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Pathological pregnancy, placental calcification, and nannobacterial infection: is there any relationship between these events?


An important sign of pathological pregnancy is increasing placental calcification (PC). The nature and mechanisms of PC development remained undefined. Meanwhile, the ultra-small bacterial forms (nannobacteria) were found in other calcified sites--in kidney stones and in dental plaque. The nannobacteria were capable of inducing the calcification in vitro. (11-14) Our article presents a new attempt to discover a cause of PC as a relationship between calcification of the placental tissues and the presence of nannobacteria there. Distribution of PC in the tissue samples was confirmed with standard ultrasonographic detection and microscopy; presence of the nannobacteria in the PC-containing samples was shown with electron microscopy. Numerous nannobacteria and grains of the mineral deposits were discovered in microcavities in the tissues; no nannobacteria were found in sites without calcification. The role of nannobacteria in placenta is discussed--they can play a pathological role in PC development through formation of mineral deposits in the placental microcavities where these bacteria form a supersaturated environment favorable for local calcification. Subsequently, the calcification process affects restricting the calcium delivery to the fetus and may cause pathological pregnancy.

Pregnancy is a physiological state characterized by increasing food intake and by important changes in carbohydrate, lipid, and protein metabolism. This adaptation is essential to sustain exponential fetal growth; it is coordinated through the placental state, namely, the maturation of placental tissues and their functional activity. The placenta is the temporary organ required for adequate delivery of oxygen, nutrients, and ions to a growing fetus and its protection against direct contact with infections of the mother. Chronic disorders of the vital functions of the placenta and its premature aging can disrupt normal development of fetal programming and lead to different diseases or fetal lethality. (1, 2) The placental mineral deposits occur quite commonly among various placental pathologic findings; mainly they are presented in the form of calcification. (3-5) Case reports in literature also present the same clinical observations about positive correlation between PC development and certain metabolic shifts in a woman's homeostasis. (6-8)

The mechanisms of calcium biomineralization probably involve one of three known mechanisms of tissue calcification: (4) physiological (like bone), pathological (ischaemia-related), and "metastatic" (mineralization in a supersaturated microenvironment), which may appear in soft tissues as placenta. According to the chemical composition, energy-dispersive X-ray analysis of PC, and its polymerase chain reaction analysis (3) have suggested that the PC development is progressing rapidly via a puzzling induction of a local supersaturated environment in the placenta. To the present time, a proposed placental site where the latter environmental conditions could appear is not yet at hand.

Considerable recent attention has been focused on ultra-small microorganisms, collectively referred to by geologists and biologists as "nanobacteria" or "nannobacteria" that are involved in biomineralization. (9) Firstly, the "nannobacteria" have been found and isolated from human stones and from human dental plaque. (10-14) In contrast, no nannobacteria were found during their search in a row of cases of tumoral calcinosis, subepidermal calcified nodule, and some others. (15) By our point of view, the findings of nannobacteria raised the intriguing possibility of whether these microorganisms can act as promoting factors for pathological calcification of placenta. Therefore, the goals of our study were to investigate the PC containing tissues and to establish the presence of the nannobacteria there. The presented electron-microscopic data of the PC investigations presented below confirm validity of our suggestion.

The transmission electron microscopy discovered the presence of three types of objects of interest in the calcified sites of the placental tissues. They were: microcavities in the tissues, nannobacteria in the microcavities and around them and mineral microdeposits (irregular grains) of calcium localized in the same sites. These objects were never found in normal placental tissues with the same methods of investigation. The microcavities were of 1 x 6 [micro]m size, however, they served as a main place of localization or concentration of the nannobacteria and the mineral microdeposits (Fig.1). Low electron density of the microcavity, in comparing with the surrounding tissues, testifies to the fact that the cavities were filled with some solution or gel favorable for accumulation of dissolved inorganic salts, i.e., for deposition of insoluble calcium compounds. The experimental finding confirms the earlier proposed mechanism of PC development (3), namely, that rapid formation of apatite mineral in placenta means the existence of some microsites with the supersaturated environment. Thus, our publication presents evidence that the placental microcavities are the same microsites where the proposed environment can be generated. The underlying cause for the microcavity formation as a fertile ground for calcium deposit is not yet known.


Our investigations on the contents of microcavities and the close surrounding tissues showed that presence of mineral microdeposits can be confronted with distribution and concentration of nannobacteria (0.15-0.20 [micro]m in diameter) within the sites. The revealed nannobacteria were coated with cellular membranes. It should be noted that some of the nannobacteria were found in direct contact with calcium microdeposits, i.e., in localization similar with that described for nannobacteria in human kidney stones or in dental plaque. (10-14) The cited authors explained localization of the nannobacteria on/in grain of mineral deposits as a cause and effect of the membrane-induced mechanism of calcification. Indeed, the bacterial membrane can accumulate inorganic ions. We found the situation during artificial formation of bacterial nannocells. 16 However, it must be mentioned that localization of nannobacteria inside of mineral grains or coating of the whole bacterial cell with mineral envelope excludes bacterial growth and multiplication because it limits their outer space. Our observations on the PC formation in microcavities are more attributable to other mechanisms of calcification, namely, development of a local environment that is supersaturated with calcium and phosphate or oxalate (3) as it occurs with urolithe formation. (17) There are some known biochemical compounds or, as well, bacterial products identified as inductors and/or promotors of tissue calcification. (18-20)

Calcium is actively transported via the placenta throughout gestation, making the fetus relatively hypercalcemic. (21) This action supports the cellular divisions in the fetus and placenta. According to clinical observations, enhanced PC is often seen in placenta associated with fetal growth restriction, probably via inadequate calcium delivery to growing fetal organs and/or disruption in Ca-dependent metabolic bonds.

Moreover, a growth-restricted fetus often has abnormalities in the bone mineralization that may be observed in a delayed appearance of ossification sites. (22) Complex of these abnormalities can break down a fetus's ability to survive or can give rise to development of different diseases.

The present study has provided the first demonstration of novel link between the PC development during a woman's pregnancy and placental microcavities containing the nannobacteria. This paper reports our initial results on the investigation and discusses a possible participation of nannobacteria in the formation of calcium placental deposits and possibilities for development of fetus pathology. Mechanisms of the PC formation by nannobacteria are still under discussion and remain to be defined in the future.

The work was supported in part by grant 00-04-48704 from Russian Foundation for Basic Research.


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(2) Benrschke, K. and Kuafmann, P. (1995). Pathology of the human placenta. New York: Springer Verlag.

(3.) Poggi, S .H., et al. (2001). Placental calcification: a metastatic process? Placenta, 22, 591-596.

(4.) Klesges, L .M., et al. (1998). Relations of cigarette smoking and dietary antioxidants with placental calcification. American Journal of Epidemiology, 147, 127-135.

(5.) Fredy, N., et al. (1993). Environmental exposure of cadmium and human birthweight. Toxicology, 79, 109-118.

(6.) Chong, S.W.L.V., Kion, S. A., and Cullen, M. U. (1999). A report of familial hyperphosphataemia in an Irish family. Irish Journal of Medical Science, 168, 262-264.

(7.) Graham, E. M., Freedman, L .J., and Forouzan, I. (1998). Intrauterine growth retardation in a women with primary hyperparathyroidism--a case report. Journal of Reproductive Medicine. 43, 451-454.

(8.) Ernst, L. M. and Parkash, V. (2002). Placental pathology in fetal Bartter syndrome. Pediatric and Development Pathology, 5, 76-79.

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(10.) Kajander, O. E. and Ciftcioglu, N. (1998). Nanobacteria: An alternative mechanism for pathogenic intro- and extra-cellular calcification and stone formation. Proceeding of the National Academy of Science USA, 95, 8274-8279.

(11.) Kajander, E. O., Bjorklund, M., and Ciftcioglu, N. (1998). Mineralization by nanobacteria. SPIE Proceedings, 3441, 86-94.

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(13.) Ciftcioglu, N., Bjorklund, M., and Kajander, E.O. (1998). Stone formation and calcification by nanobacteria in the human body. SPIE Proceedings, 3441, 105-111.

(14.) Cisar, J.O., et al. (2000). An alternative interpretation of nanobacteria-induced biomineralization. Proceeding of the National Academy of Science USA, 97, 11511-11515.

(15.) Morgan, M .B. (2002). Nanobacteria and calcinosis cutis. Journal of Cutaneous Pathology, 29, 173-175.

(16.) Vainshtein, M., et al. (1998). Formation of bacterial nanocells. SPIE Proceedings, 3441, 95-104.

(17.) Anderson, H. C. (1983). Calcific diseases: a concept. Archives of Pathology and Laboratory Medicine, 107, 341-348.

(18.) Parhami, F., et al. (2001). Leptin enhances the calcification of vascular cells artery wall as a target of leptin. Circulation Research, 88, 954-960.

(19.) Balica, M., et al. (1997). Calcifying subpopulation of bovine aortic smooth muscle cells in response to 17beta-estradioil. Circulation, 95, 1954-1960.

(20.) Papahadjopoulas, D. (1968). Surface properties of acid phospholipids: interactions of monolayers and hydrated liquid crystals uni- & bi-valent metal ions. Biochemical Biophysics Acts, 163, 240-254.

(21.) Pitkin, R. M. (1985). Calcium metabolism in pregnancy and the perinatal period. A review. American Journal of Obstetrics & Gynecology, 151, 99-109.

(22.) Zilanti, M., et al. (1987). Ultrasound evaluation of the distal femoral ephiphyseal ossification center as a screening test for intrauterine growth retardation. Obstetrics & Gynecology, 70, 361-364.

R. M. Agababov, T. N. Abashina, N. E. Suzina, M. B. Vainshtein, P. M. Schwartsburd

Corresponding author: Dr. Polina M. Schwartsburd, Sc.D. Address: Institute of Theoretical & Experimental Biophysics, Russ. Ac. Sc., Institutskaya Str. 1, Pushchino, 142290 Russia. E-mail:
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Author:Agababov, R.M.; Abashina, T.N.; Suzina, N.E.; Vainshtein, M.B.; Schwartsburd, P.M.
Publication:Frontier Perspectives
Geographic Code:4EXRU
Date:Mar 22, 2003
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