ORIGINAL ARTICLE
The comparison of vessels in elective and spontaneous abortion
decidua in first trimester pregnancies: importance of vascular
changes in early pregnancy losses
BANU DOGAN GUN, GAMZE NUMANOGLU & SUKRU OGUZ OZDAMAR
Department of Pathology, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, TurkeyAbstract
Background. To determine whether adequate trophoblastic migration and maternal placental perfusion occurs in cases of early pregnancy loss, we compared vessels in elective abortion decidua with those in spontaneous abortion decidua. Methods. Elective abortion decidua at 5/11 weeks (n/40) were compared with spontaneous abortion decidua
at 5/12 weeks (n/25). Also normal late secretory endometrial biopsy specimens (n/10) were examined. The
cross-sections of veins and arteries were counted in 25 elective and 15 spontaneous abortion materials. The number of the veins that contain trophoblastic fragments and the number of the spiral arteries converted by trophoblasts were determined. Statistical significance by Mann/Whitney U and Spearman’s correlation test was p B/0.05. Results. All sets of decidua
had dilated veins, but no secretory endometrium did. The ratio of converted spiral arteries to nonconverted arteries was much more in elective abortion decidua (113/938, 12.04%) than in spontaneous abortion decidua (11/511, 2.15%) (p B/0.001). Conclusions. The presence of converted arteries, dilated veins, and intravenous trophoblastic fragments in
decidual specimens were evidence of intervillous circulation and placental perfusion by maternal circulation in the first trimester. Also the insufficient conversion of the arteries in spontaneous abortions might be responsible for many cases of early pregnancy loss.
Key words: vessels, intervillous circulation, trophoblastic migration, decidua, abortion
Abbreviations: IT: intermediate trophoblasts, HPF: high power fields, hPL: human placental lactogen, EMA: epithelial membrane antigen
Successful implantation requires a series of complex and coordinated interactions between maternal tissue and trophoblasts (1). The intermediate tro-phoblasts (IT) that infiltrate the decidua and myo-metrium at the implantation site are responsible for remarkable physiologic structural modifications in the spiral arteries essential to increase blood flow to the implantation site (1,2).
In the early weeks of pregnancy, IT invade the decidual segments of the spiral arteries and with fibrinoid material composed of a complex fibrin, plasma constituents, and proteinaceous substances produced by trophoblasts replaces the endothelium, and the muscular and elastic tissue of the media (1,3). Exactly when in pregnancy this flow begins is
uncertain. Some investigators propose that intervil-lous circulation of maternal blood is likely to be established progressively between the 8th and 12th weeks (4/7).
These histologic observations describe a channel for blood flow but the variations in the spiral arteries alone cannot establish that passage of maternal circulation through the placenta has occurred. If placental perfusion has occurred the increased flow into maternal decidual veins may cause them to become dilated. The veins may also contain placental syncytiotrophoblastic fragments that have dissociated from the syncytial conti-nuum on the villi and entered the maternal circulation.
Correspondence: Banu Dog˘an Gu¨n, Zonguldak Karaelmas U¨ niversitesi, Tıp Faku¨ltesi, Patoloji Anabilim Dalı 67600, Kozlu, Zonguldak, Turkey. E-mail:
dogagun2@yahoo.com
(Received 27 December 2004; accepted 21 October 2005)
ISSN 0001-6349 print/ISSN 1600-0412 online # 2006 Taylor & Francis DOI: 10.1080/00016340500501731
In our study we aimed to stress the importance of vascular changes in early pregnancy losses by com-paring the vessels in elective abortion decidua with those in spontaneous abortion decidua; also to provide additional evidence about uteroplacental circulation by demonstrating the pathologic changes in arteries along with veins in first trimester abortion decidua.
Materials and methods
This study compared the vessels of elective abortion decidua with those of spontaneous abortion decidua. From January 2001 to May 2002, 40 elective and 25 spontaneous abortion specimens from the surgi-cal pathology archives of Zonguldak Karaelmas University Hospital were examined. Also 10 cases of normal secretory endometrial biopsy specimens were evaluated. The gestational ages of decidua ranged from 5 to 11 weeks in elective abortions and 5 to 12 weeks in spontaneous abortions.
All the hematoxylin-and-eosin stained sections were reviewed; it was confirmed that the specimen had contained both decidua basalis and parietalis. The necrotic and extensive acute inflammatory areas were excluded. The cross-sections of arteries and veins were counted in 25 of 40 elective abortion and 15 of 25 spontaneous abortion decidua. The number of veins that contain trophoblastic fragments were seen mostly in areas of decidua parietalis, and determined by counting 10 consecutive high power fields (HPF) (Leica DMLS, Leica Microsystems Inc., Buffalo, New York, USA, field perimeter: 2 mm). Also the number of spiral arteries that were converted by trophoblastic cells was determined by counting 10 consecutive HPF in areas of deciduas basalis. Dilated veins were identified as distended, thin-walled vascular structures, without prominent smooth muscle cells or fibrinoid material in the wall. The replacement of endothelium by endovascular trophoblastic cells, the destruction of medial elastic and muscular layers, and the presence of fibrinoid material in the wall of the arteries were determined as ‘remodeled spiral arteries’.
In both groups the ratio of converted arteries to nonconverted arteries and the ratio of veins with syncytial elements to the veins that did not contain trophoblasts were determined. Mann/Whitney
U -test was used for statistical analysis and statistical significance was set at p B/0.05.
Gestational age at the time of the termination was compared with the ratio of veins that contained syncytiotrophoblastic fragments and ratio of remo-deled arteries. Spearman’s correlation was done, and
the coefficient of the correlation was determined. Statistical significance was set at p B/0.05.
Normal late secretory endometrial biopsy speci-mens were obtained from the archives and the mean postovulatory day of the 10 samples included in this study was 10 days with a normal 28-day menstrual cycle. The vessels in tissue samples of late secretory endometrium were also evaluated and changes in arteries and veins were noted.
Gestational age at the time of the termination was compared to the number and frequency of the syncytiotrophoblastic fragments in veins and remo-deled arteries.
Results
None of the late secretory endometrial biopsy speci-mens had dilated vessels (0/10) in comparison with all sampled sets of decidua containing sponta-neous and elective abortion (65/65) (Figure 1a/c).
All of the late secretory endometrial specimens had small-calibered and narrow-lumened arterioles and did not contain fibrinoid material or atherotic change (Figure 1a).
In elective abortion decidua intravenous syncytio-trophoblastic fragments were seen in 75% of decid-ual samples stained with hematoxylin and eosin (Figure 1d) and in the 25 cases reviewed by quantitative studies, 44 of 849 cross-sections of decidual veins contained syncytial elements (5.11%). The converted spiral arterioles were pre-sent in 36 of 40 specimens (90%) (Figure 1e) and their ratio to nonconverted spiral arteries was 113/ 938 (12.04%).
In spontaneous abortion decidua the veins that contained syncytiotrophoblastic fragments were seen in 19 of 25 specimens (76%) and in the 15 speci-mens their ratio was 28/500 (5.6%). The converted vessels were present in 13 of 25 specimens (52%) (Figure 1f) and their ratio was 11/5111 (2.15%).
There were no histologic difference in remodeled arteries between elective and spontaneous abortion. Decidual glands did not contain syncytiotrophoblas-tic fragments.
Elective abortion decidua contained many more converted spiral arteries than in spontaneous abor-tion (p/0.001). However the numbers of the
syncytiotrophoblastic fragments in decidual veins were not statistically significant in either group (p/0.613) (Table I).
The gestational ages of decidua in this study range from 5 to 11 weeks (6.99/0.3) in elective and 5 to 12
weeks (8.39/0.5) in spontaneous abortion. As the
gestation progressed in elective abortions, the pro-portion of the converted arteries increased
(correla-tion coefficient/0.753, p/0.001), however the
proportion of veins that contain syncytiotrophoblas-tic fragments decreased (correlation coefficient/
0.417, p/0.038). And in spontaneous abortions,
the proportion of the converted arteries increased (correlation coefficient/0.616, p/0.014), but there
was no correlation between the proportion of tro-phoblast-containing veins and the gestational week (correlation coefficient/0.13, p/0.716).
The vessels that contained atherotic changes were noted in three vessels: one of elective and two of spontaneous abortion decidual materials (Figure 2).
Discussion
Normal placentation requires a progressive transfor-mation of the spiral arteries and infiltration of the placental bed by trophoblastic cells (3,4). This creates high-flow, low-resistance arteries that provide appropriate blood flow to the fetus via the uteropla-cental circulation. Although the mechanisms leading to impaired remodeling of uteroplacental arteries are still unclear, some investigators suggest that inflam-matory and immunologic factors may play a part in this event (8,9). Most (90%) of the decidual elective abortion samples in this study had well developed Figure 1. Arterial and venous alterations in both abortion materials and secretory endometrium. (a) Straight and inconspicuous veins with coiled spiral arteries in late secretory endometrium (H&E,/100). (b) Dilated and congested veins of spontaneous abortion (H&E,/40).
(c) First trimester decidual veins are dilated in elective abortion decidua (H&E,/100). (d) Intravenous syncytiotrophoblastic fragment in a
vein of elective abortion decidua (H&E,/100). (e) The replacement of endothelium by endovascular trophoblastic cells and fibrinoid
deposits; the remodeled spiral arteries in an elective abortion decidua (H&E,/100). (f)The converted arteries in an spontaneous abortion
spiral arteries with extensive trophoblastic cell infil-tration of the arterial wall, but patients who had spontaneous abortion demonstrated significantly increased incidence (52%) of inadequate placenta-tion and in particular reducplacenta-tion or absence of trophoblastic invasion of the placental bed and defective transformation of the spiral arteries.
Intravenous syncytiotrophoblastic fragments were seen in 75% of elective and 76% of spontaneous abortion materials in this study, indicating that maternal flow from the intervillous space into decidual veins had occurred in the early weeks of gestation. These multinucleated cells are known to leave the placenta and enter the maternal systemic venous circulation by a process called deportation. The syncytial elements dissociate from the villi and pass as multinucleated cells into the intervillous space (10).
Another important finding in our study is the observation of dilated veins in both types of abortion materials, but not in nongestational endometrium. It is therefore possible to make a diagnosis of intrau-terine pregnancy by identification of dilated veins in the absence of fetal parts, chorionic villi, or tropho-blasts. When maternal placental circulation has occurred, the increased blood flow to the maternal veins will give rise to venous dilatation (11). Another
mechanism for decidual venous dilatation may be hormonal changes of pregnancy. The presence of hormone receptors on some systemic veins suggests that some dilatation may occur by a receptor-mediated pathway (12). In our study all the decidual samples had dilated veins, but no secretory endome-trium did.
Atherotic changes were noted in three vessels: one in elective and two in spontaneous abortion materi-als, however there were none in late secretory endometrium. Acute atherosis of some spiral arteries with concentric intimal proliferation of myofibro-blasts and foamy cells in gestational endometrium can be seen. These alterations apparently occur in response to trophoblastic invasion of endometrial vessels; they are focal and more frequent in primi-gravidas. They are not associated with pre-eclamp-sia, eclamppre-eclamp-sia, diabetes, or hypertension (1,13/15).
And also none of the three cases in our study suffered from these diseases.
Intermediate trophoblastic cells are important for implantation and establishment of uteroplacental circulation (1,2). In histopathological examination, it may be difficult to distinguish these cells from decidual cells, except when multinucleated forms are present (2). Some authors propose to use cytokeratin, human placental lactogen (hPL) and epithelial membrane antigen (EMA) immunostain-ing to differentiate trophoblasts (1/3). However
intermediate trophoblastic cells have a characteristic variegated low-magnification appearance and exhi-bit specific nuclear features in the form of enlarge-ment, hyperchromasia, highly irregular outline, and deep multinucleated clefts (2). Although the use of immunostaining for detection of trophoblastic cells has the advantage of being more objective, it is also possible to discriminate these cells by morphological identification.
There are a lot of studies demonstrating the remodeling of spiral arteries (5,9,11,16,17), but only a few studied the changes in veins. Craven and Ward compared veins in decidua of elective abortus materials with those in endometrium (18). Also Genest studied the fetal stem arteries and Figure 2. Atherosis of a decidual vessel with foamy vacuolization
of endothelial cells (H&E,/200).
Table I. Vascular changes in abortion decidua and late secretory endometrium.
n Dilated vein Remodeled artery Trophoblast-containing vein Elective abortion 40 40 (100)* 36 (90)$ 30 (75)%
Spontaneous abortion 25 25 (100) 13 (52) 19 (76) Late secretory endometrium 10 0 (0) 0 (0) 0 (0) *Number (% positive).
$p B
/0.001; elective versus spontaneous abortion.
%p
villous capillaries in the placentas of stillborns and concluded that morphological alterations including sclerosis and obliterations of arteries and capillaries had begun about six hours after fetal death and been fully established within three weeks (19). We thought that the status of the fetus or embryo did not affect arterial remodeling, but primary fetal factors, mainly chromosomal aberrations, might give rise to insufficiency of arterial conversion and consequently spontaneous abortions.
This study is the first to document the histological alterations in the arteries and veins of both elective and spontaneous abortion decidua and compare them with those of secretory endometrium. The detailed analysis of these vascular alterations in both groups will give us new clues about the pathogenesis of spontaneous abortions.
In conclusion, we demonstrated that maternal decidual veins are distended and contained syncy-tiotrophoblastic fragments, indicating that maternal intervillous perfusion occurs in the first trimester of pregnancy. Furthermore it is considered that the presence of dilated veins in uterine curettings may be used diagnostically as a sign of intrauterine preg-nancy in the absence of villi or invading trophoblast. We also suggest that insufficiency of transformed arteries, perhaps associated with chromosomal ab-normalities, may give rise to early pregnancy losses. But further studies are required to evaluate the correlation between the factors causing spontaneous abortion and vessel changes.
References
1. Gersel DJ, Kraus FT. Diseases of the placenta. In: Kurman RJ, editor. Blaustein’s Pathology of the Female Genital Tract. New York: Springer-Verlag; 2002. p. 1103/91.
2. Wan SK, Lam PW, Pau MY, Chan JK. Multiclefted nuclei: a helpful feature for identification of intermediate trophoblastic cells in uterine curetting specimens. Am J Surg Pathol. 1992;/
16:/1226/32.
3. Shih IM, Kurman RJ. The pathology of intermediate tropho-blastic tumors and tumor-like lesions. Int J Gynecol Pathol. 2001;/20:/31/47.
4. Jaffe R, Jauniaux E, Hustin J. Maternal circulation in the first-trimester human placenta /myth or reality? Am J Obstet
Gynecol. 1997;/176:/695/705.
5. Valentin L, Sladkevicius P, Laurini R, Soderberg H, Marsal K. Uteroplacental and luteal circulation in normal first trimester pregnancies: Doppler ultrasonographic and mor-phologic study. Am J Obstet Gynecol. 1996;/174:/768/75.
6. Carbillon C, Challier JC, Alouini S, Uzan M, Uzan S. Uteroplacental circulation development: Doppler assessment and clinical importance. Placenta. 2001;/22:/795/9.
7. Kurjak A, Kupesic S, Hafner T, Kos M, Kostonevic-Knezevic L, Grbesa D. Conflicting data on intervillous circulation in early pregnancy. J Perinat Med. 1997;/25:/225/36.
8. Kharfi A, Giguere Y, Sapin V, Masse J, Dastugue B, Forest JC. Trophoblastic remodeling in normal and preeclamptic pregnancies: implication of cytokines. Clin Biochem. 2003;/
36:/323/31.
9. Cartwright JE, Kenny LC, Dash PR, Crocker IP, Aplin JD, Baker PN, et al. Trophoblast invasion of spiral arteries: a novel in vitro model. Placenta. 2002;/23:/232/5.
10. Johansen M, Redman CW, Wilkins T, Sargent IL. Tropho-blast deportation in human pregnancy/its relevance for
pre-eclampsia. Placenta. 1999;/20:/531/9.
11. Craven CM, Morgan T, Ward K. Decidual spiral artery remodelling begins before cellular interaction with cytotro-phoblasts. Placenta. 1998;/19:/241/52.
12. Perrot-Applanat M, Cohehn-Solal K, Milgrom E, Finet M. Progesterone receptor expression in human saphenous veins. Circulation. 1995;/92:/2975/83.
13. Salafia CM, Pezzullo CJ, Lopez-Zeno JA, Simmens S, Vinior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol. 1995;/173:/1097/105.
14. Lichtig C, Deutch M, Barnes J. Vascular changes of endome-trium in early pregnancy. Am J Clin Pathol. 1984;/81:/702/7.
15. Taylor PV, Hancock KW. Antigenicity of trophoblast and possible antigen-marking effects during pregnancy. Immuno-logy. 1975;/28:/973/82.
16. Zhou Y, Fisher SJ, Janatpour M, Genbacev O, Dejana E, Wheelock M, et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion. J Clin Invest. 1997;/99:/2139/51.
17. Sagol S, Ozkinay E, Oztekin K, Ozdemir N. The comparison of uterine artery doppler velocimetry with the histopathology of the placental bed. Aust NZ J Obstet Gynaecol. 1999;/39:/
324/9.
18. Craven CM, Ward K. Syncytiotrophoblastic fragments in first-trimester decidual veins: evidence of placental perfusion by the maternal circulation early in pregnancy. Am J Obstet Gynecol. 1999;/181:/455/9.
19. Genest DR. Estimating the time of death in stillborn fetuses: II. Histologic evaluation of the placenta; a study of 71 stillborns. Obstet Gynecol. 1992;/80:/585/92.
