Placental Failure: Clinical Implications

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Introduction
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.

Definition: 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.

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

Classification: Placental failure can be classified to 2 types:

A. Physiological placental failure (PHPF): which is characterized by the following: 

• occurs at term
• accompanied with fetal maturity
• 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:

• occurs before term
• accompanied with risk of pregnancy loss
• 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.

Etiology of Placental Failure:
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)
• decreased release of placental hormones
• decreased release of placental enzymes
• abnormal transport mechanisms of placental hormones or enzymes
• unknown causes
• maternal disease (anemia, hypertension, UTI, RTI, hypothalamic or posterior pituitary dysfunction, etc).

Clinical presentation 

• 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
• infrequent uterine contractions
• 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.

Pathophysiology: 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.

What is Oxytocin Antagonists (OAs/CAPs)?

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:

A. 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.

B. 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. 

C. 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.

Complications of Placental Failure
These include the following:

• Threatened Abortion
• Complete, incomplete or missed abortions
• Preterm labor and delivery
• IUGR
• Abruptio placentae
• 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.

Therapeutic considerations1.Prevention
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.

2.DrugsA. 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}.

B.ACTH-depot: 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.

C. Progestins: 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.

D. Oxytocin: 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.

E-estrogens: may also play some role.

Conclusion
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. 

References:

References

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.

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

19. Laustsen PG, Rasmussen TE, et al : The Complete Amino Acid Sequence Of Human Placental Oxytocinase. Biochim Biophys Acta 1997 May 2;1352(1):1-7

20. Makrigiannakis A, Margioris AN, LeGoascogne C, et al. : Corticotropin-Releasing Hormone (Crh) Is Expressed At The Implantation Sites Of Early Pregnant Rat Uterus. Life Sci 1995;57:1869-75

21. Margioris AN.: Corticotropin Releasing Hormone And The Placenta And Fetal Membranes. In: Molecular Aspects Of Placental And Fetal Membrane Autacoids, Brennecke S and Rice G (eds), CRC Press (publs) 1993;12:277-301

22. Margioris AN, Grino M, Protos P, Gold P, Chrousos G. Corticotropin-Releasing Hormone And Oxytocin Stimulate The Release Of Placental Proopiomelanocortin Peptides. J Clin Endocrinol Metab. 1988;66:922-926

23. Margioris AN, Grino M, Rabin D, Chrousos GP. Human Placenta And The Hypothalamic-Pituitary- adr Adv Exp Med Biol 1988;245:389-98

24. Matsumoto H, Mori T. : Changes In Cystine Aminopeptidase (Oxytocinase) Activity In Mouse Serum, Placenta, Uterus And Liver During Pregnancy Or After Steroid Hormone Treatments. Zoolog Sci 1998 Feb;15(1):111-5

25. Nakamura H, Itakuara A, et al : Oxytocin Stimulates The Translocation Of Oxytocinase Of Human Vascular Endothelial Cells Via Activation Of Oxytocin Receptors. Endocrinology 2000 Dec;141(12):4481-5

26. Petraglia F, Sawchenko PE, Rivier J, Vale W. Evidence For Local Stimulation of ACTH Secretion By Corticotropin-Releasing Factor In Human Placenta. Nature 1987;328:717-719

27. Petraglia F, Potter E, Cameron VA, Sutton S, Behan DP, Woods RJ, Sawchenko PE, Lowry PJ, Vale W. Corticotropin-releasing factor-binding protein is produced by human placenta and intrauterine tissues. J Clin Endocrinol Metab 1993;77:919-24

28. Riley SC, Challis JR. Corticotrophin-releasing hormone production by the placenta and fetal membranes. Placenta 1991;12:105-19

29. Roy AC, Saha N, et al : A new technique for detecting oxytocinase activity in electrophoresis gels. Electrophoresis 1992Jun;13(6):396-7

30. Ryden G.,: Cystine Aminopeptidase Activity in Pregnancy.Acta Obstet. Gynecol. 1972; 51: 329-334.

31. Sasaki A, Tempst P, et al : Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta. J Clin Endocrinol Metab 1988;67:768-73

32. Zomakis E, Makrigiannkis A,Margioris A,Stournaras C,Gravanis A : Corticotropin Releasing Hormone (Crh ) In Normal And Pregnant Uterus:Physiological Implications. Front in Bios 1,e1-8,1996

33. Toda S, Ando H, et al : Existence of placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase in human endometrial epithelial cells. J Clin Endocrinol Metab 2002 Mar;87(3):1384-9

34. Yamahara N, Nomura S, et al : Placental leucine aminopeptidase/oxytocinase in maternal serum and placenta during normal pregnancy. Life Sci 2000 Mar 3;66(15):1401-10.

Editor's Note: The information contained in this article is controversial. Oxytocin antagonists are no longer available in the US even for research.

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