Donation of Gametes and Risk of Preeclampsia

Abstract

Preeclampsia (PE) complicates between 2 and 8 % of all pregnancies, and it could be classified in two subgroups: Pre-term PE (delivery < 37 weeks of gestation) and term PE (delivery > 37 weeks). The first is believed to be due to an immune maladaptation of the mother to fetal antigens, taking place in the placenta, so there is an intrinsic placental dysfunction. This subtype is more severe, with prematurity, intrauterine growth restriction and adverse consequences for also the mother. The origin of the second is hypothesized to be in a hidden cardiovascular dysfunction of the mother that, due to the increase in hemodynamic demands secondary to the pregnancy, leads to an hypoperfusion of a primary functional placenta and finally to PE.

It has been largely described the association between gamete donation and PE, but the cause of this relationship is still on debate: the risk factors of patients undergoing oocyte donation (OD), the high multiple pregnancy rate, the ovarian failure, the infertility or the reproductive treatment could justify it. Additionally, many studies show that there is a decrease in PE after repeated exposure to partner’s sperm and an increase after oocyte or sperm donation, leading to the assumption that the the lack of recognition of embryo antigens after gamete donation have a role in the pathogenesis of PE.

Finally, the freezing of the embryos has been related to an increase of PE, always in in vitro fertilization pregnancies with own oocytes (IVF). The explanation could be in an effect of cryopreservants or the freezing/thawing process of those embryos, or also in the different endometrial hormonal milieu that fresh embryo transfer (freshET) and frozen-thawing embryo transfer (FET) IVF patients have.

This thesis consists in 4 projects that try to study the relationship between gamete donation and PE:

The first is a metaanalysis comparing the incidence of PE between OD pregnancies and IVF, to avoid the bias of compare OD with spontaneous conception pregnancies. The OR of PE in OD compared to IVF is 3.12 (2.56-3.85), and even after adjustment for maternal age and multiple pregnancy the difference remains statistically significative. This data suggest that in OD, the origin of PE is related to an immune maladaptation of the mother to fetal agents.

The second project is a retrospective cohort study of patients pregnant by OD that compares the incidence of PE between freshET and FET (with the same hormonal preparation). There is no difference in the incidence of preterm PE or term PE between groups, even after adjusting for confounding factors. With the same hormonal environment there is no difference in PE incidence, inferring that hormonal milieu has a role in the pathogenesis of PE, and that PE origin is more related to the mother or the placenta than to the embryo.

The third is a descriptive study of double-donation (DD) (donation of both sperm and oocyte) treatment. These patients have multiple risk factors (advanced maternal age, nuliparity, multiple pregnancy and gamete donation) for developing PE.

The last is a retrospective cohort study that compares the incidence of PE between OD pregnancies and DD pregnancies. DD cases compared to OD have an OR of 2.68 [95%CI 1.02, 7.04, p=0.038] for preterm PE, but no difference in term PE. After adjustment for confounding factors, the rate of preterm PE is still increased on DD with significance. These results support the immunological theory of PE origin, as in DD pregnancies, the embryo is completely allogenic to the mother, thus increasing only preterm PE comparing to OD. In assisted reproduction, the more the donated gametes a recipient receive, the more the risk for developing PE.

Preterm PE is more severe, but an early diagnose could lead to preventing measures, as giving aspirin. OD and DD patients should be aware of their high risk for developing PE, as well as their physicians.

La preeclampsia (PE) se clasifica en PE pretérmino (parto < 37 semanas) y PE a término (parto >

37 semanas). La primera se debe a una mala adaptación inmunológica de la madre al feto que tiene lugar en la placenta, dando lugar a una disfunción placentaria intrínseca, y es la más severa. La segunda se debe a un defecto cardiovascular materno que, secundario al incremento en las demandas hemodinámicas por la gestación, lleva a una hipoperfusión de una placenta inicialmente funcional, y finalmente a la PE.

La relación entre PE y donación de gametos se ha descrito en múltiples ocasiones, pero la causa de dicha asociación sigue siendo debatida. También se ha descrito un incremento de PE en gestaciones obtenidas tras transferencia de embriones vitrificados (FET) comparado con embriones en fresco (freshET), siempre en pacientes que realizaron ciclos de fecundación in vitro con óvulos propios (FIV), teniendo ambos grupos diferente ambiente hormonal endometrial. Esta tesis consiste en 4 proyectos que estudian la relación entre donación de gametos y PE:

El primero en un meta análisis que compara PE en donación de óvulos (OD) y FIV, evitando el sesgo de comparar OD con gestaciones espontaneas. La OD confiere el triple de riesgo de PE que la FIV, sugiriendo que en OD, el origen de la PE está relacionada con una mala adaptación inmunitaria de la madre a antígenos embrionarios. El segundo es un estudio retrospectivo de cohortes que compara, en gestantes tras OD, la incidencia de PE en freshET con FET. Con la misma preparación endometrial, no hay diferencia

en PE pretémino ni a término entre grupos. El origen de la PE se relaciona más con factores maternos o placentarios que embrionarios.

El tercero es un estudio descriptivo de tratamientos de doble donación (DD) (recepción de tanto óvulos como semen de donantes), que revela que se trata de pacientes con múltiples factores de riesgo para desarrollar PE. El cuarto es un estudio de cohortes retrospectivo que compara PE en DD con OD. La DD incrementa la PE pretérmino comparado con OD, pero no a término, apoyando la teoría inmunológica de la PE, ya que en DD el embrión es completamente alogénico a la madre.