Said Elaccari, MD

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 All obstetricians and reproductive endocrinologists know the placenta as  the uppermost important organ for normal fetal growth till maturity.  This endocrinological organ can be affected by many pathological states  like other maternal organs. So placental failure can occur like heart  failure, renal failure, respiratory failure etc, all can occur from  childhood till old age but mostly encountered in the elderly people. The  same situation with placental failure, which usually occurs at term, if  earlier, than it may result in pregnancy loss.
 
 

PF can be defined as inability of the placenta to  provide the proper environment for fetal growth at any gestational age,  which may lead to pregnancy loss.
 
 

  The exact incidence of placental failure is still not  known exactly, from our observation it represents about 20-30% of  causes of pregnancy loss.
 
 

  Placental failure can be classified to 2 types:
 
 

A. Physiological placental failure (PHPF):

 which is characterized by the following: 

permanent changes cannot be treated or stimulated and involves all cotyledons. 

The outcome is a normal live baby; no therapy needed.

B. Pathological placental failure (PAPF):

 this type is characterized by the following:

transient or partial affecting some cotyledons only

corrected either spontaneously or can be stimulated externally, and the changes are temporal. 

The outcome is pregnancy loss, there is a need for therapy. 

Clinically we are concerned about this pathological placental failure because it can be diagnosed and treated before the event of pregnancy loss. 

According to degree of severity placental failure can be classified as follows:

Grade-I: mild form of PPF it is transient self-limited and usually  needs no therapy, observation, maternal blood levels of oxytocin  antagonists.

Grade-II: moderate form of PPF occurs more frequently and affects more than one cotyledon, needs therapy

Grade-III: severe type of PPF usually large areas of the placental cotyledons is affected. Emergency therapy is needed.


 This includes the following major predisposing factors:

decreased synthesis of placental hormones (CRH, ACTH, Estrogen or Progesterone).

decreased synthesis of placental enzymes (Cystine amino peptidases, Aromatase, etc)

abnormal transport mechanisms of placental hormones or enzymes

maternal disease (anemia, hypertension, UTI, RTI, hypothalamic or posterior pituitary dysfunction, etc).

low abdominal pain and/or low backache, irregular in nature, occurring at any gestational age, several times a day

vaginal spotting or bleeding may be recurrent its severity depends on grading of PPF

in more advanced cases profuse vaginal bleeding or passage of parts of conception in early pregnancy or as preterm delivery     will result in pregnancy     loss

history of previous bleeding or pain in the same pregnancy, and history of     unexplained previous pregnancy loss.

Diagnosis: 1-clinical, 2-laboratory, 3- CTG and 4-USG


 The most useful indicator for placental failure in my opinion is the  clinical situation and maternal blood levels of placental cystine  -aminopeptidases /oxytocinases. These enzymes usually rise progressively  till term (placental failure) at which time they decrease and so  oxytocin well occupies the free receptors and labor well occur.
 
 

  The placenta (blastocyst) remains the most  important endocrinological organ during pregnancy. It is well known that  the placenta synthesize and release several hormones, proteins, enzymes  and many other substances (1), all of which are responsible for normal  progress of fetal growth till maturity and delivery at term  (physiological failure).
 
 These substances include large amounts of sex steroid hormones (estrogen  and progesterone), the increased sensitivity of hypothalamus and  posterior pituitary glands to sex steroid hormones, results in increased  synthesis and release of oxytocin to the maternal circulation. The  function of this hormone is known to stimulate uterine contractions at  term and milk ejaculation after delivery. The new very important  function of oxytocin by its interaction with oxytocin placental  receptors during pregnancy is the stimulation of placental tissues to  synthesize and release CRH.
 
 


 
 This placental CRH acts on placental tissues to synthesize and produce  ACTH (26), which indeed stimulates the placental and peripheral tissues  to synthesize and release cystine amino-peptidases (CAP1 & CAP2) and  many other substances. 
 
 Both these enzymes (Oxytocinases), were found to increase progressively  with pregnancy progress till term (2,14,15,16,30,34), at which time the  placenta fails (physiological failure) to produce these substances and  delivery of normal baby is the final outcome. Two molecular species of  oxytocinases were found in human placenta (CAP I/ CAPII). (8) 
 
 In my opinion the mode of action of such enzymes is a competitive  inhibition of oxytocin, by interaction with oxytocin receptors in the  uterus and breast throughout the whole pregnancy (3). 
 
 The first maintains uterine relaxation till fetal maturity while the  other well prevent milk ejaculation till delivery, so oxytocin well be  acting most of the time on the placenta to produce CRH, because no free  ORs. This explains the major function of placental CRH, which was found  to increase from conception till term. 
 
 In relation to the above observation a new term should be given to such  peptidases in relation to the mode of action, that is a natural oxytocin  antagonist. I choose this word because antagonists are known as drugs.  On the other hand if we consider the placenta as a temporal foreign  industry in the maternal body, they can be named simply as oxytocin  antagonists because, they pass to the maternal circulation to the uterus  and breast looking for oxytocin receptors. Previously were described as  oxytocin analogues by Professor Klimek R. (which means exerting an  action similar to that of oxytocin), but indeed they inhibit its action  and itself produce no specific effect. This makes difficulty to accept  his opinion by other obstetricians in the world. The following  information explains the exact function of these enzymes, and their  relation to other placental substances in (Figure1). For better explanation of these results I named these antagonists  according to site of action as follows:

1.	The first is oxytocin uterine antagonist (OUA-CAP1) 


 This antagonist is produced mostly from the placenta and to a lesser  extent from the peripheral tissues. It interacts with oxytocin uterine  receptors (OUR) and so it prevents uterine contraction till placental  failure, this explains the following facts:

 Failure of induction of labor with synthetic oxytocin,  which means that the placenta still functioning and so, no free oxytocin  receptors were found (occupied by OUA). In such patients there is  increased risk of operative premature delivery.
 
 

 The failure of tocolysis in patients with threatened abortion  or preterm labor, because these are due to placental failure  (pathological failure), which can be prevented and treated. 
 
 

  The observation of intermittent attacks of uterine  contraction, which resolve spontaneously without treatment, that is due  to focal transient defect in release of OAs, and many other  observations.

2. The second is oxytocin breast antagonist (OBA-CAP2) 


 This antagonist mostly produced from the peripheral tissues and a little  by the placenta. It prevents milk ejaculation till few hours after  delivery of the placenta, by its interaction with oxytocin breast  receptors (OBR). This also explains the milk ejaculation in patients,  which delivered in the second or third trimester before fetal maturity  due to pathological placental failure. 
 
 From the previous discussion a placental feedback mechanism can be  illustrated below, to explain such conclusion which, is positive in  normal placental function gestations till biological fetal maturity  (Figure1). The keys of this PFBM is as follows:
 [Estrogen, progesterone, oxytocin, CRH, ACTH, OUA, OBA] 
 
 All these substances were found to increase gradually from conception  till maturity, by several workers but the exact function was not  explained. More explanation can be obtained from (Figure 2) the  placental factory model. 
 
 From the above observation, comes the answer to the question why instead  of high levels of blood oxytocin no uterine contractions or milk  ejaculation well occur till maturity? 
 
 The previous explanation is the decreased number of oxytocin receptors  before term, indeed oxytocin receptors present in the pregnant and  non-pregnant uterus (32). 
 
 In my opinion the oxytocin receptors (ORs) are occupied by oxytocin  antagonists (OAs) till placental failure at term. Because in cases of  placental failure the maternal blood levels of OAs were decreased, and  the circulating oxytocin interacts with the free OR and labor will  start.
 
 

Unexplained fetal deaths at the 3rd trimester, this indicates premature placental failure.

The end result of such complications is pregnancy loss if the correct intervention not advised.
 
 


 This type of placental failure can be prevented with serial measurements  of maternal blood oxytocin antagonists /oxytocinases as a screening  method in such patients with risk of pregnancy loss because the levels  decrease before the clinical state of placental failure (3,12,14). So if  any abnormal levels are observed then treatment can be given to  restimulate placental function and repair the placental feedback  mechanisms.
 
 

A. Oxytocin Antagonists (Cystine aminopeptidases):

 If we consider  the major predisposing factor for placental failure (uterine  contractions) is the diminished synthesis and / or production of OAs  which can be measured easily in the maternal circulation, the best  treatment well be the true synthetic oxytocin antagonists {still to be  synthesized}.
 
 

  At the present time we refer the cause of  abnormal low levels of OAs due to abnormalities in placental ACTH  production or transport in the placental tissues (3,4,5,13,17). 

This observation was seen when synthetic corticotrophin is given to  such cases with placental failure or as a clinical test for placental  function (17,18). That is elevation of maternal blood enzymes  subsequently. In most of the cases one course was enough to continue  pregnancy till term. This corticotrophin therapy appears to stimulate  endogenous placental production of ACTH and direct synthesis and release  of OAs. Which is indicated by progress of pregnancy till term, due to  repair of the MPFBM. The course of therapy consists of 0.5mg ACTH given  IM on 3 alternate days, followed by antibiotic for 5 days (Klimek). It  can be repeated if clinical or laboratory indications appear again later  in pregnancy. No complications were observed in all patients received  this therapy.
 
 

  Especially in early pregnancy in relation to the  observed decreased levels in many patients. The dose recommended is  250mg IM once per week for 4 weeks, can be repeated.
 
 

  In small dose may prove effective in some cases  with hypothalamic hypopituitary dysfunction, which result in negative  placental feedback mechanisms. In practice this explains the unexplained  silent fetal death without apparent cause.
 
 


 This clinical overview on the pathological placental failure and its  pathophysiologic complications explains to us the relationship of this  pathology to pregnancy loss, the major function of placental CRH and  ACTH in preventing uterine contractions till fetal maturity and so  preventing the event of pregnancy loss, and the exact role of  oxytocinases/oxytocin antagonists in maintaining pregnancy progress till  biological maturity. More concentration on the placental endocrinology  will open for us new methods of diagnosis and therapy to reduce the  incidence of pregnancy loss, which still representing a big disaster in  many couples and to many physicians. 
 
 Lastly I would like to recommend the serial measurement of oxytocin  antagonists (OUA) to all pregnant women in risk of pregnancy loss in  other areas of the world because this leads to discovery of the defect  before the occurrence of events, and invite drug researchers and  companies to start produce the true oxytocin antagonists and to find  fast reagents to detect such enzymes. 

1.    Creasy and Resnik : Endocrinology of Pregnancy; Maternal Fetal Medicine: Principles and Practice . 2nd ed,1989,W. B. Saunders Company.

2.    Edebin A.A., Mack D.S., and McDonald D.J. Philipf J.: The Stability And Short-Term Fluctuations In Serum Oxytocinase Activity In Pregnancy. I.J.obstet.gynecol1989; 28:331-335.

3.    Elaccari S ,Saidi N.,Placental Failure and Pregnancy Loss. 3rd International Royan Congress on Reproduction and Infertility.Tahran.Iran.September.2002.

4.    Elaccari S., Bekderna A.: Prevention & Treatment of Pregnancy Loss with Synthetic ACTH-depot (Synacthan-depot/Cortrosyn-depot)    Third National Libyan Congress of Scince.Tripoli.1996.

5.    Elaccari S, Soklicki Z, Skucinska D, and Skolicka E: Prevention and Treatment of Premature Deliveries with ACTH Depot    II world congress of prenatal medicine, Rome, 1993.

6.    Fuchs A.R., Fuchs F., Husslein P., Soloff N.S.: Oxytocin Receptors In The Human Uterus During Pregnancy And Parturition. Am. J.obstet.Gynecol.1984;150;734.

7.    Grino M, Chrousos G, Margioris A. The Corticotropin-Releasing Hormone Gene Is Expressed In Human Placenta. Biochem. Biophys. Res. Com. 1987;148:1208-1214.

8.    Itoh C, Watanabe M, Nagmastu A, et al : Two Molecula Species Of Oxytocinase (Cystine Aminopeptidase) In Human Placenta.Purification And Characterisation. Biol Pharm Bull1997 Jan;20(1)20-4. 

9.    Kleiner H.Dictus V.C. May C.C. et al: Human Placental Oxytocinase And Relationship To Pregnancy Plasma Oxytocin. Cl.Chem.Acta. 1980; 101:113-12

10.    Kliman HJ, McSweet JC, La T. Syncytial Knots Are The Source Of Placental CRH. Society for Maternal Fetal Medicine, Reno, NV, 2001.

11.    Klimek R.; Pietrzycka M.: Biochemical Method for the Determination of Oxytocinase and its Clinical Value. Clin Chim Acta,1961,6,326.

12.    Klimek R. : Enzymes As The Most Important Obstetrical Markers. In: Seminars In Perinatal Medicine-Evaluation Of Selected Enzymes In Pregnancy Monitoring. R.Klimek,G.Breborowicz (ed),Poznan,1999,II,9-22.

13.    Klimek R., Fraczek A.,Kaim I., et al: Results of Corticotropin Therapy of Threatened Pregnancies Due to Maternal hypothalamic insufficiency Syndrome. Clinical Perinatology &Gynecology,1996,16,182-186.

14.    Klimek R., Kupik A.: Enzyme (oxytocinase)-Aided Diagnosis and Prediction of Fetus at Risk of Death. International Congress of The Society “ The Fetus As A Patient ”,Fetal Diag. Ther.,Abst.1997,28,p116.

15.    Klimek R. :ENZYMATIC MONITORING OF PREGNANCY. EAGO PLB ISPPM.Cracow 1991.

16.    Klimek R. et al.: The Value Of Oxytocinase Determination In Fetal Monitoring Of Late Pregnancy. Gin.Pol. 1984;55:101.

17.    Klimek R. Michalski A. Milewicz S. Elaccari S. : Results Of Psychohormonal Prevention Of Premature Deliveries. Int. J. Prenatal Perinatal Studies.1991; 3;87-95.

,: Clinical Test For Placental Function Activity Using DHEA Sulphate and ACTH Injections in The Pregnant Woman. Acta Endocr. 1967; 119: 188.

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All obstetricians and reproductive endocrinologists know the placenta as the uppermost important organ for normal fetal growth till maturity. This endocrinological organ can be affected by many pathological states like other maternal organs.

Author | Said Elaccari, MD

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