TABLE 3.
Human studies of uNK cell abundance and function with pregnancy outcomes.
| Author | Year | Study population | Timing of Bx/path sample | Quantification technique for uNK cells | Conclusions | Category | |
|---|---|---|---|---|---|---|---|
| Klentzeris et al. (63) | 1994 | 24 unexplained infertility; 24 fertile controls | Secretory endometrial biopsies (LH surge +4, +7, +10, and +13) | Immunohistochemistry | Significantly decreased numbers of CD56+ cells in infertile population compared with fertile controls | Infertility | |
| Fukui et al. (66) | 1999 | 76 women undergoing IVF | Midsecretory endometrial biopsy | Flow cytometry | No difference in % uNK cells in women with infertility who failed to get pregnant and those who became pregnant after IVF and between miscarriage and live birth in those who were pregnant Higher subpopulation of CD56+ uNK cells in women who had live birth compared with miscarriage No normal range reported |
Infertility | |
| Lynch et al. (50) | 2007 | 12 infertile women undergoing surgical tubal patency assessment, 7 fertile women undergoing elective surgery | Endometrial biopsy at time of elective surgery | Flow cytometry | Increased proportion of NK progenitors in endometrium of infertile women | Infertility | |
| McGrath et al. (67) | 2009 | 18 women with unexplained infertility; 10 parous control women | Endometrial biopsy at time of elective surgery | Flow Cytometry | Increased secretory-phase expression of CD94 and CD158b and proliferative-phase expression of CD158a by uNK cells in infertile women No difference in the number of uNK cells between fertile and infertile women across the menstrual cycle |
Infertility | |
| Kofod et al. (65) | 2017 | 41 infertile (hydrosalpinx, history of salpingectomy, or unexplained), 20 control (Caucasian only) | Midsecretory endometrial biopsy (LH surge + 7 days) | Immunohistochemistry | Decreased number of CD56+ uNK cells in infertile women compared with fertile controls Increased number and percentage of CD56+ uNK cells predictive of pregnancy in future IVF treatment cycle |
Infertility | |
| Recurrent implantation failure | Ledee-Bataille (69) | 2004 | 15 women with >2 IVF cycle failures undergoing natural IVF | Midsecretory endometrial biopsy | Immunohistochemistry | No difference in number of uNK cells in women with infertility who failed to get pregnant and those who became pregnant after IVF | Infertility, RIF |
| Matteo et al. (70) | 2007 | 10 women with unexplained infertility and RIF (>3 IVF failures with unsuccessful embryo transfers of at least 2 high-grade blastocysts), 25 historical controls undergoing gynecologic surgery | Midsecretory endometrial biopsy (d22–26) | Flow cytometry | Uterine NK cell percentage did not differ between infertile women and historical controls | Infertility, RIF | |
| LeDee (71) | 2016 | 394 women with RIF (no ongoing pregnancy > 10 weeks despite multiple embryo transfers with a total of at least 6 embryos transferred on day 3 or 5), 26 fertile controls with male factor infertility and successful pregnancy after IVF | Midsecretory endometrial biopsy | Immunohistochemistry | No difference in uNK abundance between infertile and fertile populations but substantial subpopulation of both overactivation and low activation of uNK cells | Infertility, RIF | |
| Donoghue et al. (72) | 2019 | 14 women with RIF, 9 women with potential implantation failure, 11 controls with implantation success | Midsecretory endometrial biopsy (LH surge + 6–8 days) | Immunohistochemistry | No difference in cell density of CD56+ or CD16+ uNK cells in RIF compared with women with implantation success or potential RIF Significant reduction in uNK density in parous women compared with nulliparous, regardless of current implantation status |
Infertility, RIF | |
| Tohma et al. (73) | 2020 | 16 women with RIF (3 unsuccessful IVF/ICSI treatments despite transfer of good-quality embryos), 25 infertile patients without RIF | Midsecretory uterine lavage | Flow cytometry | Increased percentage of uNK cells in controls vs. study group (P = .026) | Infertility, RIF | |
| Recurrent pregnancy loss | Chen et al. (74) | 2017 | 97 women with recurrent miscarriage, 34 women with RIF, 84 fertile controls | Midsecretory endometrial biopsy (LH surge + 7 days) | Immunohistochemistry | Women with infertility fell both above and below the reference range for uNK % compared with fertile controls Significant increase in percentage of uNK cells in both recurrent miscarriage (P= .042) as well as RIF (P = .048) compared with fertile controls |
Infertility, RIF, RPL |
| Marron (75) | Feb, 2019 | 178 women with RIF (>2 unsuccessful embryo transfers of high-grade blastocysts), 155 women with RPL (>2 clinically detectable consecutive or nonconsecutive miscarriages), 130 women with primary infertility, 114 women with secondary infertility, 35 control women with male factor infertility < 38 years of age | Endometrial biopsy following standard hormone replacement therapy protocol after 5 days of vaginal progesterone | Flow cytometry | Patients with history of RIF had significantly higher numbers of uNK cells compared with controls and patients with RPL (P< .0001) | Infertility, RIF, RPL | |
| Marron (76) | March, 2019 | 149 women with RIF (>2 unsuccessful embryo transfers of high-grade blastocysts), 121 women with RPL (>2 clinically detectable consecutive or nonconsecutive miscarriages), 76 women with primary infertility, 80 women with secondary infertility, 29 control women with male factor infertility < 38 years of age | Endometrial biopsy following standard hormone replacement therapy protocol after 5 days of vaginal progesterone | Flow cytometry | Infertile populations with increased concentrations of peripheral-type NK cells (P = .016) | Infertility, RIF, RPL | |
| Parkin et al. (64) | 2011 | 24 women with unexplained RPL, 31 women with unexplained infertility, 10 controls with no history of infertility | Midsecretory endometrial biopsy | Immunohistochemistry | CD56+ uNK cells significantly lower in unexplained infertility compared with controls (P= .002) as well as in unexplained RPL compared with controls (P= .035) Differences between study groups for CD56+ uNK cells not significant nor were there significant differences in CD16 or NKG2a-positive cells | Infertility, RPL | |
| Giuliani et al. (68) | 2014 | 21 women with unexplained RPL, 30 women with unexplained infertility, 10 controls without history of infertility, RPL, or endometriosis | Midsecretory endometrial biopsy | Immunohistochemistry | No significant difference of CD56+ uNK cells in women with unexplained RPL or unexplained infertility compared with fertile women Ratio of NKp46+:CD56+ cells higher in women with unexplained RPL and unexplained infertility compared with fertile patients |
Infertility, RPL | |
| Hill et al. (79) | 1995 | 20 women with RPL (>4) Controls are 20 elective terminations |
Placental tissue | Immunohistochemistry | No difference in CD56+ cells | RPL | |
| LaChapelle et al. (80) | 1996 | 20 women with RPL (>2), idiopathic | Midsecretory endometrial biopsy (days 18–25) | Flow cytometry | No difference in % total uNK cells in women with miscarriage and ongoing pregnancy No normal range reported |
RPL | |
| Vassiliadou and Bulmer (84) | 1996 | 40 women with SA Controls are 19 elective terminations |
Placental tissue | Immunohistochemistry | 50% had significantly increased numbers of “classic” CD57 NK cells compared with normal human pregnancy | RPL | |
| Clifford et al. (85) | 1999 | 29 women with RPL (>3) Controls are 10 parous women |
Midsecretory endometrial biopsy (days 20–23) | Immunohistochemistry | Increased CD56+ uNK cells in RPL over control group (P= .001) When stratified by miscarriage type, difference maintained only if history of early pregnancy loss |
RPL | |
| Kwak (77) | 1999 | 71 women with RPL (>3) Controls are 20 elective terminations |
Placental tissue | Immunohistochemistry | 29.6% (P= .03) demonstrated elevated CD57+ uNK cells at the implantation site | RPL | |
| Quenby et al. (86) | 1999 | 22 women with RPL (>3) Controls are 9 fertile women (2 or more prior pregnancies, no miscarriages) |
Midsecretory endometrial biopsy (day 19–23) | Immunohistochemistry | 8/22 had few CD57+ uNK cells vs. none in the controls Women with miscarriages had significantly more CD4+, CD14+, CD16+, and CD56+ (uNK) leukocytes than either those who had live births or women with proven fertility |
RPL | |
| Quack et al. (81) | 2001 | 17 women with RPL of normal male pregnancy Controls are 20 elective terminations and 21 unexplained RPL with trisomy 16 |
Placental tissue | Immunohistochemistry | No difference in CD56+ uNK cells Decreased CD56:CD45 ratio in women with RPL of normal male pregnancy compared with normal elective abortion |
RPL | |
| Emmer et al. (87) | 2002 | 9 unexplained RPL (>1 consecutive miscarriage before 16 weeks), 9 controls with healthy pregnancy at time of CVS sampling, 2 controls of hysterectomies with 12–13-week pregnancies | Tissue collected after miscarriage/curettage of nonvital pregnancy | Immunohistochemistry | Increased expression of CD56+ and CD16+ uNK cells in miscarriage tissue compared with healthy pregnancy | RPL | |
| Michimata et al. (83) | 2002 | 17 women with RPL (≥2 with normal karyotype) Controls are 15 women with male factor in fertility |
Midsecretory endometrial biopsy (day 18–21) |
Immunohistochemistry | No difference in CD56+ or CD16+ uNK cells No normal range reported |
RPL | |
| Shimada et al. (82) | 2004 | 20 women with unexplained RPL (>1 miscarriage) Controls are 17 fertile women (history of 1 or more normal live birth, no history of miscarriage or ectopic pregnancy) |
Midsecretory endometrial biopsy | Flow cytometry | No significant difference in uNK cell percentages between women with RPL and fertile controls. Evaluated CD56+, CD56+CD16+, and CD56+CD16- | RPL | |
| Tuckerman et al. (78) | 2007 | 87 women with RPL 10 normal controls |
Midsecretory endometrial biopsy (LH surge + 7–9 days) |
Immunohistochemistry | Significantly higher CD56+ uNK cells in women with RPL vs. control No difference in % uNK cells in women who conceived following biopsy with respect to pregnancy outcome (miscarriage vs. live birth) |
RPL | |
| Hosseini et al. (88) | 2014 | 15 women with recurrent spontaneous abortion (2 or more successive miscarriages < 20 weeks), 15 healthy fertile controls (at least 1 prior live birth, no history of abortion) | Menstrual blood collection | Flow cytometry | Higher percentage of CD56+CD3−CD45RO+ uNK cells in menstrual blood of fertile women compared with infertile. No other significant difference in menstrual blood for other uNK subtypes | RPL | |
| Preeclampsia | Fraser et al. (92) | 2012 | Elective terminations screened by uterine artery Doppler ultrasound to categorize into high arterial resistance vs. normal arterial resistance | 9–14-week termination tissue | Immunohistochemistry | No difference in uNK cell abundance in decidua from high- vs. low-uterine-artery-resistance pregnancies Decreased trophoblast motility when treated with supernatant of uNK cells from high-resistance pregnancies than supernatant of uNK cells from normal-resistance pregnancies In elevated resistance pregnancies, uNK cells secrete fewer proinvasive factors, fail to induce vascular apoptosis, and secrete fewer apoptotic factors |
Preeclampsia |
| Wallace et al. (93) | 2015 | Elective terminations screened by uterine artery Doppler ultrasound to categorize into high arterial resistance vs. normal arterial resistance | First trimester termination tissue | Flow cytometry | Reduction in receptor expression for HLA-C and HLA-G on trophoblast in uNK cells from high-resistance pregnancies uNK cells with reduced receptor expression for HLA-G has altered production of two cytokines known to be significant in uNK-trophoblast interactions |
Preeclampsia | |
| Accreta | Laban et al. (97) | 2014 | 10 patients with unseparated placenta accreta, 16 patients with separated placenta accreta, 25 patients with placenta previa, 25 patients with normal placentation | Decidual biopsies at time of cesarean section | Immunohistochemistry | Possible quantitative difference in pregnancy NK cells in placenta accrete vs. normal placentation with decreased uNK score associated with cases of morbidly adherent placenta accreta | Placenta accreta |
Note: ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; LH = luteinizing hormone; RIF = recurrent implantation failure; RPL = recurrent pregnancy loss; SA = semen analysis; uNK = uterine natural killer.