGROUND: The relationship between elevated basal FSH and embryo quality remains a topic of heated discussion among practitioners of ART. Some authors suggest a negative effect of raised FSH on the quality of embryos and therefore on IVF treatment outcome. We postulate that women with elevated FSH who respond well to ovarian stimulation and have embryos to transfer, have the same chance of conceiving like women of a similar age with normal FSH. To test this hypothesis, we studied women with elevated basal FSH who made enough embryos to qualify for blastocyst culture and day 5 embryo transfer. METHODS: Analysis of data collected prospectively, on women age 25-43 years, who underwent IVF between January 2005 and December 2006. The women were divided into: those with high FSH (> or = 10 IU/L) and women with normal FSH (<10 IU/L). We analysed data to show treatment outcome in the two groups, following embryo transfer on day 3 and after transfer on day 5. Outcome measures include number of oocytes retrieved, number of embryos available, implantation rate, pregnancy and live birth rate. RESULTS: Among the 1,858 women who under-went a day 3 transfer, 1,368 had basal FSH < or = 10 IU/L, and in 492 basal FSH was above 10 IU/L. The average number of oocytes retrieved was lower among women with elevated FSH (10.12 +/- 5.6 Vs 6.16 +/- 3.9). Women with a normal FSH, had a higher pregnant and live birth rate than those with elevated FSH (43.3% vs 27.9% p = 0.021) and (30.8% vs 17.6% p = 0.028) respectively. 398 women made enough embryos to qualify for extended embryo culture to blastocysts. Of these 366 had an FSH < or = 10 IU/L and 32 had FSH > 10 IU/L. In this group, there was no significant difference in the pregnancy and live birth rates between women with elevated and those with normal FSH, (67.2% vs 65.6%) and (51.9% vs 43.8%) respectively. In this selected group of women where quantity is not an issue, the quality of embryos was same irrespective of whether the basal FSH was low or high. CONCLUSION: Women with elevated basal FSH who respond well to stimulation and generate a good number of oocytes / embryos have a chance of becoming pregnant and having a live birth similar to that of women of their age. Women should therefore not be denied the benefits of IVF based solely on the basal FSH level as a subset may respond well and therefore have a good chance of taking home a baby.

Reducing multiple pregnancy in assisted reproduction technology: towards a policy of single blastocyst transfer in younger women.

OBJECTIVES: To investigate the effects of single blastocyst transfer (SBT) on live birth and multiple pregnancy in women undergoing in vitro fertilisation (IVF). DESIGN: Descriptive cohort study. SETTING: A London private IVF/postgraduate training unit. SAMPLE: A total of 700 fresh and 102 frozen blastocyst cycles performed between January 2005 and December 2006. METHODS: Young women aged 25-37 years and those aged 38-43 years were further divided into those who had SBT and those who received two blastocysts (double blastocyst transfer [DBT]). Live birth and multiple pregnancy rates were compared between groups. Cumulative live birth was compared between women who had DBT and those who received a SBT followed by a frozen blastocyst if the fresh cycle was unsuccessful. MAIN OUTCOME MEASURES: Live birth rate, cumulative live birth rate, multiple pregnancy rate, uptake of SBT. RESULTS: Among women aged 25-37 years, live birth rate following SBT was 59.0 versus 60.7% following DBT. The twin pregnancy rate in this group was 2.3 and 47.6% respectively. For women aged 38-43 years, live birth following SBT was 29.4% and multiple pregnancy rate was 33.3%. DBT in older women gave a higher live birth rate (44.3%) and a multiple pregnancy rate of 36.4%. Cumulative live birth following SBT in women aged 25-37 years was 72.8% versus 60.5% following DBT. Among the women aged 38-43 years, cumulative live birth was higher (63.3%) following DBT versus 28.6% following SBT. CONCLUSION: Single blastocyst transfer followed by transfer of a frozen blastocyst if the preceding fresh cycle was unsuccessful resulted in a better cumulative live birth and lower twin pregnancy in young women. In older women, two fresh blastocysts gave better results than one fresh followed by a frozen cycle. Older women should have the option of replacing two fresh blastocysts as this optimises their chances of taking home a baby.

The basis and value of currently used immunomodulatory therapies in recurrent miscarriage.

Recurrent miscarriage (RM) without an obvious identifiable cause may arise from excessive maternal T and natural killer (NK) cell activity against the trophoblast or early embryo. Impaired regulatory T cell function leading to increased pro-inflammatory Th17 and NK cell cytotoxicity may be central. Ongoing subclinical endometrial infection and/or inflammation with increased secretion of TNFα and stimulation of autoimmunity to heat shock proteins may also be contributory. Therapies with a varying theoretical basis and clinical evidence aimed at reducing excessive endometrial immune activity have been used non-selectively in women with RM with variable success. Recent work has now improved our understanding of the role of the different immune cells and proteins that are important at each stage of a normal pregnancy. The vulnerability of the early embryo to T and NK cell-mediated rejection suggests that immune-based therapies need to be maximally effective during early pregnancy. Targeting RM women with demonstrable T and NK cell activity may improve the overall clinical efficacy of these treatments. It may also prevent costly and possibly harmful use in women who are unlikely to respond, and make better use of scarce resources. This report describes the underlying principles behind the use of the different immune-based therapies. The broad evidence supporting their efficacy is also described, as are the possible adverse consequences. Suggestions are also made on how the maternal immune system may be positively modulated using current, widely available treatments that have minimal or no side effects.

Intrauterine insemination in natural cycle may give better results in older women.

BACKGROUND: Controlled ovarian hyper-stimulation (COH) in combination with intrauterine insemination (IUI) has been shown to result in significantly higher pregnancy rates compared to un-stimulated (natural cycle) IUI. This may however not be true in all ages. METHODS: We performed a retrospective cohort study and analysed data collected prospectively on 1759 IUI cycles in couples with unexplained infertility. The results were analysed to show the outcome of IUI with COH, and IUI in natural cycle (unstimulated), in younger women compared to their older counterparts. RESULTS: In women age 37 and younger, COH resulted in a significantly higher pregnancy rate (13.0% vs 6.5%) and live-birth rate (10.7% vs 5.2%) compared to natural cycle IUI (p = 0.025, p = 0.045 respectively). However for older women age >37 years, natural cycle (unstimulated) IUI, resulted in a significantly higher pregnancy rate (12.0% vs 8.5%) live-birth rate (7.5%vs 3.5%) than IUI with COH ((p = 0.0037). This difference is even more significant when COH was performed with clomiphene citrate (7.5% vs 2.1%) (p = 0.0017). CONCLUSION: COH was associated with a lower live birth rate in older women, irrespective of the agent used, and it seems to be worse when the anti-oestrogenic drug clomiphene citrate was used for COH. Older women may benefit more from natural cycle (unstimulated) IUI. A randomised controlled trial is required to confirm this observation.

The influence of body mass index to in-vitro fertilisation treatment outcome, risk of miscarriage and pregnancy outcome.

The aim of this work was to evaluate the effects of extreme body mass index (BMI) on assisted reproductive treatment outcome and pregnancy outcome. This is a descriptive cohort study that evaluated 8,145 consecutive in-vitro fertilisation/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycles in which BMI were known, from July 1997 to June 2005 in an inner London major fertility clinic. The data were collected prospectively and analysed retrospectively on women undergoing IVF/ICSI and ET. Patients' weight and height were established prior to treatment. IVF/ICSI treatment was then started using either a long or an antagonist protocol. Patients were divided into five groups: Group A (BMI < 19); Group B (BMI between 19 and 25.9); Group C (BMI between 26 and 30.9); Group D (BMI between 31 and 35.9); Group E (BMI > 36). The main outcomes measured were number of eggs collected, fertilisation rate, number of embryos available for transfer, pregnancy rate (PR), live-birth rate (LBR) and miscarriage rate (MR). The results showed no significant difference in the average number of days taking follicle stimulating hormone (FSH) for ovarian stimulation, the average amount of gonadotrophin used for stimulation, number of eggs collected and fertilisation rate. The pregnancy rate, miscarriage rate and the live-birth rate were not statistically different between all groups. However, in group E the miscarriage rate was significantly higher and the LBR was statistically lower compared with group B. We concluded that extreme BMI did not affect the super-ovulation outcome fertilisation rate and pregnancy rate. Women with a BMI > 35 had a higher miscarriage rate and hence a lower live-birth rate, but a reasonable pregnancy and live-birth rate can be achieved. For women with a BMI < 20 there was no difference in assisted reproduction treatment (ART) outcome and pregnancy outcome when compared with women with a normal BMI. This information should be used to advise patients who wish to embark on ART with extreme BMI.

Repeated testing of basal FSH levels has no predictive value for IVF outcome in women with elevated basal FSH.

BACKGROUND: It is a common practice to repeatedly test the level of basal FSH early in the cycle and to start IVF treatment only when the FSH level is below a certain threshold value. This is based on the idea that these women will respond better to ovarian stimulation when the basal FSH level is lower at the start of the cycle. The aim of this study is to assess the value of this practice. METHODS: Between January 1995 and January 2003, 39 women were identified. These women underwent two IVF treatment cycles within a 12 month period. The basal FSH level prior to each of these cycles was known to have changed. The treatment cycles were divided into cycles with a high basal FSH (> or =10 IU/l) and cycles with a low basal FSH (<10 IU/l). RESULTS: The 39 women underwent a total of 78 treatment cycles (in the first cycle 20 had elevated level of FSH and 19 had low FSH and vice versa in the second cycle). Therefore, there were 39 cycles with high FSH and 39 cycles with low FSH. There was obviously no live birth in the first treatment cycle, hence the reason for the patient undergoing another treatment cycle within 12 months of the first one. In the high FSH group, six became pregnant [pregnancy rate (PR) = 15.4%] and five delivered [live birth rate (LBR) = 12.8%]. In the low FSH group, three became pregnant (PR = 7.7%) and two delivered (LBR = 5.1%). The difference in PR and LBR, however, was not significant. Neither were there significant differences between the two groups with regard to the number of oocytes collected, oocytes fertilized, embryos transferred or miscarriage rate. CONCLUSION: The results of this study reveal that women who are poor responders or with reduced ovarian reserve have a poor outcome and repeatedly testing them will add no value. Cycling women with a history of elevated FSH should be offered treatment without further delay. Delaying treatment for these women could be counterproductive, as they may have to wait for many months, during which time they are getting older and closer to their menopause.

Simple enumerations of peripheral blood natural killer (CD56+ NK) cells, B cells and T cells have no predictive value in IVF treatment outcome.

BACKGROUND: To evaluate the association between the absolute counts of the peripheral natural killer (NK) cells (including total CD56(+) NK cells, CD56(dim) NK cells and CD56(bright) NK cells), B cells and T cells on the implantation rate and miscarriage rate after IVF treatment. METHODS: This was a prospective observation study. A total of 138 patients who underwent IVF treatment from December 2002 to July 2003 were recruited to the study. Blood samples were obtained on the day of vaginal oocyte retrieval prior to the procedure. The absolute counts of lymphocytes, NK cells, B cells and T cells were identified by flow cytometry. These absolute counts and their relationships to IVF treatment outcome and miscarriage rate were analysed. RESULTS: There were no significant differences with regard the mean values of absolute lymphocyte count, T cell count, B cell count and NK cell count (including total CD56(+) NK, CD56(dim) NK and CD56(bright) NK cells) between the pregnant and non-pregnant groups and also between the ongoing pregnancy and miscarriage groups. The cause of infertility, duration of infertility, basal FSH levels, number of previous failed IVF treatments, number of previous miscarriages and stimulation characteristics were not significantly different between the pregnant and non-pregnant groups. Previous studies have suggested that women with a history of recurrent miscarriage and those with infertility accompanied by recurrent failed IVF treatments are associated with a peripheral blood NK cell percentage >12%, therefore further analysis of peripheral CD56(+) NK cell levels <12% (group A) and >12% (group B) was performed. There was no significant difference in implantation rate (group A: 17.0%; group B: 23.2%), pregnancy rate (group A: 36.6%; group B: 47.7%) or miscarriage rate (group A: 23.3%; group B: 28.6%). CONCLUSION: There were no significant differences between simple enumerations of peripheral blood NK cells (including total CD56(+) NK, CD56(dim) NK and CD56(bright) NK cells), B cells and T cells with IVF treatment outcome and pregnancy outcome. Women who had a peripheral NK cell level >12% did not have higher number of previous pregnancy losses. Importantly their pregnancy rate was not reduced and their miscarriages were not increased compared to women who had a peripheral NK cells level <12%.

An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve.

BACKGROUND: Many cycling women with elevated basal FSH level have been discouraged from undergoing IVF treatment. This is because elevated basal FSH is associated with poorer assisted reproduction treatment outcome. It has been argued that high FSH reflects not only reduced ovarian reserve but also poor oocyte quality. The aim of this study is to assess the value of treating cycling women who have elevated basal FSH and to assess the reasons for the reduction in both pregnancy rate (PR) and live birth rate (LBR). METHODS: Between January 1997 and December 2001, 2057 patients underwent 3401 consecutive IVF/ICSI cycles in which the basal level of FSH (days 2-4) was determined at an earlier cycle. Analysis, however, was only performed for a single cycle per patient. All cases were divided into four cohorts according to FSH levels: group A, FSH <10 IU/ml; group B, 10.1-15 IU/ml; group C, 15.1-20 IU/ml; and group D, FSH >20 IU/ml. Each group was stratified further into subgroups according to age, < or =38 and >38 years. RESULTS: Both PR (A, 32.3%; B, 19.8%; C, 17.5%; and D, 3%) and LBR (A, 24.7%; B, 13.2%; C, 13.8%; and D, 3%) were significantly reduced in the higher FSH level groups. LBR was significantly higher in the younger subgroups (A, 32.2%; B, 21.8%; C, 20%; and D, 16.7%) as compared with the older subgroups (A, 12.1%; B, 8.3%; C, 10.5%; and D, 0%). Higher levels of FSH were significantly associated with more cycle cancellation, a larger amount of gonadotrophin required to achieve follicular maturity, and a lower number of eggs collected, embryos available and embryos transferred. In all cases, however, there was no significant correlation between FSH levels and fertilization rate or miscarriage rate. Younger cycling women with elevated FSH had significantly higher LBR compared with older women with normal FSH (21.2% versus 12.1%). Furthermore, the cumulative LBR after three cycles in these younger patients with elevated FSH levels was 49.3%. CONCLUSION: Although there is a reduction in both PR and LBR associated with higher levels of basal FSH, it is clear that in cycling women, high basal FSH is not a contraindication to IVF treatment, and a respectable PR and LBR can be achieved especially in young women. The reduction in PR and LBR is due to reduced reserve rather than poor oocyte quality. Clinics refusing to treat cycling women with elevated basal FSH levels may be denying these women a reasonable, albeit low, chance of achieving a birth with their own genetic material. Clinicians should use basal FSH levels as a guide to advise patients about their chances of achieving a live birth, not to exclude patients with a predicted lower success rate from a treatment programme.

Does egg-sharing compromise the chance of donors or recipients achieving a live birth?

BACKGROUND: To evaluate the effect of egg-sharing and the outcome of assisted reproductive treatment (ART) in standard IVF/ICSI patients, egg-sharing donors and egg-sharing recipients. METHODS: Descriptive cohort study to evaluate 276 egg-sharing cycles involving 192 egg-sharers, 274 recipient cycles receiving eggs from egg-sharers and 1098 non-egg-sharing standard IVF/ICSI cycles from January 1998 to December 2002. Patients were divided into three groups: group A, egg-sharers; group B, non-egg-sharers, age <36 years, FSH <10 IU/l, BMI <30 kg/m(2); and group C, egg-sharing recipients, all ages. Duration and amount of gonadotrophin required to achieve follicular maturity, number of eggs collected and donated, fertilization rate, pregnancy rates and live birth rates were compared between donor, recipient and standard IVF/ICSI patients. The chi(2 )test was used to test for statistical significance (P < 0.05). RESULTS: There was no significant difference in pregnancy rate and live birth rate of egg-sharers, group A (42.0%, 33.0%), non-egg-sharers, group B (40.0%, 30.9%) and recipients, group C (41.4%, 28.6%). The number of oocytes collected, number of mature follicles and amount of gonadotrophin used was not significantly different between the two groups (A and B). The average number of embryos transferred and the mean number of eggs allocated between egg-sharers and recipients was not statistically different. CONCLUSION: Egg-sharing does not compromise the chance of achieving a pregnancy or live birth for the egg-sharer or the recipient as compared to standard IVF/ICSI patients. The egg-sharers were not at a higher potential risk of ovarian stimulation syndrome and there was no imbalance of egg allocation.

An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome.

BACKGROUND: Our aim was to evaluate the effect of the absolute count of the activation marker (CD69), IgG Fc receptor (CD16) and inhibitor marker (CD94) expression on peripheral blood natural killer (NK) cells on implantation and miscarriage rates after IVF treatment. METHODS: Prospective observational study of 138 randomly selected women who underwent IVF treatment from December 2002 to September 2003. NK cells were identified as CD56(+) (dim + bright) and CD3(-) by flow cytometry. The absolute counts of the CD69(+), CD16(+) and CD94(+)expressing NK cells were recorded and their relation to IVF treatment outcome and miscarriage rate was analysed. RESULTS: The mean (+/-SD) absolute count of the CD56(dim)CD16(+)CD69(+) NK cells for women who had a successful ongoing pregnancy was 0.61 x 10(6)/l (+/-0.31). For those women who failed to achieve a pregnancy, the mean value of the absolute count of CD56(dim)CD16(+)D69(+) NK cells was significantly (P=0.003) higher at 1.66 x 10(6)/l (+/-0.52). The absolute count of CD56(dim)CD16(+)CD94(+) and CD56(dim)CD16(+) NK cells did not show any statistically significant differences between those women with successful and failed IVF treatment. Receiver operating characteristic (ROC) curve analysis was performed to select a CD69 threshold for further statistical analysis. The implantation rate (IR) was significantly lower (13.1%) and miscarriage rate (MR) was significantly higher (66.7%) for women with an absolute CD56(dim)CD16(+)CD69(+) NK cell count of >1.0 x 10(6)/l compared to women with count below this value (IR 28.2% and MR 16.7%). Further analysis of the absolute count of CD56(bright)CD69(+) and CD56(bright)CD94(+) NK cells did not show any significant difference between those women with successful and failed IVF treatment. CONCLUSIONS: An increase in the absolute count of activated NK cells (CD56(dim)CD16(+)CD69(+)) in the peripheral blood is associated with a reduced rate of embryo implantation in IVF treatment. Furthermore, women with high CD56(dim)CD16(+)CD69(+) peripheral blood NK cell absolute count, who are able to achieve pregnancy, have a significantly higher miscarriage rate.