By Pelinescu-Onciul, Dimitrie
Abstract The objective of the study was to evaluate the efficacy of progestogenic therapy for the prevention of spontaneous abortions in patients with subchorionic hemorrhage. One hundred pregnant women with bleeding and ultrasonographic evidence of subchorionic hematoma were treated with oral dydrogesterone 40 mg/day. Only cases in which the embryo was viable were included. The follow-up included ultrasonography and intravaginal examination. Of the 100 pregnancies, 93 had a favorable evolution with maintenance of pregnancy. The abortion rate was therefore 7%. This compares with an abortion rate of 18.7% obtained in a previous study in women with subchorionic hematoma treated with micronized progesterone. The abortion rate was therefore reduced by up to 37% with dydrogesterone, as most cases had large-volume hematomas at Hie first visit and thus a poor prognosis. In conclusion, the marked immunomodulatory effect of dydrogesterone in maintaining a T helper- 2 cytokine balance means that it is a good choice for preventing abortion in women suffering from subchorionic hemorrhage.
Keywords: Subchorionic hemorrhage, dydrogesterone, progesterone, abortion, pregnancy, immunomodulation
Subchorionic hematoma (subchorionic hemorrhage) is a specific pathology of early pregnancy (first trimester); it arises due to partial detachment of the chorionic plate from the underlying decidua in a genetically normal ovum, and is associated with abnormal blood accumulation at the subchorial level. It is important to stress that subchorionic hematoma accounts for around 18% of all cases of bleeding during the first trimester .
Subchorionic hematoma can be diagnosed only by ultrasonography and clinical examination, as the sonographic findings must be associated with clinical symptoms (i.e. bleeding)  (Figure 1). The ultrasonographic image is specific, showing a normal gestational sac bounded by a sonolucent gap between the chorion and the deciduas (Figure 2). This image has a characteristic appearance of a half moon or rocket and occupies part of the circumference of the gestational sac (Figure 3). In some cases, the subchorionic hematoma appears at opposite poles of the ovular yolk and is therefore called bipolar subchorionic hemorrhage (Figure 4). When the investigation is performed with a high-resolution ultrasound machine, poor signals may occur in the anechogenic gap indicating a tendency towards clotting (Figure 5).
Once the image has been detected, the health of the embryo should be assessed; for example, a heart rate less than 85 beats/min is an indicator of a poor prognosis. Other important prognostic factors include the site, size and volume of the subchorionic hemorrhage. Localization of the hematoma at the level of the implantation site represents a poor prognosis because it reduces or interrupts embryo- maternal exchange. A hematoma with a large surface area can almost totally separate the ovum from the uterine cavity, resulting in a spontaneous abortion. A better prognosis is associated with a surface less than one-quarter of the gestational sac area. One study has demonstrated that large subchorionic hematomas (defined as greater than two-thirds of the gestational sac circumference) increase the frequency of spontaneous abortion to 49% . The evolution of subchorionic hematoma can proceed in two ways; either it is gradually fully resorbed and the pregnancy develops normally, or the volume increases, gradually separating the ovum from the decidua and resulting in the death of the embryo.
Figure 1. Recent subchorionic hemorrhage.
Figure 2. Sonolucent gap between chorion and decidua.
Figure 3. Characteristic appearance of subchorionic hemorrhage occupying one-third of the circumference of the gestational sac.
Figure 4. Bipolar subchorionic hemorrhage.
Figure 5. Poor signals in the anechogenic gap indicating a tendency towards clotting.
Subchorionic hematoma is thought to result from an immunological conflict at the fetomaternal interface due to a failure of immunomodulator mechanisms mediated by progesterone. This hypothesis is supported by the fact that subchorionic hematoma is considerably more common in pregnancies resulting from medically assisted procedures, such as stimulation of ovulation or in vitro fertilization (IVF), that are frequently accompanied by varying degrees of luteal insufficiency. It is very difficult to estimate the true frequency of spontaneous abortion due to subchorionic hematoma because the diagnosis can only be made by ultrasound and, in many cases, the death of the embryo has already occurred. Some studies have demonstrated that, at the level of the decidual interface, there is a relationship between increasing coagulation in decidual vessels and rejection of normal chromosomal embryos. The mechanism implicated in subchorionic hematoma is under T helper type 1 (Th1) cytokine control . Endothelial cells activated by interleukin (IL)-1, tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (INFgamma) release prothrombinase, which converts prothrombin to activated thrombin. Activated thrombin stimulates endodielial cells to secrete IL-8, which recruits polymorphonuclear (PMN) cells. These PMN cells destroy the decidual endothelial cells activated by IL-1, TNFalpha and INFgamma, and this leads to coagulation in the decidual vessels. Under normal conditions, this coagulation is prevented by IL-4 and IL-10, which inhibit the activity of endothelial prothrombinase stimulated by cytokines .
The mechanism behind subchorionic hematoma is associated with Th1 cells, while the protective mechanism against intravascular coagulation and amputation of decidual vessels is under Th2 control. Because subchorionic hemorrhage appears to be due to immunological vasculitis in the decidual vessels, we have started to treat this condition with dydrogesterone, which is known to influence the immune decidual processes by stimulating immune processes under Th2 control. In an initial cohort of 125 pregnant women diagnosed with subchorionic hematoma, treatment with oral and vaginal micronized progesterone 400 mg/day was generally effective as shown by the loss of only 23 pregnancies (18.7%) . Encouraged by recent findings with dydrogesterone , we have now started to use it in place of micronized progesterone. The objective of the present study was to evaluate the efficacy of dydrogesterone therapy for the prevention of spontaneous abortions in patients with subchorionic hemorrhage.
In this open study, 100 pregnant women with bleeding and ultrasonographic evidence of subchorionic hematoma between 7 and 11 weeks of pregnancy were treated with oral dydrogesterone 40 mg/day until the 16th week of pregnancy. The study was conducted in women who presented at the clinic over a one-year period. Only cases in which the embryo was viable were included. The women were aged between 20 and 39 years (45% were older than 35 years), the majority (64%) were primagravida and 11% had a history of recurrent abortions. It is interesting to note that 68% of the pregnancies resulted from IVF. The study was approved by the hospital ethics committee and the women provided informed consent.
Women with significant bleeding remained in hospital for a few days. All women were advised to avoid stress and physical activity. The follow-up included ultrasonography and intravaginal examination, performed weekly in cases with favorable prognostic characteristics or whenever necessary in cases with continuous bleeding.
Plasma progesterone levels were not measured due to the high variations seen at this stage of pregnancy, even in normal pregnancies, which means they have a poor predictive value. In previous cases where plasma values of progesterone have been determined, they were in the range of 10-25 ng/ml .
Of the 100 pregnancies, 93 had a favorable evolution with maintenance of pregnancy. The abortion rate was therefore only 7%, compared with 18.7% obtained in our previous study in women with subchorionic hematoma treated with micronized progesterone  (Figure 6). Using the Pearson chi^sup 2^ test to compare these two cohorts, a p value of 0.002 was obtained. This suggests that the abortion rate was reduced by up to 37%, considering that most of the cases had large-volume hematomas at the first visit and therefore a poor prognosis. There were no significant pregnancy complications (five cases of pregnancy-induced hypertension and two of intrauterine growth restriction in the two studies). It is important to note that all of the pregnancies resulting from IVF were successful.
In the cases in which pregnancy was maintained, signs of favorable evolution were initially ultrasonographic, showing cessation of hematoma growth. These effects appeared as early as the first week of dydrogesterone treatment. The clinical symptom, bleeding, was reduced and maintained over variable periods of time. We consider that the bleeding that evacuates the hematoma could have a favorable effect as it limits the separation of the gestational sac from the decidua by the mechanical effect of blood accumulation in the hematoma.
Ultrasound examination with high-resolution machines using a 3D technique was used to follow the evolution of the condition closely, allowing a simultaneous diagnosis and real-time assessment of the well-being of the embryo. One very interesting element, observed in pregnancies with a favorable evolution, was the appearance of a color Doppler signal at the level of the hematoma, which appears to represent the resumption of decidual circulation and therefore decidual revascularization (Figure 7) . We consider that this is due to two mechanisms under progesterone control: (1) the cessation of immune processes associated with decidual vascular amputation, determined by a reduction in cytokines involved in the release of prothrombinase (IL-1, TNFalpha, INFgamma) and activation of PMN cells (IL-8), and by an increase in cytokines (IL-4, IL-10) that oppose the destruction of decidual endothelial cells by PMN cells; and (2) the angio-reconstructive action of progesterone that contributes to revascularization of affected areas. It is interesting that, during the process of decidual revascularization of the hematoma area, a number of transformations occur. After the first vascular invasion of the blood clot, a vascular network organization with the appearance of vascular lakes (Figure 8) is followed by a regular vascular network (Figure 9) and, finally, after the chorion joins the caduca, the recovery is virtually complete. Figure 6. Evolution of pregnancies treated with dydrogesterone and results from a previous study in which pregnancies were treated with micronized progesterone .
The only side-effect reported with dydrogesterone was drowsiness.
Figure 7. First vascular signals in the clot after subchorionic hemorrhage.
Figure 8. Vascular network with vascular lakes.
Recent findings demonstrating the immunomodulatory effects of dydrogesterone have led us to use it in place of micronized progesterone for the treatment of subchorionic hematoma. Although it has a lower binding affinity to progesterone receptors than natural progesterone (approximately 75% of that seen with the natural hormone), its better bioavailability and the presence of metabolites that retain the retrosteroid structure mean that the active dose of dydrogesterone is 10- to 20-fold less than that of natural progesterone . Dydrogesterone has also the advantage of oral administration, which is very convenient for the patients without diminishing the progestogenic effects.
The immunomodulatory effect of changing the Th1/Th2 balance, increasing the number of progesterone receptors on peripheral and decidual lymphocytes (CD56^sup +^) and stimulating the production of progesterone-induced blocking factor (PIBF), thereby tipping the immunological scale towards type 2 control, is in our opinion essential for the prevention and treatment of subchorionic hemorrhage . This is because the amputation of decidual vessels, which generates subchorionic hemorrhage and hematoma, is an immune mechanism dependent on Th1. An insufficiency of progesterone secretion by the corpus luteum plays a primordial role, and the mechanism that opposes intravascular coagulation of decidual vessels is of type 2. A recent study has shown that women with threatened abortion have a deficiency of progesterone, and reduced levels of PIBF, which may be corrected by treatment with dydrogesterone .
A large study is now required to investigate the immune modifications associated with subchorionic hemorrhage and the potential protective mechanisms of dydrogesterone. Such a study is particularly necessary because this condition is more common in pregnancies resulting from medically assisted procedures, and therefore accounts for a significant number of failures.
Figure 9. Regular vascular network in the late phase of revascularization.
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Filantropia University Hospital, Bucharest, Romania
(Received 17 May 2007; accepted 5 September 2007)
Correspondence: D. Pelinescu-Onciul, Clinica de Obstetrica- Ginecologie, Filantropia University Hospital, bd. Ion Mihalache no. 11, Bucharest, Romania. Tel/tax: 40 3104175. E-mail: [email protected]
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