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Case of a 39 year old woman experiencing successful pregnancy without IVF after suppression of the NK cytotoxic activity

Nowadays, there is statistic evidence worldwide that more than 10% of couples are infertile. Some times, there is no evidence for the couple’s infertility and many couples proceed to the in vitro fertilization (IVF) (Nelson and Lawlor 2011). Up to 3 % annual births in developed countries occurred because of assisted reproductive techonologies (ARTs) (Gosden et al., 2003). Most women at their 40 years of their age and over are seeking fertility through ARTs and specifically IVF (Smajdor A. 2011).

In our case, 39 year old woman was trying intensively to be pregnant the last 2 years without success. The last 9 months started asking for some tests to figure out what was the problem. The investigation started with the husband’s sperm excluding that he was infertile. The husband’s sperm was detected for motility, biochemistry and microbiology markers and finally DNA fragmentation index. All tests for the condition of the sperm were fine, which means that the husband is eligible in contributing positively in fertilization.

Then the parameters that were tested for the woman were any anatomical abnormalities in endometrium and uterus and the adequacy of primary follicles during the third day of the cycle. Then the hormonal levels were tested (LH, FSH, PRL, E2, TESTO, DHEA-S, SHBG, AMH), anti-thyroid antibodies (ATA), anti-thyroglobulin antibodies (TAT), and anti-microsomal antibodies (MAT). All serum levels of the previous tests were normal and the condition of that particular woman was considered fine. Then, a first attempt was sperm insemination was performed at the beginning of December without pregnancy success. Then the next series of tests included complete immunophenotype (CD3+, CD3+DR+, CD4+, CD8+, CD19+, CD19+CD5+, CD3-/CD16+CD56+), NK activity, Embryototoxicity assay, Anti-nuclear antibodies (ANA), and the full panel of the 21 anti-phospholipid antibodies (APA). All these markers were normal except the NK activity, which was 15.1 %, while the normal value is validated to be less than 10%. The woman’s NK cells were treated in vitro by IVIg and soya oil emulsion and both suppressed the NK activity.  Intravenous infusion with targeted dose of soya oil emulsion was administered to the woman in order to suppress the abnormal NK activity. The duration of soya’s action is measured in vivo and is active for 2 months. In the beginning of February, second sperm insemination was taken place with no result. In March, the woman got pregnant naturally with no insemination or IVF techniques. Pregnancy was confirmed by intravaginal ultrasound and at 19th week of gestation amniocentesis was performed for any genetic abnormalities. The result after the investigation with molecular techniques (amnio PCR) didn’t show any genetic abnormalities and it was supported after two weeks by a normal karyotype of 23 chromosomes XY.

This case can be encouraging for infertile couples because elevated peripheral NK activity in women with unexplained infertility is a risk factor for attaining pregnancy success (Matsubayashi H et al. 2005). Suppression of abnormal NK functionality with soya oil emulsion is important in successful pregnancies even though the mechanism of action is not know yet (Roussev et al. 2004). Different studies have showed the suppressive effect of intralipid in modulating the immune system (Granato D. et al. 2000, Mayer K. et al. 2003). On the other hand, it is of great importance of testing the numbers of NK cells and their cytotoxic activity in women with reproductive failures (Coulam CB. et al. 1995, Lachapelle MH et al. 1996). NK levels and NK activation assay are considered a very good diagnostic tool in reproductive cases such as implantation failure (Fukui A. et al. 1999, Coulam CB and Rousev RG 2003, Miko E et al. 2010) prediction of pregnancy outcome (Coulam CB et al.1995), pathogenesis of endometriosis (Sikora J et al. 2011), recurrent spontaneous abortions (RSA) (Kwak-Kim J and Gilman-Sachs A. 2008), and infertility (McGrath E et al. 2009).

In conclusion, immunological biomarkers such as ETA, APA, ANA, ATA, NK levels and NK activation assay should be performed in daily routine, when other important diagnostic parameters for a woman are normal (anatomical, chromosomal, hormonal etc.). These markers can be investigated in women with infertility problems, reproductive failures, recurrent pregnancy loss and IVF failures.

References

Nelson SM, Lawlor DA. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles PLoS Med. 2011;8:1-10.

Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 2003;361:1975–1977.

Smajdor A. The ethics of IVF over 40.Maturitas 2011;69:37-40. Int J Androl. 2010;doi: 10.1111/j.1365-2605.2010.01129.x. [Epub ahead of print].

Matsubayashi H, Shida M, Kondo A, Suzuki T, Sugi T, Izumi S, Hosaka T, Makino T. Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility Am J Reprod Immunol 2005;53(3):126-31.

Granato D, Blum S, Rossle C, Le Boucher J, Malnos A, Dutot G. Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro J Parenter Enterak Nutr 2000;24:113–118.

Mayer K, Meyer S, Reinholz-Muhly M, Maus U,Merfels M, Lohmeyer J, Grimminger F, Seeger W.Short-time infusion of fish-oil based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans J Immunol 2003;171:4837–4843.

Coulam CB, Goodman C, Roussev RG, Thomason EJ, Beaman KG: Systemic CD56+ cells can predict pregnancy outcome Am J Reprod Immunol 1995; 33:40–46

Fukui A, Fujii S, Yamaguchi E, Kimura H, Sato S, Saito Y:Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization Am J Reprod Immunol 1999;41:413–422.

Coulam CB, Goodman C, Roussev RG, Thomason EJ, Beaman KG:Systemic CD56+ cells can predict pregnancy outcome Am J Reprod Immunol 1995;33:40–46.

Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z Role of natural killer cell activity in the pathogenesis of endometriosis Curr Med Chem 2011;18(2):200-8.

Kwak-Kim J, Gilman-Sachs A. Clinical implication of natural killer cells and reproduction Am J Reprod Immunol 2008;59(5):388-400.

Miko E, Manfai Z, Meggyes M, Barakonyi A, Wilhelm F, Varnagy A, Bodis J, Illes Z, Szekeres-Bartho J, Szereday L. Possible role of natural killer and natural killer T-like cells in implantation failure after IVF Reprod Biomed Online 2010 Dec;21(6):750-6.

McGrath E, Ryan EJ, Lynch L, Golden-Mason L, Mooney E, Eogan M, O’Herlihy C, O’Farrelly C. Changes in endometrial natural killer cell expression of CD94, CD158a and CD158b are associated with infertility Am J Reprod Immunol 2009;61(4):265-76.

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