The Correlation Between Immunological Reaction of the Seminal Fluid in the Mother's Blood and Pregnancy Complications
The Correlation Between Immunological Reaction of the Seminal Fluid in the Mother's Blood and Pregnancy Complications
It is known that if there isn't an efficient exposure to the paternal antigens before
 conception, there is an increased risk for the pre-eclampsia (PE) cascade and other pregnancy
 complications to take place.

 It is possible that maternal immune system that doesn't develop tolerance to the paternal
 antigens that the seminal fluid carries, doesn't developed an adequate immune tolerance to
 the trophoblast cells and due to that, they are being under greater attack during
 placentation. Thus, the cells don't go through a normal differentiation, don't perform normal
 pseudo-vasculogenesis and the PE cascade is more likely to be carried out.

 Both the maternal immune system and the paternal alloantigens have a role in the development
 of PE. Although the specific etiology remains unclear and can be only hypothesized.

 In this study the investigators aim is to try and prove that there is a difference in the
 immunological reactions to semen prior to conception and that these changes are related to PE
 and/or other obstetric complications.

 Hence the investigators aim to study the immune response to semen of women that will be
 exposed to the culprit semen for the first time compare to women that have been exposed to a
 culprit semen more than once previously (namely more than 1 insemination prior to the time of
 evaluation). After that, in a prospective cohort study the investigators would follow those
 women through their pregnancies and check for different pregnancy outcomes.

 In this manner, the investigators are hoping to create a screening tool that will help to
 predict pregnancy and fetal complications before conception related to maternal immune
 responses of paternal antigens.
The pathophysiology of preeclampsia (PE) likely involves both maternal and fetal/placental
 factors. It has been established that poor placentation followed by oxidative
 stress/inflammation and abnormalities in the development of placental vasculature early
 during pregnancy may result in relative placental ischemia, which then leads to a release of
 antiangiogenic factors into the maternal circulation. Thus, it changes the maternal systemic
 endothelial function and cause hypertension and other manifestations of the disease.

 Defects in spiral artery remodeling and trophoblast invasion, two related but separate
 processes, are characteristic of hypertensive disorders of pregnancy and fetal growth
 restriction. Still, the exact etiology of PE remains elusive.

 In normal pregnancies, the cytotrophoblast cells of the developing placenta migrate through
 the decidua and part of the myometrium to invade both the endothelium and highly muscular
 tunica media of the maternal spiral arteries. In addition to that, they alter their adhesion
 molecule expression, a process referred to as pseudo-vasculogenesis.

 By comparison, in PE, cytotrophoblasts fail to penetrate the myometrial segment and fail to
 go through pseudo-vasculogenesis.

 Consequently, the spiral arteries fail to develop into large, tortuous vascular channels,
 resulting in placental hypoperfusion and ischemia. This defect in deep placentation has been
 associated with development of multiple adverse pregnancy outcomes like PE, fetal death,
 abruptio placentae, IUGR, Preterm labor etc.

 One of the possible mechanisms responsible for defective trophoblast invasion of the spiral
 arteries is defective differentiation of trophoblasts. The focus on immunologic factors as a
 possible contributor to abnormal placental development was based, in part, upon the
 observation that prior exposure to paternal antigens is inversely correlated with the risk of
 preeclampsia. For instance, nulliparous women, women who change partners between pregnancies,
 have long interpregnancy intervals, use barrier contraception and conceive via
 intracytoplasmic sperm injection, all of which have less exposure to paternal antigens and a
 higher risk of developing PE. Moreover, there are also paternal contributions to PE such as a
 new partner, limited sperm exposure and the concept of a "dangerous father" (a father
 aged>45, obese and with a familial history of early-onset cardiovascular disease or
 hypertension). Last but not least, one of the most significant finding in this field is that
 donor sperm pregnancies (artificial insemination) which hold no pre-exposure to paternal
 antigens are much more likely to lead to PE.

 In contrast, oral sex (with the father's baby) was found to protect against PE, a finding
 that from an immunological point of view due may be explained by the relatively greater
 exposure of sperm antigen to the mother immune system via the buccal mucosa.

 Taking it all together the investigators assume that these putative risk factors cannot be
 entirely attributed to the maternal nor the paternal side, but to the encounter between those
 two. If there isn't an efficient exposure to the paternal antigens before conception, there
 is an increased risk for the PE cascade and other pregnancy complications to take place. This
 hypothesis can help in explaining the gap in the process that the investigators already
 described. It is possible that maternal immune system that doesn't develop tolerance to the
 paternal antigens that the seminal fluid carries, doesn't developed an adequate immune
 tolerance to the trophoblast cells and due to that, they are being under greater attack
 during placentation. Thus, they don't go through a normal differentiation, don't perform
 normal pseudo-vasculogenesis and the PE cascade is more likely to be carried out.

 There are several immunological mechanisms that support this assumption:

 -  The interaction between NK cells and extra-villous trophoblast cells: In PE, conflict
 between maternal and paternal genes is believed to induce abnormal placental
 implantation through increased NK cell activity.

 -  HLA-G: A gene with few alleles, that can be found both in the placental interface and in
 the paternal seminal fluid, has a significant role in inhibiting maternal immune
 responses against foreign (paternal) antigens.

 -  Regulatory T cells (Treg): Much of present thinking seems to involve a critical role for
 Treg in maintaining immunological tolerance during pregnancy. It has been suggested that
 during evolution, a mechanism of extra-thymic differentiation of Treg emerged in the
 placental to enforce maternal-fetal tolerance.

 Men has a clear evolutionary interest in ensuring that the immune system of his female
 partner accepts the semi-allogenic fetus. Due to that, he tries to "prime" the woman's immune
 system pre-conception.

 In conclusion, it is well established that both the maternal immune system and the paternal
 alloantigens have a role in the development of PE. Although the specific etiology remains
 unclear and can be only hypothesized. Therapies should aim not to suppress the maternal
 immune tolerance system but rather to enhance tolerance.

 In this study the investigators aim is to try and prove that there is a difference in the
 immunological reactions to semen prior to conception and that these changes are related to PE
 and/or other obstetric complications.

 Hence the investigators aim to study the immune response to semen of women that will be
 exposed to the culprit semen for the first time compare to women that have been exposed to a
 culprit semen more than once previously (namely more than 1 insemination prior to the time of
 evaluation). After that, in a prospective cohort study the investigators would follow those
 women through their pregnancies and check for different pregnancy outcomes.

 In this manner, the investigators are hoping to create a screening tool that will help to
 predict pregnancy and fetal complications before conception related to maternal immune
 responses of paternal antigens. If the investigators hypothesize turn out to be true, it can
 cause sperm banks all over the world to change their matching protocols and to test seminal
 fluid in the maternal blood sample before putting her through artificial insemination with a
 poor prognosis.

 For the best of the investigator's knowledge evaluation of immunological reaction to paternal
 seminal fluid in the mother's blood prior conception has never been tried before.
Inclusion Criteria:

 -  Age 18-45

 -  50 women for each group.

 -  Primigravid or first insemination from a new partner/sperm donor (group I)

 -  Women exposed to sperm (from the same donor/partner ≥ 2 times) (Group II)

 -  Singleton gestation

 -  Obtained verbal/written consent to participate in study

 Exclusion Criteria:

 -  o Multiple gestation

 -  Multifetal gestation

 -  Chronic hypertension

 -  Chronic renal disease

 -  Autoimmune disease (antiphospholipid syndrome, systemic lupus erythematosus)

 -  Vascular disease

 -  Pregestational diabetes mellitus