What matters in the woman?
Implantation of a human embryo in the uterus is a delicate balance between support and rejection, which depends on the genetic constitution of both mother and father. Contrarily to earlier views, the so-called killer cells in the female uterus are not detrimental, but necessary for implantation, provided they get the correct signals from the embryo. In women, the corresponding constitution is coded in the KIR genes, which vary greatly from one woman to another. KIR genes are located on the long arm of chromosome 19 (lower bottom picture).
Position of KIR genes on chromosome 19.
Activating signals (blue) in KIR group B.
Activating KIR genes (green), inhibiting (red).
KIR genes are classified in groups A and B (see picture on the upper right). When a woman possesses two copies of KIR genes group A and thus none of group B, her killer cells cannot receive activating signals of Group B genes (blue boxes 2DS2, 2DS3, 3DS1, 2DS5, 2DS1).
What matters in the man?
The male partner imparts the embryo those genetic features that are recognized as foreign by the uterus. The paternal HLA-C tissue compatibility genes on chromosome 6 are key in this process.
In a constellation where a father possesses HLA genes of group C2, and the mother has only inhibiting KIR genes of group A (KIR-AA), uterine killer cells will attack the young placenta. This will result in miscarriage or insufficient depth of placentation, which in turn can produce pregnancy-induced hypertension and preeclampsia.
Genetic testing of both partners AND MORE
Testing consists of specialised blood tests defined by Dr Alecsandru (KIR and HLA genes, blood clotting workup, auto-antibodies, test for early diabetes). As soon as the results are available, a remote medical visit is scheduled with the specialist at IVI Madrid. She will ask specific questions about personal and family history, interpret the results and possibly order treatments (like aspirin, anti-thrombosis injections, cortisone tablets or growth factors). The comprehensive workup is partly covered by health insurance, genetic lab testing abroad plus the virtual counselling generate out-of-pocket cost of approx. 1000 CHF. This will be more than outweighed, should the subsequent IVF treatment finally succeed thanks to treatment.
Immunological treatment in maternal KIR-AA and paternal HLA-C2
The absent activating signals on maternal killer cells can be compensated for by injecting a so-called growth factor. NEUPOGEN (Filgrastim, G-CSF) is a growth factor for haematopoietic (blood-forming) cells; it is usually used in children with lack of white blood cells and to induce faster recovery of the blood system during chemotherapy. Neupogen is being used «off-label» to promote implantation in mothers with KIR-AA genes and paternal HLA-C2; it is a natural substance which has been shown to have no negative effects on the child.
Diabetes and celiac disease
The research group of Dr Alecsandru found more exciting connections between immune system and reproduction, like between undiscovered diabetes or, newly, undiscovered gluten intolerance and recurrent miscarriages or IVF failure. In selected cases, a simple intervention like gluten-free diet was able to improve the outcome of pregnancy!
Selection of important scientific papers on the topic
February 2020 / Dr M Singer