Role of micronized vaginal progesterone in preventing miscarriage. Which route and what kind of progesterone is superior.

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Vaginal NMP  in immune modulation

Certain   immune factors are required to be inhibited for the fetus  to survive since it is a semi allograft. This is    a selective  process so that it does not have  an impact on the maternal general immune  suppression Cytotoxic   T cells    and natural killer cells are the two main effect or     cells that need to be suppressed . Moreover progesterone  secretion that influences circulating   PIBF may be an important factor  in cellular  immune suppression Progesterone  is also shown to may act in an extra nuclear  manner to suppress T cell   rejection of    the fetal semi  allograft. The pivotal role of progesterone   receptor mediated immune modulation in a  successful  pregnancy  is summarized .

Researchers  determined if exposure to progesterone alone was sufficient to increase the  production of the  immunomodulatory protein PIBF  . They also determined  what method of progesterone delivery  or form of progesterone best stimulated  PIBF   secretion. They   evaluated the serum samples from infertile  patients for both PIBF   and progesterone    at various  times during the follicular phase and the luteal  phase in both natural cycles and cycles involving   embryo  transfer after endogenous   and exogenous progesterone exposure.

A marked increase in serum PIBF  was observed with progesterone alone without exposure  to the fetal  Allogenic  stimulus .

 The serum PIBF  levels  for the combined  progesterone  groups      were significantly higher   in the luteal  phase than the follicular  phase controls. Therefore  exposure  of the fetus to an  Allogenic stimulus   is not   needed to cause a marked rise in PIBF. Exposure   to a high  concentration of progesterone is sufficient  to secrete high   levels of PIBF.

Progesterone promotes the development of a cytokine   microenvironment   which   favours  pregnancy  maintenance. The expression of Th2  type cell  responses   and leukemia inhibitory factor is   increased  in the presence   of progesterone ,.Therefore  elevated concentrations of progesterone   promote  an immune environment  that favours  pregnancy   maintenance.

Point VII :- spiral   artery pulsatility and resistance   index and systolic / diastolic ratio  is decreed satisfactorily in MNP group than in   oral Dydrogesterone treatement Group:: Vaginal   NMP  improves utero placental blood flow than oral supplementation.

A study   was conducted in cases of  threatened  abortion to compare the influence of vaginal micronized progesterone  and oral dydrogesterone  supplementation for 6 weeks   on utero placental circulation   in early  pregnancy complicated  by threatened  abortion. Researchers demonstrated that vaginal   progesterone administration resulted   in the decrease      in the spiral   artery pulsatility and resistance   index and systolic / diastolic ratio but not   oral Dydrogesterone treatement . Dydrogesterone   treatment   was only accompanied by the decrease in the uterine artery  systolic / diastolic ratio. Analysis of the spiral artery impedance indices suggests   increased  vascular    resistance   in these  vessels  were partly  normalized  by vaginal   progesterone supplementation which  potentially resulted to improved  oxygen    and nutrient supply to the embryo Peri conceptional  progesterone early during the luteal   phase  in women    with history  of RPL

At the start of the luteal phase   patients  were administered  400 mg vaginal  progesterone  pessaries or placebo  twice   daily and were   continued after a positive   pregnancy  test till 28 weeks of gestation. Measuring   the cytokines  levels  through first second and third trimester:-

Findings   revealed that Observation 1:-A significantly lower  miscarriage rate in the vaginal   progesterone   group  and a  significant    improvement in rate of pregnancy   continuation   beyond  20  weeks  in the vaginal   progesterone group . Observation 2:- A significant improvement   in the liver birth rate in the vaginal   progesterone group   in comparison to placebo  group . Observation 3:-There  was no statistical change  in levels     of cytokines pre conceptionally  between  the 2 groups. However  there was  significant progressive  increase   in IL- 10 and  decline in IL-2 and TNF α in the vaginal   progesterone   group   as compared    to the placebo  through  1^st , 2^nd   and 3^rd  trimester. The   immunomodulatory effect  in the vaginal  progesterone  group  as compared   to the control is outlined  .

This was the first study that correlated   clinical findings   with the laboratory    findings by measuring   the cytokines  levels  through first second and third trimester .Greater  changes in cytokines levels were observed in the progesterone group   as compared    to placebo. This reflected the  immunomodulatory   action of  progesterone associated  with lower  miscarriage   rates and higher live birth rates. Periconceptional vaginal NMP administered  during the luteal    phase effectively reduces  the risk of miscarriage in women with unexplained RPL. It may   also lower   the risk of   PTB   and lead to higher   live birth  owing  to its immunomodulatory actions.

Point VIII: Take home message :

Progesterone   secreted by corpus  luteum  during the luteal phase plays an essential role in  endometrial   transformation   and maintenance of early pregnancy .

Progesterone  supplementation may help to improve  its physiological  levels primarily arising due to some  of the key defects in RPL  including smaller   trophoblast   volume and reduced   trophoblast  growth  defects  in utero placental   circulation luteal   phase defects   and immunomodulatory   actions. Application  of micronized progesterone in the vagina doubles the concentration in the uterine arterial blood compared  with peripheral  arterial blood. Progesterone  concentration after vaginal   administration is 10-20  times greater compared    with parenteral    administration in doses resulting in identical  peripheral  plasma   values. Use  of luteal   start vaginal   micronized progesterone  is associated  with improved  pregnancy  success in women with   a history  of unexplained RPL. 

Peri conception vaginal   NMP  is effective in reducing  the risk of miscarriage  in women   with unexplained   RPL when     administered   during the luteal  phase of the  cycle. It may also lower   the risk of PTB  and higher    live birth   owing to its  immunomodulatory    actions.