Download Recurrent miscarriage – if a woman has experienced a sereise of at

Name:
Keren Shakhar (David)
Faculty: Psychology
Address:
Department of Psychology
Tel Aviv University
P.O. Box 39040
Tel Aviv 69978
Israel
Tel: 03-640-7018 (work); 03-732-3847 (home)
Fax: 03-640-9547
E-mail: [email protected]
Advisors: Prof. Shamgar Ben-Eliyahu, Dr. Shoshana Shilo
Papers published in peer reviewed journals:
Shakhar, K., Shakhar, G., Rossene, E., and Ben-Eliyahu, S. (2000). Timing within the menstrual
cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell
activity. British J. of Cancer, 83, 1630-1636.
Ben-Eliyahu, S., Shakhar, G., Shakhar, K., and Melamed, R. (2000). Timing within the estrous
cycle modulates adrenergic suppression of NK activity and resistance to metastasis:
Possible clinical implications. British J. of Cancer, 83, 1747-1754.
Ben-Eliyahu, S., Shakhar, G., Page, G.G., Stefanski, V., and Shakhar, K. (2000). Suppression of
NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines
and beta-adrenoceptors. NeuroImmunoModulation, 8, 154-164.
Yovel, G., Shakhar, K., and Ben-Eliyahu, S. (2001). The effects of gender, menstrual cycle, and
oral contraceptives on the number and activity of natural killer cells. Gynecology Oncology,
81, 254-262
Bar-Yosef, S., Melamed, R., Page, G.G., Shakhar, G., Shakhar, K., and Ben-Eliyahu, S. (in
press). Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats.
Anesthesiology, 94, 1066-1073
“Just relax and stay pregnant”
A psychoneuroimmunological perspective of recurrent miscarriage
During the last fifteen years, the interest in the contribution of psychological factors to fertility
problems between psychological factors and fertilty problems has increased. Although most
studies demonstrate that high levels of stress are associated with unexplained pregnancy failure, it
is still unclear whether stress is an etiological factor in the failure or merely its outcome. If stress
indeed contributes to pregnancy failure, the underlying biological mechanisms remain to be
established.
Recurrent miscarriage and stress
About 1 in a hundred couples experience recurrent miscarriages (RM). RM is defined as a series
of at least three involuntary losses of seemingly normal pregnancies before the 29 th week of
pregnancy. . The percentage of RM that may be attributed to known biological causes (e.g.
genetic defects) is at most 50%, while the majority of the cases are as yet unexplained. No doubt,
this condition is highly stressful
If stress does indeed contribute to RM, this could lead couples into a vicious circle: after
each miscarriage, levels of stress rise, leading to a higher risk of miscarriage during the next
pregnancy. Four studies have evaluated the effect of psychological support and therapy on
miscarriage in women suffering unexplained RM. All four reported that women who received
psychological support had approximately three-fold lower miscarriage rates than those who did
not. Although these studies suffer from several methodological problems, it is unlikely that these
problems account for such a marked reduction in abortion rates (from approximately 65% to
20%). However, since the success of psychological treatment is still under debate, and since the
biological mechanisms mediating its effects are unclear, integrating psychological treatment into
medical routines remains at a low priority.
A possible mediating mechanism: Immunity, NK cells and pregnancy
Pregnancy confronts scientists with a paradox: based on knowledge from transplantation
immunology, and on the fact that the fetus inherits half of its genetic makeup from the father, it is
expected that fetal tissue would be recognized as foreign and destroyed by the mother’s immune
system. However, in normal pregnancies, the fetus is not rejected and it does not evoke an
immune response characteristic of organ rejection. The complex mechanisms that protect the
embryo from immunological rejection are beginning unravel.
Natural killer (NK) cells are a subtype of lymphocytes (cells of the immune system),
capable of killing various types of foreign organisms and abnormal cells. During the last 10
years, these cells have drawn much attention in respect to normal pregnancy, spontaneous
abortion, and recurrent miscarriage. The numbers of these cells in the uterus markedly fluctuate
during the menstrual cycle, and high numbers of NK cells are maintained in the uterus along the
first trimester of pregnancy (~70% of all leukocytes, compared to ~3% in the blood). These cells
are absent from the uterus before menarche and after menopause. The function of uterine NK cells
is still unclear, but their abundance at the uterus suggests that they play an important role in
implantation and fetus development.
Recurrent miscarriage and NK cells
One of the most popular theories for the cause of unexplained RM is over activation of NK cells
in the uterus. Studies in both humans and animals support this notion. Women diagnosed with
RM exhibit higher numbers and activity of NK cells than normal women, and among these
women higher levels of NK activity predict subsequent miscarriage (70% vs. 20%). Studies in
mice have shown that activation of the immune system causes abortion, whereas such activation
has no effect if NK cells are depleted beforehand.
Stress, the immune system, and NK cells
Stress is a heterogeneous phenomenon that has been shown to affect various immune indices in
different ways. Our lab, as well as others, has reported that the number and activity of NK cells
increase or decrease depending on the type of stressor, specific organ (blood, spleen, uterus, etc),
timing, and various preexisting conditions (levels of sex hormone, activation status of the immune
system, etc.). Academic exams, care-giving for relatives with Alzheimer’s disease, social
confrontation, and parachuting jumps, have each been reported to highly affect the number and/or
the activity of NK cells. It is therefore possible that NK cells participate in mediating the effects
of stress on pregnancy in general, and on RM in particular.
Aims of the study
1. To replicate and refine on the findings that increased number or activity of NK
cells characterizes women with RM
2. To assess the effects of a psychological intervention aimed at alleviating stress in
women diagnosed with RM in respect to: psychological well-being, biological and
immunological measures, and pregnancy outcome. Women with RM will be
randomly assigned into two groups: one group will serve as a control group which
will receive standard care and the second group will be offered to participate in a
behavioral-cognitive intervention based on the Mind/Body Program for infertility
of
Harvard
Medical
School.
More specifically, this study will assess whether:
a. The psychological intervention indeed lowers stress levels (both
self-reported and assessed by biological parameters such as stress
hormones and blood pressure)
b. The intervention reduces miscarriage rates in women diagnosed
with RM
c. The intervention affects number and activity of NK cells, as well
as other immune measures related to it (e.g., different cytokines)
d. The effects of the psychological intervention on miscarriage rates
are mediated by alteration in stress hormones and immune function