If I go a week without being asked about natural killer cells, I’d be surprised.  The topic of natural killer cells is really messy: do they cause miscarriage? Do you want a lot of them or none of them for a successful pregnancy? Should we be testing for them?  If so, where do we test for them: blood or uterine lining? Do they even matter?

What are NK cells?

Natural killer (NK) cells are white blood cells found in everyone’s blood stream and in the uterine lining (called the endometrium). There are two main types ( https://pubmed.ncbi.nlm.nih.gov/11698225/#:~:text=Human%20NK%20cells%20can%20be,each%20with%20distinct%20phenotypic%20properties ) and the amount of these types in the blood stream is different than the amount in the uterus.  Further, the amount in the uterus varies by the day of the menstrual cycle.

What do they do?

They secret cytokines or signals that tell the endometrium to increase blood flow and permit implantation and invasion of the placenta into the uterus.

If NK cells are too high in concentration they can cause excessive blood flow to the implanting embryo causing excessive oxidative stress ( https://www.webmd.com/a-to-z-guides/what-is-oxidative-stress ) (similar to why if you give someone too much oxygen its bad - too much of a good thing).  One type of NK cell can also release toxic cytokines in the uterine lining which is harmful for pregnancy.

So, too many NK cells, particularly one type, is bad for implantation and early pregnancy and can cause a failed embryo transfer and/or miscarriage.

Why don’t we test for them?

If you are going to test NK cells ( https://www.olivefertility.com/fertility-services/fertility-tests ), it is best to test the in the uterus as it doesn’t seem blood levels correlate very well to uterine NK levels.  Some reproductive immunologists will test for them in blood, some in the uterus and many don’t test at all but still treat with immune therapies like prednisone or dexamethasone. Testing is controversial and generally not been shown to be valuable in improving outcomes.

How can we treat them to prevent failed embryo transfers and/or miscarriage?

Prednisone might help.  We tend to treat without testing as testing hasn’t been very helpful, historically.  

We know there are prednisone (corticosteroid) receptors on NK cells. Treating with prednisone might reduce the number of bad NK cells in the uterus and may impact what signals the NK cells release.

Studies have shown you can reduce NK levels in the uterus with treatment with oral prednisone.  Other studies have suggested improved live birth rates in women with recurrent pregnancy loss, when treated with oral prednisone in early pregnancy.

Is prednisone safe for the baby?

Most (90%) of prednisone is broken down by the placenta so there is actually little exposure to the embryo/fetus.  Now, high doses later in pregnancy can be harmful - being associated with premature rupture of the membranes, low birth weight and potential cognitive issues in the child.

Should you take prednisone?

If you have a history of recurrent pregnancy loss or recurrent implantation failure it is worth discussing with your doctor. 

References:

Tang AW, Alfirevic Z, Turner MA, Drury JA, Small R, Quenby S. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum Reprod 2013;28:1743–52.

Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral pred- nisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet 2014;290:757–62.

Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S, et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol Assess 2016;20:1–92.

Visser J, Ulander VM, Helmerhorst FM, Lampinen K, Morin-Papunen L, Bloemenkamp KW, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost 2011;105:295–301.

Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey A-AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Ob- stet 2008;278:33–8.

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