Abstract—Numerous morphopathological observations of the

placenta, membranes and umbilical cord detect the ascending

intrauterine infection and the placental vasculopathy as being

dominant in the etiopathogeny of preterm labor.

When it is possible to exclude the vasculopathy early, in the

asymptomatic phase of the intrauterine infection by means of precise

and rapid tests, such as serum C-reactive protein dosing, it results the

necessity of routinely performing the histopathologic exam of the

conception product, as an essential step of orienting the standard

complex investigation of the recurrent abortion.

The thrombophilia defects can generate either extended placental

thromboses or defects of placentation and embryonic implantation. It

is thus necessary to introduce in the standardized investigation of the

recurrent abortion the repeated screening for resistance to activated C

protein, the molecular diagnosis for Leiden mutation of coagulation

factor V, antithrombin III dosing, protein C and S concentrations,

factor XII, the fibrinogen, the plasminogen, the normality of the

fibrin plate lysis, congenital or acquired hyperhomocysteinaemia and

to demonstrate in the laboratory the antiphospholipid antibodies that

are persistent in the peripheral blood.

Keywords—abortion, thrombophilia, chorioamnionitis, C-

reactive protein, histopathology.

I. INTRODUCTION

HE abortion constitutes the most frequent complication of

a pregnancy (affecting 15% of gestations [1]), and it's

financial and emotional impact becomes considerable in the

situation of recurrent abortions (defined as the loss of at least

three consecutive pregnancies [2]) which, in 20% of cases are

appearing in the second gestational trimester [3]. Nonetheless,

in 1995, Wolf and Horger [4] focus the community’s attention

C. A. Bulucea is with the University of Medicine and Pharmacy of

Craiova, Obstetrics and Gynecology Department, Romania (e-mail:

abulucea@gmail.com).

N. E. Mastorakis is with the Military Institutions of University Education -

Hellenic Naval Academy, Greece (e-mail: mastorakis4567@gmail.com)

M. F. Paun is with the University of Medicine and Pharmacy of Craiova,

Obstetrics and Gynecology Department, Romania.

A. Patrascu is with the University of Medicine and Pharmacy of Craiova,

Obstetrics and Gynecology Department, Romania.

A. D. Neatu is with the University of Medicine and Pharmacy of Craiova,

Obstetrics and Gynecology Department, Romania (e-mail:

aneatu@gmail.com).

on the necessity of a standardized investigation of recurrent

abortion.

II. ANALYSIS AND DISCUSSION

Romero and collaborators [5, 6] and Arias and team [7]

introduced, and the studies of Rai et al [3, 8, 9, 10] and Spong

et al [11] supported, the valuable notion of histopathologic

placental screening for intrauterine ascending infectious

lesions and vascular placental lesions.

Numerous morphopathologic observations of the conception

product are systematically detecting, but in various

proportions, both in late abortion as well as in preterm labor

(that are overlapping, between weeks 20 to 28 of the gestation

[12, 13]) the placental ischemia (fig. 1) and/or the acute

amniochoriodecidual inflammation (fig. 2) as the most

frequently involved pathological processes in the multifactorial

and little understood etiology of the preterm labor [14, 15, 16,

17, 18].

Fig. 1 Old placental infarction. Large areas of accelerate aging of

chorionic villi that appear abnormally small, avascular, with intense

sclera hyalinization. (Hematoxylin-Eosin; ob.10)

Romero and collaborators [5, 6] reach the conclusion that in

preterm labor, with or without premature rupture of

membranes, the histopathologic examination of the placenta is

a valuable and non-invasive screening for the possibility of

microbial invasion of the amniotic cavity, because,

systematically, severe subclinical acute chorioamnionitis,

funiculitis and umbilical vasculitis, as well as the marginal or

Histopathologic exam of the placenta,

membranes and umbilical cord – essential step

in orienting the standard complex investigation

of recurrent abortion

Carmen A. Bulucea, Nikos E. Mastorakis, Mariana F. Paun, Anca Patrascu and Alina D. Neatu

T

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ISBN: 978-1-61804-022-0 188

mixed inflammation of the choriodecidua are tightly correlated

to the positive culture of the amniotic fluid obtained via

amniocentesis (fig. 3, fig. 4).

Fig. 2 Acute chorioamnionitis. Polyploid aspect of amniotic

membrane with rich inflammatory exudates in the chorioamniotic

axe; edema and exudates in the capsular deciduas - the severity of the

amniochoriodecidual granulocyte reaction suggests just like the acute

marginal choriodecidual inflammation the ascending intrauterine

infection (Hematoxylin-Eosin; ob.10)

Fig. 3 Umbilical vasculitis. Acute intravascular and intraparietal

inflammatory exudates, parietal edema. Umbilical vasculitis, as

funiculitis, is an indicator of maximal specificity (higher positive

predictive value)of microbial invasion of amniotic cavity

(Hematoxylin-Eosin; ob.20)

Fig. 4 Acute inflammation of the chorial board (Acute placentitis)

is the most sensitive indicator (higher negative predictive value) of

microbial invasion of amniotic cavity. Vacuolar decidual dystrophy

with the inflammatory limfoplasmocitary exudates focal suggests the

invasion of the amniotic cavity with Ureaplasma urealyticum (Van

Gieson; ob.20)

Bernal and team [15] show that prevention of preterm labor

complicated with chorioamnionitis is difficult, because

numerous medical and socio-economic predisposing factors

exceed the obstetrician’s control possibilities, suggesting, on

the other hand, that early diagnosis of chorioamnionitis in

pregnant women with preterm labor, by means of rapid and

precise tests, that should be developed (for instance, CRP [19,

20, 21, 22, 23]), followed, as early as possible, by an adequate

treatment with efficient antibiotics and strong and side effects

free anti-inflammatory could stop the preterm labor with a

considerable improvement of the perinatal mortality.

According to Burns group [24], the relation infection-

recurrent abortion is a current active research subject in order

to establish if there is a connection between the inherited

predisposition for the infection and the recurrent abortion

(including the second trimester) or if it is possible to delegate a

strong association between specific groups of vaginal bacteria

and the pregnancy prognosis [5, 7, 11].

The vaginal infections role causing recurrent preterm labor

is a new area of research [25] that seems to orientate with

predilection on the vaginal bacteriosis, defined as the

alteration of the vaginal flora, where the number of the

lactobacillus which usually predominate, is very low or they

are absent [26, 27].

Arias and co-authors [7], in accordance with Spong and

collaborators [11], are mentioning that 70% of preterm labors,

with or without premature rupture of membranes, are the result

of ascending intrauterine infection and placental vasculopathy.

As the Arias group [7], Rai and collaborators [9, 10], and

also Dizon-Townson and co-researchers [28] are suggesting

that the histopathologic examination of the placenta, which

reveals a infarction like placental vasculopathy expanded to

over 10% of the surface, with or without calcifications [29]

and/or accelerated and unequal maturation of the placental villi

next to multiple syncytial nodes, possibly the lack of

adaptation of the decidual spiral arterioles, represents a useful

screening in recurrent late abortions, preterm labor,

preeclampsia and growth delay or fetal death in the uterus.

In addition, the same three groups of researchers, in

accordance with observations of the utero and fetoplacental

arterial flux via ultrasonography [30], agree with the

possibility that the deficiency of the trophoblast to produce

adaptive modifications in the spiral arterioles is the cause of

the inadequate and unequal utero-placental blood flow that

would constitute the basis of both the accelerated maturation,

with numerous syncytial nodes and fibroses of the placental

villi and placental infarctions, of various intensities, knowing,

on the other hand, that thrombophilic defects [10] can generate

either extended placental thromboses or placentation and

embryonic implantation defects.

According to H. Marret and collaborators [31], the

thrombophilias can be acquired (primary and secondary anti

phospholipid syndromes, nephrotic syndromes), congenital

(quantitative and qualitative constitutional deficits in the

natural inhibitors of coagulation: C and S protein and

antithrombin) or mutations that pose an interest to the target

factors of these inhibitors and prevents their action: factor V

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Leiden and that of the prothrombin or G202A10 mutation. To

these one can add some of the more complex anomalies such

as hyperhomocysteinaemia.

The Quinn group [32] observes the fact that the human

infection with Ureaplasma urealyticum is capable to induce the

appearance of antiphospholipid antibodies which are

responsible for thrombotic placental lesions (by reducing the

placental syncytiotrophoblast annexin [24] fig. 5).

Fig. 5 Placental infarction. Fibrinoid necrosis near the atrophic

villi with intense sclero-hyalinization focus, marked calcification –

the last suggesting the possible aggression by antiphospholipid

antibodies type IgM (Hematoxylin-Eosin; ob.10)

The autoimmune explanation for a suggestive proportion of

recurrent abortion, not rarely complicating the second

trimester of pregnancy, is unanimously accepted today, on the

basis of the primary antiphospholipid syndrome which refers

to the association of recurrent abortions to venous thrombosis,

with the demonstration in the laboratory of the

antiphospholipid antibodies persistent in the peripheral blood

[33, 34].

The sanguine screening for antiphospholipid antibodies is

usually repeated in the first weeks of pregnancy for the fact

that some women with recurrent abortions present abnormal

results in this test only during gestation [1].

The resistance to activated C protein is the most studied

thrombophilic defect nowadays, following the primary

antiphospholipid syndrome, in the genesis of recurrent

abortion, which affects with predilection the second gestational

trimester [35].

The resistance to the anticoagulant effects of the activated C

protein is autosomal dominantly inherited and is recognized as

being the most important cause of venous thrombosis (with a

prevalence of up to 60% among people with venous

thrombosis) and familial thrombophilia [9].

In over 90% of resistance to activated C protein cases, the

cause is represented by a ''single point'' mutation (Glutamine-

Arginine) at the nucleotide in position 1691 in the coagulation

factor V gene (Leiden mutation of factor V), and the factor V

with the Leiden mutation is resistant to inactivation through

the activated C protein (which, normally, cleaves and

inactivates the factors Va and VIIIa, in the presence of the

cofactor – the S protein), which leads to the generation of

increased quantities of thrombin and implicitly to a state of

hypercoagulability [3].

Starting from the data provided by the literature of specialty,

drawing the attention both on the placental thrombotic etiology

of late abortion [15, 7, 9], as well as on the large prevalence of

the resistance to activated C protein among those affected by

venous thromboembolic disease, Rai and collaborators [10]

investigated the association of activated C protein resistance to

late abortion.

The results for this investigation of the Ray group [10] show

a prevalence of activated C protein resistance significantly

larger among women with recurrent late abortion in priors,

with respect to those with repeated abortion in the first

trimester, as well as to those from the control group. The

authors conclude that these results suggest that the resistance

to activated C protein can be an important mechanism of late

abortion, possibly connected to the intravascular

hypercoagulability which accompanies the pregnancy,

knowing that the activated C protein resistance is developed

during pregnancy as a part of the normal hemostatic

modifications of the pregnancy, which makes women with

activated C protein resistance, preceding the pregnancy,

develop an even more accentuated activated C protein

resistance once the pregnancy installs and evolves with time.

Rotmensch and collaborators [35] indicate the necessity of

introducing, in the standardized investigation of the recurrent

abortion, of the repeated screening for the activated C protein

resistance, alongside the molecular diagnosis for the Leiden

mutation of the coagulation factor V.

Fig. 6 Umbilical vein thrombosis. Endothelial lesions. Parietal

edema (Van Gieson; magnifier)

The Rai group [9, 10] completes the list of thrombophilic

defects exploration with the dosing of antithrombin III, of C

protein and of S protein (total and free) concentration, of

factor XII, of fibrinogen, plasminogen and of the normality of

the fibrin plate lysis, but also of acquired or congenital

hyperhomocysteinaemia (rapidly correctable by means of folic

acid supplements), which, although much rarer than the

antiphospholipid antibodies and resistance to activated C

protein are nowadays more and more frequently associated to

the second trimester abortion via extended placental infarction.

Dizon - Townson and the co-researchers [28] mention,

nonetheless, that 42% of the placentas with over 10% of the

surface infarcted reflect the fetus’s state of carrier of the factor

V Leiden mutation (the most frequent genetic predisposition to

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ISBN: 978-1-61804-022-0 190

thrombosis, often marked by the umbilical blood vessels

thrombosis, alongside extended placental infarction – fig. 6).

III. CONCLUSIONS

The fact that the etiopathogeny of late abortion and preterm

birth is dominated by the placental vasculopathy and by the

ascending intrauterine infection, in the conditions of the

possibility of excluding the vasculopathy as early as the

asymptomatic phase of the intrauterine infection, by means of

the serum CRP screening, focuses the attention to the necessity

of routinely applying, in case of late abortion and preterm

birth, of the histopathologic exam of the conception product,

as an essential step of orientation of the standard complex

investigation of recurrent abortion, which would allow not

only important economies of funds, time and emotions for the

maternity and the affected families, but also the application of

modern, preventive and curative therapy in the early stages of

preterm labor, when, evidently, the systematic classical

tocolysis appears superfluous.

Because of the large percentage of extended placental

thromboses which are caused by the Leiden mutation of factor

V, the most frequent genetic predisposition to venous

thromboses, it is necessary to adopt as early as possible, in the

investigation of the etiology of late spontaneous abortion, the

exploration of the activated C protein resistance, which once

detected in case of a patient with abortion, especially a

recurrent one, imposes the exploration of her relatives, thus

increasing efficiency, not only in fighting recurrent abortion by

starting the antithrombotic therapy before conception, but also

the risk of thrombosis in the general population.

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